- Email: [email protected]
Integration of hepatic drug transporters and phase II metabolizing enzymes: Mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/ejps
Review
Integration of hepatic drug transporters and phase II metabolizing enzymes: Mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites Maciej J. Zamek-Gliszczynski, Keith A. Hoffmaster, Ken-ichi Nezasa, Melanie N. Tallman, Kim L.R. Brouwer ∗ University of North Carolina at Chapel Hill, School of Pharmacy, Chapel Hill, NC 27599, USA
a r t i c l e
i n f o
a b s t r a c t
Article history:
The liver is the primary site of drug metabolism in the body. Typically, metabolic conversion
Received 4 November 2005
of a drug results in inactivation, detoxification, and enhanced likelihood for excretion in
Accepted 6 December 2005
urine or feces. Sulfation, glucuronidation, and glutathione conjugation represent the three most prevalent classes of phase II metabolism, which may occur directly on the parent compounds that contain appropriate structural motifs, or, as is usually the case, on func-
Keywords:
tional groups added or exposed by phase I oxidation. These three conjugation reactions
Phase II metabolism
increase the molecular weight and water solubility of the compound, in addition to adding
Transport
a negative charge to the molecule. As a result of these changes in the physicochemical
Sulfation
properties, phase II conjugates tend to have very poor membrane permeability, and neces-
Glucuronidation
sitate carrier-mediated transport for biliary or hepatic basolateral excretion into sinusoidal
Glutathione conjugation
blood for eventual excretion into urine. This review summarizes sulfation, glucuronida-
Multidrug resistance-associated
tion, and glutathione conjugation reactions, as well as recent progress in elucidating the
protein
hepatic transport mechanisms responsible for the excretion of these conjugates from the
Breast cancer resistance protein
liver. The discussion focuses on alterations of metabolism and transport by chemical mod-
Liver
ulators, and disease states, as well as pharmacodynamic and toxicological implications of hepatic metabolism and/or transport modulation for certain active phase II conjugates. A
Abbreviations:
brief discussion of issues that must be considered in the design and interpretation of phase
SULT, sulfotransferase; PST, phenol
II metabolite transport studies follows.
sulfotransferase; PAPS, phosphoadenosine phosphosulfate; UGT, uridine diphosphate-glucuronosyl transferase; UDP-GA, uridine diphosphate-glucuronic acid; GST, glutathione-S-transferase; Oat, organic anion transporter; Oatp, organic anion transporting polypeptide; Mrp, Abcc, multidrug
∗
Corresponding author. Tel.: +1 919 962 7030. E-mail address: [email protected] (K.L.R. Brouwer).
0928-0987/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2005.12.007
© 2006 Elsevier B.V. All rights reserved.
448
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
resistance-associated protein; Bcrp, Abcg2, breast cancer resistance protein; Mdr1, P-glycoprotein, P-gp, Abcb1, multidrug resistance protein 1; Bsep; Abcb11, bile salt export pump; Mdr2, Abcb4, MDR3 in humans, multidrug resistance protein 2; CAR, constitutive androstane receptor; CMVs, canalicular membrane vesicles
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.
Overview of phase II metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
449
2.1.
Sulfation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
449
2.2.
Glucuronidation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
450
2.3.
Glutathione conjugation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
451
Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
452
3.
4.
1.
448
3.1.
Basolateral (sinusoidal) excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
452
3.2.
Biliary excretion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
455
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
459
4.1.
Co-modulation examples. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
459
4.2.
Cholestasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
459
4.3.
Pharmacodynamic consequences. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
460
4.4.
Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
461
4.5.
Species differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
461
4.6.
Transporter multiplicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
464
4.7.
Model systems for studying hepatic excretion of sulfate, glucuronide, and glutathione conjugates . . . . . . . . . . . . . . . . . . . . . .
474
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
476
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
476
Introduction
The liver has long been recognized as the primary site of drug metabolism in the body. Drug metabolism is classified into phase I and phase II reactions. Phase I metabolism usually does not result in a large change in molecular weight or water solubility of the substrate, but is of great importance because oxidative reactions add or expose sites where phase II metabolism can subsequently occur. In contrast, phase II conjugation typically results in an appreciable increase in molecular weight and water solubility. Phase I reactions are mediated primarily by the cytochrome P450 family of microsomal enzymes, but others (e.g. flavin monooxygenases, peroxidases, amine oxidases, dehydrogenases, xanthine oxidases, etc.) also catalyze oxidation of certain functional groups (Low, 1998). Inhibition, induction, and polymorphisms of cytochrome P450 enzymes are an intense area of research, because this class of metabolic enzymes is responsible for the biotransformation of the majority of drugs, thus their modulation has important therapeutic and toxic implications (Evans and Johnson, 2001; Rendic and Di Carlo, 1997). Most compounds undergo phase I oxidation prior to phase II conjugation [e.g. phenobarbital (Crayford and Hutson, 1980)], but molecules with sites amenable to conjugation may undergo phase II reactions directly [e.g. acetaminophen (Gram and Gillette, 1971)]. Molecules that undergo direct phase II conjugation may also undergo competing (e.g. acetaminophen) or additional [e.g. troglitazone (Kawai et al., 1997)] phase I oxidation.
Unbound compounds in sinusoidal blood are taken up into hepatocytes typically by a transporter-mediated mechanism or by diffusion across the basolateral membrane, depending on molecular lipophilicity, charge, size, and three-dimensional structure. Substrates of phase II metabolism are typically lipophilic (e.g. acetaminophen, 4-methylumbelliferone, dehydroepiandrosterone) and access the intracellular space by diffusion (Iida et al., 1989; Miyauchi et al., 1988; Miyazaki et al., 1983; Reuter and Mayer, 1995). In contrast, phase II conjugates formed inside the hepatocyte are typically too hydrophilic to passively diffuse across the canalicular membrane into bile or across the hepatic basolateral membrane into sinusoidal blood, and necessitate carrier-mediated transport to cross this diffusional barrier. Distinct transport proteins are present in the apical (canalicular) and basolateral (sinusoidal) domains of the hepatocyte’s plasma membrane, where they efficiently pump substrates out of the cell. This review provides a summary of the three most relevant phase II drug conjugation reactions, sulfation, glucuronidation, and glutathione conjugation, as well as documented interactions between these metabolites and hepatic efflux transporters (both canalicular and basolateral). Discussion of key issues in the study of hepatic transport of conjugates follows, with special emphasis on examples of comodulation of phase II metabolism and transport, multiplicity of hepatic transport mechanisms, and choice of appropriate model systems for investigating the hepatic transport of conjugates.
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
2.
Overview of phase II metabolism
2.1.
Sulfation
Hepatic sulfation of xenobiotics is a common phase II metabolic mechanism for increasing molecular hydrophilicity in preparation for biliary excretion or efflux across the hepatic basolateral membrane for subsequent renal clearance. Xenobiotic detoxification may occur by direct sulfation of the parent compound [e.g. acetaminophen (Gram and Gillette, 1971)] or may follow phase I oxidation [e.g. hydroxyphenobarbital (Crayford and Hutson, 1980)]. However, hepatic xenobiotic sulfation also can lead to activation of hepatotoxins [e.g. phenacetin: covalent microsomal protein binding (Mulder et al., 1977); troglitazone: potent bile salt export pump inhibition leading to cholestasis (Funk et al., 2001)]; DNA-binding carcinogens [e.g. safrole (Boberg et al., 1983), tamoxifen (Glatt et al., 1998)], and prodrugs [e.g. minoxidil (Buhl et al., 1990)]. Sulfation is a high affinity and low capacity phase II reaction, which works in concert with glucuronidation on overlapping substrates; sulfation predominates at low substrate concentrations and glucuronidation at high substrate concentrations, when sulfation has been saturated (Pang et al., 1994). Since sulfation activity is higher in the periportal region of the liver, and glucuronidation in the perivenous region, saturation of sulfation results in a concave-up parabolic increase in glucuronidation rate, so that the combined rate of these two reactions is linear and hepatic extraction ratio constant, until glucuronidation is saturated at very high substrate concentrations (Morris et al., 1988; Pang and Terrell, 1981; Pang et al., 1981, 1983, 1994; Ratna et al., 1993). Conjugation of hydroxyl, but also amino, N-oxide, and sulfhydryl groups on xenobiotics and small endobiotics with sulfate occurs in the cytosol, while sulfation of carbohydrates attached to peptides or lipids, as well as proteins occurs in the Golgi network (Strott, 2002). Intracellular inorganic sulfate originates from hydrolysis of sulfoconjugates, oxidation of reduced organic sulfur, or uptake of sulfate from blood across the basolateral membrane (Markovich, 2001). In the cytosol, inorganic sulfate is conjugated with adenosine monophosphate by ATP sulfurylase to form adenosine 5 -phosphosulfate (APS), which is subsequently phosphorylated by APS kinase to form 3 -phosphoadenosine-5 -phosphosulfate (PAPS), the donor of sulfonate groups (SO3 − ) in all sulfate, or more correctly sulfonate, conjugation reactions (Low, 1998). Synthesis of PAPS is fast, but is limited by hepatic sulfate concentrations, which are largely dependent on equilibration with circulating inorganic sulfate (Hjelle et al., 1985; Kim et al., 1992; Mulder and Scholtens, 1978). In addition to the strong correlation between circulating inorganic sulfate and hepatic PAPS, changes in systemic sulfate concentrations result in similar changes in hepatic sulfate and PAPS levels, suggesting that uptake from blood and not hepatic biosynthesis is the major source of inorganic sulfate in the liver (Gregus et al., 1994a,b). Hepatic PAPS concentrations [∼80 (rat) and ∼23 (human) nmol/g liver, as compared with ∼400 (rat) and ∼300 (human) nmol/g liver uridine diphosphate-glucuronic acid (Cappiello et al., 1989, 1991; Hjelle et al., 1985)] are low enough to be depleted rapidly, and at substrate concentrations lower than those necessary to
449
achieve sulfotransferase maximal velocity (Hjelle et al., 1985; Kim et al., 1992). Hence, sulfation in many cases is a cofactorand not enzyme-limited reaction. However, many in vitro systems (e.g. single-pass isolated perfused liver and hepatocytes) inherently maintain a constant extrahepatic inorganic sulfate concentration, so that hepatic PAPS is not depleted and saturation of sulfation is caused by attainment of sulfotransferase maximal velocity (Pang et al., 1981; Sweeny and Reinke, 1988). The class of cytosolic sulfotransferase (SULT) enzymes is subdivided into three families: SULT1 [phenol sulfotransferase (PST) family], SULT2 [hydroxysteroid sulfotransferase (HST) family], and brain-specific SULT4 (Falany et al., 2000; Weinshilboum et al., 1997). The SULT1 family is further subdivided into four subfamilies: SULT1A (phenolic-type xenobiotics), SULT1B (dopa/tyrosine and thyroid hormones), SULT1C (hydroxyarylamines), and SULT1E (estrogens); while the SULT2 family is subdivided into two subfamilies: SULT2A (neutral steroids/bile acids) and SULT2B (sterols) (Her et al., 1998; Otterness et al., 1992; Strott, 2002; Yamazoe et al., 1994). Sulfation of xenobiotics is primarily mediated by the SULT1A subfamily, which catalyzes sulfation of hydroxyl groups and monoamine groups on phenolic-type molecules (Williams et al., 2001; Yamazoe et al., 1994); however, SULT1C also plays a role in xenobiotic sulfation by sulfating hydroxyarylamines, which can be activated into carcinogens by sulfation [e.g. Nhydroxy-2-acetylaminofluorene (Nagata et al., 1993)]. Humans express three isoforms of SULT1A: thermostable SULT1A1 and SULT1A2, which catalyze sulfation of hydroxyl groups on phenolic-type molecules (sometimes referred to as PPST1 and P-PST2), and thermolabile SULT1A3, which catalyzes sulfation of monoamine groups on aromatic molecules (MPST) (Wood et al., 1994; Zhu et al., 1993a,b, 1996). SULT2A is primarily responsible for conjugation of bile acids with sulfate (Falany et al., 1995; Radominska et al., 1990). It is important to note that while individual SULT isoenzymes have substrate preference, there is evidence of substrate overlap at the level of subfamilies and even families [e.g. SULT1A1 sulfates N-hydroxy-2-acetylaminofluorene, albeit at a lower rate than SULT1C1 (Nagata et al., 1993); the major soy isoflavone, genistein, is sulfated by SULT1A1, SULT1E, and SULT2A1, although the sulfation rate by SULT2 is three- to five-fold slower than that observed for SULT1 (Doerge et al., 2000)]. Although numerous functional studies in isolated perfused livers have proven conclusively and repeatedly that xenobiotic sulfation occurs primarily in the periportal region of the liver, Western blots from periportal and perivenous hepatocytes, as well as immunohistochemical analysis of liver sections, indicate that SULT1A is distributed fairly evenly throughout the liver (Tan and Pang, 2001; Tosh et al., 1996). These data suggest that zone-dependent xenobiotic sulfation cannot be explained by higher periportal SULT1A expression, but rather must be caused by more complex physiological phenomena. Despite SULTs being only weakly inducible, significant effort has been made in identifying the receptors and prototypical agents responsible for induction. Steroids, and especially glucocorticoids, induce SULTs in rats and humans (Duanmu et al., 2000; Liu and Klaassen, 1996; RungeMorris et al., 1996). In contrast, phenobarbital and 3-
450
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
methylcholanthrene alter mRNA levels of certain SULTs, but ultimately have no effect on SULT protein levels (Runge-Morris et al., 1998). Induction of SULT1A in rat occurs by glucocorticoid receptor activation, while SULT2A transcription appears to be controlled by both the glucocorticoid receptor and transcriptional factor(s) (Duanmu et al., 2001; Runge-Morris et al., 1999). Rat SULT1C and SULT2A function is increased by growth hormone, presumably due to upregulation of enzyme expression (Yamazoe et al., 1987; Yamazoe et al., 1989). Rat SULT2A transcription is effectively repressed by androgens through a mechanism involving the androgen receptor (Runge-Morris et al., 1999); however, effects of this repression on protein and functional activity remain to be demonstrated. Human SULT2A also is inducible by dexamethasone, but in contrast to rat, human SULT1A is unaffected by dexamethasone treatment (Duanmu et al., 2002). Activation of the pregnane X receptor is, at least in part, responsible for induction of SULT2A in rat, mouse, and human hepatocytes (Duanmu et al., 2002; Sonoda et al., 2002). The farnesoid X receptor also has been shown to control SULT2A transcription in rats (Sonoda et al., 2002), which may be of great physiological importance considering that this transcription factor is activated by bile acids (Duanmu et al., 2002), and SULT2A is responsible for bile acid sulfation (Radominska et al., 1990). However, effects of this transcription factor on protein and functional activity remain to be investigated. Lack of changes in protein levels following phenobarbital and 3-methylcholanthrene treatments suggest that constitutive androstane receptor and aryl hydrocarbon receptor are ultimately of little consequence to SULT protein levels and function (Radominska et al., 1990; Wei et al., 2000). Relative to cytochrome P450 enzymes, little is known about the transcriptional control of SULTs, especially the PSTs, which are most relevant to drug metabolism. This limited knowledge may be due to the cofactor-limited maximal velocity of sulfation and relatively moderate extent of SULT induction, usually two- to three-fold. SULTs are generally cofactor-limited in rats and humans, thus induction of SULTs is not expected to profoundly change the maximal velocity of sulfation (Galinsky and Levy, 1981; Kim et al., 1992; Slattery and Levy, 1979). However, under linear conditions, SULT induction causes increased sulfation rates in the cytosol (Liu and Klaassen, 1996; Sonoda et al., 2002), which has been demonstrated to result in significant pharmacodynamic changes in vivo (Duanmu et al., 2000). Inhibition of sulfation may be achieved by either inhibition of SULTs or depletion of PAPS. The commonly used SULT1 inhibitors, 2,6-dichloro-4-dinitrophenol and pentachlorophenol (both are mechanism-based inhibitors), do not significantly inhibit glucuronidation, glutathione conjugation, acetylation, or biliary excretion at low concentrations used for inhibition of sulfation. These inhibitors are eliminated slowly, and effectively inhibit sulfation, thus shifting the reaction from a cofactor- to an enzyme-limited process (Koster et al., 1979, 1982; Meerman et al., 1983; Seah and Wong, 1994; Singer et al., 1984). Molybdate (MoO4 2− ) competes with inorganic sulfate for transport into tissues and tubular reabsorption, as well as for ATP-sulfurylase, resulting in decreased sulfate and PAPS levels which leads to impaired sulfation (Bandurski et al., 1956; Mason and Cardin, 1977; Oguro et al., 1994; Schneider et al., 1984). It is important to note that sulfate
conjugation is reversible; sulfate conjugates may be desulfated in the liver by sulfatases, subsequently re-conjugated, deconjugated, etc., giving rise to the phenomenon of ‘futile cycling’ between the parent compound and sulfate metabolite (Pang et al., 1994).
2.2.
Glucuronidation
In many ways, glucuronidation complements sulfation, in that conjugation with glucuronic acid occurs on many of the same molecular moieties as sulfation, but is most prevalent at higher substrate concentrations, when sulfation has become saturated either due to co-substrate depletion or enzymesaturation. Like sulfate metabolites, glucuronides usually are inactivated detoxification products ready for biliary or urinary excretion, but there are a few notable exceptions. Morphine-6glucuronide is as, if not more, potent an analgesic as the parent compound (Romberg et al., 2004). Furthermore, numerous molecules with a carboxylic acid group may form an acyl glucuronide that undergoes molecular rearrangements, known as acyl migration, resulting in an isomeric sugar whose free aldehyde can react with nitrogen-containing amino acid side chains to form a Schiff base covalent adduct between protein and the glucuronide conjugate (Smith et al., 1990a). Alternatively, the acyl carbon on the glucuronide conjugate may undergo direct nucleophilic attack by an oxygen, nitrogen, or sulfur atom on an amino acid side chain making a covalent adduct between a protein and the aglycone drug (SpahnLangguth and Benet, 1992). Therefore, like sulfate conjugates, glucuronides cannot be viewed as simply pharmacologically and toxicologically inactive species. Unlike sulfation, xenobiotic glucuronidation occurs exclusively inside microsomal membranes. Uridine diphosphateglucuronosyl transferases (UGTs) are anchored via the Cterminus to the endoplasmic reticulum membrane, with the enzyme facing the inside of the lumen. Substrates for the UGTs include compounds containing nucleophilic functional groups, such as carboxyl, hydroxyl, thiol, amino, or activated carbon centers. The co-factor in glucuronidation reactions, uridine diphosphate-glucuronic acid (UDP-GA), is synthesized by a two-step reaction in the cytosol. Glucose-1-phosphate is conjugated with uridine diphosphate (UDP) by UDP-glucose pyrophosphorylase to UDP-glucose, which is subsequently oxidized to UDP-GA by UDP-glucose dehydrogenase (Clarke and Burchell, 1994; Dutton, 1980). Although the mechanism by which hydrophilic UDP-GA gains access to the endoplasmic reticulum lumen is not well understood, it has been speculated that a carrier-mediated process is involved. Highly watersoluble glucuronide conjugates are thought to leave the microsomal lumen via a carrier-mediated process, perhaps via a bi-directional mechanism shared with UDP-GA (RadominskaPandya et al., 1999). This transport process is disrupted in vitro in isolated microsomal incubations; thus, low detergent or pore-forming peptide (alamethacin) concentrations are necessary to allow UDP-GA to enter and glucuronide conjugates to exit the microsomal lumen in order to approach glucuronidation rates comparable to intact hepatocytes (Dutton, 1980; Fisher et al., 2001; Soars et al., 2003). Intracellular UDP-GA concentrations are higher than PAPS, ∼300–400 nmol/g liver, but may be depleted by high concentrations of substrates under-
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
going glucuronidation (e.g. acetaminophen) (Cappiello et al., 1991; Hjelle et al., 1985). UGT enzymes are subdivided into two families: UGT1 and UGT2. Isoenzymes in the UGT1A subfamily all contain a conserved C-terminal region that is responsible for UDPGA binding and attachment to the endoplasmic reticulum membrane, and that is encoded by the same four exons. What differentiates the various members of UGT1A subfamily is the N-terminal region, which is encoded by different exon 1 sequences and is thought to be responsible for binding of the aglycone substrate (Ritter et al., 1992). Nine functional isoforms comprise the UGT1A subfamily (Guillemette, 2003; Ritter et al., 1992; Tukey and Strassburg, 2000). UGT1A1 is of particular interest because it is responsible for glucuronidation, and thus the detoxification, of the hepatic heme breakdown product, bilirubin (Bosma et al., 1994). Deficiency of UGT1A1 causes unconjugated hyperbilirubinemia, as observed in the Gunn rat and patients with Crigler-Najar or Gilbert’s syndrome (Bosma et al., 1995). UGT1A6 traditionally has been recognized as the isoform responsible for the glucuronidation of phenols (e.g. acetaminophen), but more recent work indicates that there is considerable substrate overlap between the isoenzymes of the UGT1A subfamily (Court et al., 2001; Williams et al., 2004). In contrast, UGT2 family enzymes are all products of distinct genes (Monaghan et al., 1994). The UGT2A subfamily contains only one isoenzyme, UGT2A1, which has garnered fairly little attention in systemic drug disposition due to its primary localization in olefactory tissues (Jedlitschky et al., 1999; Tukey and Strassburg, 2001). The UGT2B subfamily is comprised of seven isoenzymes. The UGT2B family plays an important role in the glucuronidation of many endobiotics (Ethell et al., 2003). UGT2B7 is recognized for its role in glucuronidation of morphine, one of only a few pharmacologically active glucuronide conjugates (Coffman et al., 1997). UGT modulation is an area of active research. In general, the induction of UGTs results in only a two- to threefold increase in protein, which is in sharp contrast to the cytochrome P450 family. Prototypical inducers of the UGT1A subfamily include aromatic hydrocarbons, such as 3-methylcholanthrene, and the phase II specific monofunctional inducers, such as oltipraz (Prochaska and Talalay, 1988; Rushmore and Pickett, 1990). Recent data have suggested that certain UGTs also are responsive to pregnane X receptor, constitutive androstane receptor, glucocorticoid receptor, and peroxisome proliferator-activated receptor ligands (Barbier et al., 2003; Sugatani et al., 2001, 2005; Xie et al., 2003). Specific UGT probes have been employed as competitive inhibitors of particular UGT isoforms (Cummings et al., 2004). Probenecid inhibits glucuronidation both as a competitive inhibitor and an inhibitor of UDP-GA import into the endoplasmic reticulum lumen (Abernethy et al., 1985; Hauser et al., 1988; Smith et al., 1985). 7,7,7-Triphenylheptyl-UDP has been utilized as a mechanism-based UGT inhibitor (Said et al., 1992). Alternately, UDP-GA may be depleted (e.g. diethyl ether) and glucuronidation impaired due to limited availability of the cofactor (Eriksson and Strath, 1981; Gregus et al., 1983). Like sulfation, glucuronide conjugation is reversible. Some glucuronide conjugates can be deconjugated in an acidic environment, but in vivo, this is usually accomplished enzymat-
451
ically via -glucuronidases. Low -glucuronidase activity is present in the liver, and -glucuronidase has maximal activity at pH 5. Thus, hepatic futile cycling observed for many sulfate metabolites typically is not appreciable for glucuronide conjugates, but is considerable for acyl glucuronides because as esters they are cleaved by esterases in the liver (Liu and Smith, 2006; Smith et al., 1990b). However, high -glucuronidase activity in the gut microflora may result in enterohepatic recycling of parent drug after cleavage of glucuronide metabolites (Naderer et al., 2005). Many glucuronide conjugates excreted in bile into the duodenum subsequently are deconjugated to the aglycone, which may be reabsorbed resulting in enterohepatic cycling of that compound, a form of reversible metabolism (Roberts et al., 2002). Glucuronidation activity in the liver is not uniformly distributed, but rather increases from the periportal region to the perivenous region, where it is highest. Thus, hepatic glucuronidation activity is distributed in a manner opposite to sulfation (Pang and Terrell, 1981; Pang et al., 1983). From a physiological perspective, the distribution of glucuronidation activity is logical since it is a microsomal reaction that often occurs on molecular handles created by phase I oxidation, which also is localized to the lumen of the endoplasmic reticulum and is highest in perivenous hepatocytes.
2.3.
Glutathione conjugation
Glutathione conjugation is of particular importance because substrates of this reaction are often potent electrophiles. Conjugation with intracellular glutathione results in the detoxification of these species, which could otherwise covalently bind intracellular macromolecules. A broad spectrum of diverse electrophiles can undergo glutathione conjugation. Molecular moieties amenable to glutathione conjugation include electrophilic carbon atoms as well as electrophilic nitrogen, oxygen, and sulfur atoms (Parkinson, 2001). Substrates of glutathione conjugation can be parent compound electrophiles, as well as electrophilic phase I metabolites, and even certain phase II conjugates. Given the high intracellular concentrations (∼10 mM) of glutathione in the liver, glutathione conjugation may occur spontaneously, but is much more efficient when catalyzed by GSTs (Parkinson, 2001). GSTmediated metabolism predominantly occurs in the cytosol, but some GST activity also resides in the endoplasmic reticulum (Morgenstern et al., 1984). Since, hepatic concentrations of glutathione are by far the highest of the co-factors utilized in the three discussed reactions, intracellular glutathione is difficult to deplete. When intracellular glutathione is depleted, severe hepatotoxity may follow. The unique role of glutathione conjugation in detoxification is perhaps best illustrated by glutathione itself not being a high-energy unstable cofactor, like PAPS or UDP-GA, but rather a stable tripeptide that reacts with high-energy unstable substrates. For this very reason, many pharmaceutical companies have begun screening drug candidates for glutathione adducts primarily as predictors of the formation of unstable metabolites that may form toxic covalent adducts with intracellular molecules. Glutathione is synthesized by the formation of a peptide bond between glutamic acid and cysteine catalyzed by ␥-glutamylcysteine synthetase and subsequent addition of
452
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
glycine by glutathione synthetase. Although intracellular glutathione is difficult to deplete in the liver due to its very high concentrations, it can be accomplished at extremely high doses of substrate. Furthermore, glutathione levels may be decreased by administration of buthionine-S-sulfoximine, via inhibition of ␥-glutamylcysteine (Parkinson, 2001). In addition to its myriad physiological roles, glutathione represents an important co-factor for conjugation and detoxification of electrophilic xenobiotics or metabolites. The high intracellular concentration gradient of glutathione is thought to provide the driving force for non-ATP-mediated transport processes (e.g. organic anion transporting polypeptides), as well as to stimulate the function of ATP-driven transport processes (e.g. multidrug resistance-associated protein 2) (Haimeur et al., 2004). Glutathione conjugation is catalyzed by a family of detoxification enzymes known as glutathione-S-transferases (GSTs). GSTs are present in both membrane and cytosolic fractions, and are classified by their cellular localization. Cytosolic or soluble GSTs are responsible predominantly for conjugation of xenobiotics with glutathione. Approximately 20 cytosolic GSTs have been identified in vertebrates, and have been categorized into seven distinct classes: alpha, pi, mu, theta, omega, zeta, and sigma. The membrane bound isoforms include the mitochondrial and the microsomal GSTs; some membranebound GST isoforms have been implicated in the metabolism and biotransformation of drugs in mammals (Zhang et al., 2004, 2005). Cytosolic GSTs have very little structural similarity to their membrane-bound counterparts, and exist as hetero(only alpha and mu) or homo-dimers in the cytoplasm. Dimerization is necessary for GSTs to carry out their function in catalyzing glutathione conjugation as well as some reduction reactions (Parkinson, 2001). Although some GSTs have been shown to be upregulated in tumorigenesis, the specific pathways involved in maintaining basal regulation of these proteins is not understood completely. Regulation of GSTs has been hypothesized to occur through an Nrf-2 mediated pathway, impacted in part by the disposition of endogenous electrophiles (Ikeda et al., 2004). Induction of GST expression by xenobiotics commonly occurs after ingestion of many naturally derived products such as plant phenols, extracts of natural products (e.g. St. John’s Wort, Ginkgo biloba), and even common herbs, such as garlic (Ameen et al., 2003; Krajka-Kuzniak et al., 2004; Shibayama et al., 2004). Common therapeutic agents also can impact the expression of the GST enzymes. Several examples include rifampin-mediated induction of GSTP1 (as well as UGT1A), induction of GSTs by some NSAIDS, and increases in GST activity by some quinolones (Le and Franklin, 1997; Patten and DeLong, 1999; Rae et al., 2001). Furthermore, induction studies suggest that expression of some GSTs is controlled by the constitutive androstane receptor, pregnane X receptor, and arylhydrocarbon receptor (DePierre et al., 1984; Rae et al., 2001; Shibayama et al., 2004). An important feature of glutathione conjugates is that they typically are not deconjugated in the same manner as sulfate or glucuronide metabolites. However, the peptide bonds in the glutathione molecule of the metabolite may be hydrolyzed sequentially to form a cysteinylglycine metabolite, which can be hydrolyzed to a cysteine metabolite, followed by
N-acetylation to form a mercapturate metabolite (Parkinson, 2001). Other phase II reactions (e.g. amino acid conjugation, acetylation, and methylation) are less common metabolic pathways for xenobiotics. Amino acid conjugation occurs predominantly on very small molecules, which are rare in current drug development. Acetylation and methylation result in decreased water solubility. Therefore, these phase II metabolites are not discussed further in this review.
3.
Transport
Generally, sulfate, glucuronide, and glutathione metabolites are too hydrophilic to diffuse passively out of hepatocytes into either bile or sinusoidal blood following intrahepatic formation. Therefore, carrier-mediated processes are required to transport phase II conjugates across either the canalicular or basolateral membrane. Although the field of hepatic transport is a relatively new discipline, it is now widely recognized as a critical process in hepatobiliary drug disposition. While numerous transport proteins are present on the hepatic sinusoidal and canalicular membrane, thus far it appears that only apical multidrug resistance-associated protein 2 (Mrp2, Abcc2) and breast cancer resistance protein (Bcrp, Abcg2), as well as basolateral Mrp3 (Abcc3) and Mrp4 (Abcc4) play a major role in the hepatic biliary and basolateral excretion of sulfate, glucuronide, and glutathione metabolites. Therefore, this review focuses on reported interactions between these four transport proteins and phase II metabolites. Other transport proteins, which play a minor role in hepatic excretion of phase II metabolites are mentioned only briefly.
3.1.
Basolateral (sinusoidal) excretion
Excretion of drugs and/or metabolites from the hepatocyte across the basolateral membrane into sinusoidal blood theoretically may be mediated by one of the bidirectional transporters [organic anion transporting polypeptides (Oatps) or organic anion transporters (Oats)]. However, since Oatps and Oats are hypothesized to be driven by ion exchange (glutathione and ␣-ketoglutarate, respectively), they most likely function as uptake transporters under physiologicallyrelevant conditions. While members of the Oatp and Oat family can transport some phase II conjugates and exhibit bidirectional transport behavior in expression systems in vitro, their driving force strongly favors inwardly-directed transport in the liver in vivo. Given the focus of this review on hepatic excretory mechanisms, these proteins are not discussed further. Members of the ATP-driven Mrp family are primarily responsible for basolateral excretion of xenobiotics and endobiotics from hepatocytes. In the liver, Mrp3, Mrp4, Mrp5, and Mrp6 reside on the basolateral membrane and pump organic anions and bile acids from the hepatocyte into sinusoidal blood (Homolya et al., 2003). Of the hepatic basolateral efflux transporters, Mrp3 has been the most extensively studied, due to its important physiological function as the compensatory efflux mechanism when Mrp2 is absent or impaired (Konig et al., 1999). Interactions between Mrp3 and phase II conju-
453
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 1A – Summary of reported interactions between sulfate conjugates and Mrp3 X-sulfate
Experimental system
Species of Mrp3 origin
Interaction with Mrp3
Affinity
Reference
Lithocholate-S
Sf9 vesicle Sf9 vesicle
Human Human
Not determined IC50 ∼ 7.3 M
Akita et al. (2002) Zelcer et al. (2003a)
Sf9 vesicle LLC-PK1 vesicle
Rat Rat
Direct transport Etoposide-G uptake inhibition Direct transport Direct transport
Not determined Not determined
Akita et al. (2002) Hirohashi et al. (1999)
Glycolithocholate-S
Sf9 vesicle
Human
IC50 ∼ 10.6 M
Zelcer et al. (2003a)
Taurolithocholate-S
Sf9 vesicle Sf9 vesicle
Human Human
Not determined IC50 ∼ 9.1 M
Akita et al. (2002) Zelcer et al. (2003a)
Sf9 vesicle Sf9 vesicle LLC-PK1 vesicle LLC-PK1 vesicle LLC-PK1 vesicle
Human Rat Rat Rat Rat
Etoposide-G uptake inhibition Direct transport Etoposide-G uptake inhibition E2 17G uptake inhibition Direct transport Direct transport E2 17G uptake inhibition Taurocholate uptake inhibition Direct transport E2 17G uptake inhibition Taurocholate uptake inhibition Direct transport Direct transport Etoposide-G uptake modulation E2 17G uptake inhibition
Competitive KI ∼ 11 M Not determined KM 3.1 ± 0.6 M IC50 ∼ 0.81 M IC50 ∼ 1.3 M
Zelcer et al. (2003a) Akita et al. (2002) Hirohashi et al. (2000a) Hirohashi et al. (2000a) Hirohashi et al. (2000a)
Not determined IC50 ∼ 10.7 M IC50 ∼ 12.4 M
Hirohashi et al. (2000a) Hirohashi et al. (2000a) Hirohashi et al. (2000a)
KM 46.3 ± 7.3 M Not Observed Not observed (0–50 M)
Lee et al. (2004a,b) Zelcer et al. (2003b) Zelcer et al. (2003b)
IC50 ∼ 276 M
Hirohashi et al. (1999)
Not observed 2–20 M: stimulated (<4×), 100 M: inhibited (>30%) 2–100 M: stimulated (<5×), 20 M: decreased EEG KM ∼ 18× 0–100 M: stimulates (<70%) 500 M: inhibits (∼75%) Conc. dependent (∼2.5× at 166 M) Not observed
Chu et al. (2004) Chu et al. (2004)
Not observed
Zelcer et al. (2003a)
Conc. dependent (∼6× at 500 M) ∼35%
Hirohashi et al. (1999)
∼35%
Zamek-Gliszczynski et al. (2006d, in press) Manautou et al. (2005)
Taurochenodeoxycholate-S LLC-PK1 vesicle LLC-PK1 vesicle LLC-PK1 vesicle
Rat Rat Rat
Dehydroepiandrosterone-S
MDCKII vesicle Sf9 vesicle Sf9 vesicle
Human Human Human
Estrone-3-S
LLC-PK1 vesicle
Rat
Ethinylestradiol-S
Sf9 vesicle Sf9 vesicle
Human Human
Direct transport E2 17G uptake modulation
Sf9 vesicle
Human
Ethinylestradiol-G(EEG) uptake stimulation
E3040-S
LLC-PK1 vesicle
Rat
E2 17G uptake modulation
4-Methylumbelliferone-S
Sf9 vesicle
Human
Sf9 vesicle
Human
Sf9 vesicle
Human
LLC-PK1 vesicle
Rat
E2 17G uptake stimulation Etoposide-G uptake stimulation Leukotriene C4 (LTCH) uptake stimulation E2 17G uptake stimultion
Abcc3−/− mouse liver perfusion
Mouse
Impaired basolateral excretion
Abcc3−/− mouse liver perfusion Abcc3−/− mouse liver perfusion Abcc3−/− mouse
Mouse
Abcc3−/− mouse liver perfusion
Mouse
Impaired basolateral excretion Impaired basolateral excretion Lower plasma concentrations Impaired basolateral excretion
Acetaminophen-S
Harmol-S
Mouse Mouse
gates are summarized in Tables 1A–1C. Mrp3 is responsible for basolateral excretion of bile acids and other organic anions, and is especially important in the excretion of glucuronide metabolites into sinusoidal blood. While Mrp3 can efficiently transport sulfated bile acids, which are also good competitive inhibitors of this transporter, interactions of sulfated xenobi-
Not observed Slight decrease, not significant ∼30%
Chu et al. (2004)
Hirohashi et al. (1999)
Zelcer et al. (2003a) Zelcer et al. (2003a)
Zamek-Gliszczynski al. (2006d, in press)
et
Manautou et al. (2005) Zamek-Gliszczynski al. (2006d, in press)
et
otics and steroids with Mrp3 are very weak. Sulfate conjugates of xenobiotics stimulate Mrp3 function in a concentrationdependent manner at M concentrations and require nearly mM concentrations to exert notable inhibitory effects. Furthermore, in rats, basolateral clearance of glucuronide conjugates is generally in good agreement with Mrp3 expression
454
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 1B – Summary of reported interactions between glucuronide conjugates and Mrp3 X-glucuronide
Experimental system
Species of Mrp3 origin
Interaction with Mrp3
Affinity
Reference
Estradiol-17-(DG)
Sf9 vesicles Sf9 vesicles Sf9 vesicles HEK293 vesicles HEK293T vesicles
Human Human Human Human Human
Direct transport Direct transport Direct transport Direct transport Direct transport
Akita et al. (2002) Zelcer et al. (2001) Bodo et al. (2003) Zeng et al. (2000) Letourneau et al. (2005)
MDCKII vesicles Sf9 vesicles
Human Human
HEK293 Vesicles Sf9 vesicles Sf9 vesicles LLC-PK1 vesicles Sf9 vesicles
Human Rat Rat Rat Rat
LLC-PK1 vesicles
Rat
Sf9 vesicles Sf9 vesicles
Human Human
Sf9 vesicles
Human
Sf9 vesicles LLC-PK1 vesicles Sf9 vesicles
Rat Rat Rat
Sf9 vesicles
Rat
LLC-PK1 vesicles
Rat
HeLa vesicles
Rat
Sf9 vesicles
Human
Sf9 vesicles
Human
Sf9 vesicles
Rat
LLC-PK1 vesicles
Rat
Abcc3−/− mouse liver perfusion
Mouse
Direct transport Methotrexate uptake inhibition Direct transport Direct transport Direct transport Direct transport Methotrexate uptake inhibition Taurocholate uptake inhibition Direct transport Methotrexate uptake inhibition E2 17G uptake inhibition Direct transport Direct transport Methotrexate uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition Impaired basolateral excretion
KM 42.9 ± 4.3 M KM 17.7 ± 2.6 M KM ∼ 25–30 M KM 25.6 ± 5.4 M Not determined, GSH independent KM 24.2 ± 5.8 M Conc. dependent, ∼70% at 100 M Not determined KM 33.4 ± 2.2 M Not determined KM ∼ 110 M Conc. dependent, ∼90% at 100 M ∼20% at 75 M
Harmol-G
Abcc3−/− mouse liver perfusion
Mouse
Naphthol-G
LLC-PK1 vesicles
Rat
E3040-G
4-Methylumbelliferone-G
Not determined Conc. dependent, ∼70% at 50 M KI 5.6 ± 1.0 M
Lee et al. (2004b) Akita et al. (2002) Liu et al. (2003) Akita et al. (2002) Ito et al. (2001a) Hirohashi et al. (1999) Akita et al. (2002) Hirohashi et al. (2000a) Akita et al. (2002) Akita et al. (2002) Akita et al. (2002)
Not determined Not determined Conc. dependent, ∼90% at 50 M KI 2.6 ± 0.2 M
Akita et al. (2002) Hirohashi et al. (1999) Akita et al. (2002)
IC50 ∼ 2.3 M
Hirohashi et al. (1999)
IC50 ∼ 3.7 M
Hirohashi et al. (1999)
KI 105 ± 21 M
Akita et al. (2002)
∼30% at 50 M
Zelcer et al. (2003a)
KI 77 ± 11 M
Akita et al. (2002)
IC50 ∼ 39 M
Hirohashi et al. (1999)
∼85%
Zamek-Gliszczynski al. (2006d, in press)
et
Impaired basolateral excretion
∼65%
Zamek-Gliszczynski al. (2006d, in press)
et
E2 17G uptake inhibition Direct transport
IC50 ∼ 39 M
Hirohashi et al. (1999)
KM 11.4 ± 2.6 M
Zelcer et al. (2001)
KM 9.2 ± 2.3 M KI 5.0 ± 0.6 M
Chu et al. (2004) Chu et al. (2004)
No effect (0–100 M)
Chu et al. (2004)
IC50 <1 M
Cummings et al. (2004)
Not determined
Lee et al. (2004b)
Akita et al. (2002)
Etoposide-G
Sf9 vesicles
Human
Ethinylestradiol-G
Sf9 vesicles Sf9 vesicles
Human Human
Sf9 vesicles
Human
NU/ICRF505-G
Sf9 vesicles
Human
Bilirubin-mono-G
MDCKII vesicles
Human
Direct transport E2 17G uptake inhibition EthinylestradiolS(EES) uptake modulation E2 17G uptake inhibition Direct transport
Bilirubin-bis-G
MDCKII vesicles
Human
Direct transport
Not determined
Lee et al. (2004b)
Acetaminophen-G
Sf9 vesicles
Human
IC50 ∼ 2 mM
Zelcer et al. (2003c)
Sf9 vesicles
Rat
E2 17G uptake inhibition Direct transport
KM 910 ± 10 M
Xiong et al. (2002)
455
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 1B (Continued ) Experimental system
Species of Mrp3 origin
Interaction with Mrp3
Affinity
Reference
Abcc3−/− mouse liver perfusion Abcc3−/− mouse liver perfusion Abcc3−/− mouse
Mouse
∼96% ∼65%
Zamek-Gliszczynski et al. (2006d, in press) Manautou et al. (2005)
Mouse
∼90%
Manautou et al. (2005)
Hydroxyphenobarbital-G
Sf9 vesicles
Rat
IC50 , 0.46 ± 0.03 mM
Xiong et al. (2002)
Morphine-3-G
Sf9 vesicles HEK293 cells Sf9 vesicles
Human Human Human
KM ∼ 0.5–1 mM Not determined KI ∼ 290 M
Zelcer et al. (2005) Zelcer et al. (2005) Zelcer et al. (2005)
Abcc3−/− mouse
Mouse
∼98%
Zelcer et al. (2005)
Morphine-6-G
HEK293 cells Abcc3−/− Mouse
Human Mouse
Not determined ∼50%
Zelcer et al. (2005) Zelcer et al. (2005)
Nicotine-N-G
HEK293T vesicles
Human Human
HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
Not observed at 100 M Not observed at 100 M Not observed at 100 M Not observed at 100 M IC50 ∼ 100 M, GSH independent IC50 ∼ 100 M, GSH independent
Letourneau et al. (2005)
HEK293T vesicles
Impaired basolateral excretion Impaired basolateral excretion Lower plasma concentrations Acetaminophen-G uptake inhibition Direct transport Direct transport E2 17G uptake inhibition Lower plasma concentrations Direct transport Lower plasma concentrations E2 17G uptake inhibition Methotrexate uptake inhibition E2 17G uptake inhibition Methotrexate uptake inhibition Methotrexate uptake inhibition Methotrexate uptake inhibition
X-glucuronide
Cotinine-N-G
Hydroxycotinine-O-G
Mouse
levels, unlike sulfate conjugates, which do not seem to be affected by Mrp3 induction (Slitt et al., 2003; Takenaka et al., 1995a; Xiong et al., 2000). Glutathione itself does not appear to be an Mrp3 substrate, and does not stimulate Mrp3 function, but prototypical glutathione-containing endobiotics have some affinity for Mrp3 in expression systems in vitro. As is evident in Table 1C, there are conflicting reports regarding the ability of the prototypical glutathione-conjugated xenobiotic, dinitrophenyl-S-glutathione, to inhibit Mrp3 function at a moderate potency, as well as the ability of this glutathione conjugate to be transported by Mrp3 with an appreciable efficiency. Furthermore, biliary excretion of acetaminophen glutathione, as well as plasma and hepatic concentrations of this conjugate were not altered in Mrp3 gene knockout mice (Manautou et al., 2005). Ultimately, the importance of Mrp3 in the basolateral excretion of glutathione conjugates remains to be established, but current available data suggest that this is not the major hepatic basolateral efflux transport system for this class of phase II conjugates. Mrp4 and Mrp5 were identified initially as basolateral excretion mechanisms for cyclic nucleotides and nucleoside analogs (Haimeur et al., 2004; Rius et al., 2003; Sampath et al., 2002). Interactions between phase II conjugates and Mrp4 are summarized in Tables 2A and 2B. Sulfate conjugates of bile acids and steroids appear to exhibit high affinity for Mrp4. Although current data indicate that glucuronide metabolites also interact with Mrp4, they appear to have a lower affinity for this transporter than sulfate conjugates. While glu-
Letourneau et al. (2005) Letourneau et al. (2005) Letourneau et al. (2005) Letourneau et al. (2005) Letourneau et al. (2005)
tathione itself is a very low affinity Mrp4 substrate and does not appear to stimulate its activity, limited data suggest that Mrp4 can transport and be inhibited by glutathione conjugates, and thus might play some role in hepatic basolateral efflux of glutathione conjugates (Rius et al., 2003). Mrp5 is expressed at relatively low levels in healthy liver, but Mrp5 mRNA is up-regulated under cholestatic conditions, suggesting that Mrp5 protein levels may be increased as part of hepatic response to cholestatic conditions (Donner et al., 2004). Mrp5 can transport a spectrum of substrates similar to (although narrower than) Mrp4, including glutathione conjugates and cyclic nucleotides (Wijnholds et al., 2000), and could play a role in hepatic basolateral excretion of anionic conjugates. Mrp6 has been shown to localize to the basolateral/lateral surface of hepatocytes (Madon et al., 2000; Scheffer et al., 2002); Mrp6 transports glutathione conjugates and BQ123, a cyclicpentapeptide endothelin receptor antagonist (Belinsky et al., 2002; Ilias et al., 2002). Relatively little is known about the contribution of Mrp5 and Mrp6 to hepatic basolateral excretion of conjugated organic anions, and further studies are needed to evaluate their potential contribution.
3.2.
Biliary excretion
Biliary excretion of drugs and metabolites, as well as endogenous substances such as bile acids, phospholipids, and cholesterol, is a carrier-mediated, energy-dependent process. The bile salt export pump (Bsep; Abcb11) is responsible for the
456
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 1C – Summary of reported interactions between glutathione conjugates and Mrp3 X-glutathione
Experimental system
Species of Mrp3 origin
Interaction with Mrp3
Affinity
Reference
GSH
Sf9 vesicle MDCKII cells Ovarian carcinoma 2008 cells HEK293T vesicles
Human Human Human
Direct transport Direct transport Direct transport
Not observed Not observed Not observed
Zelcer et al. (2001) Kool et al. (1999) Kool et al. (1999)
Human Human Human Human Human
Not observed at 3 mM Not determined Not determined KM 5.3 ± 2.6 M KI > 10 M
Letourneau et al. (2005)
Sf9 vesicle MDCKII vesicle HEK293 vesicle Sf9 vesicle
Akita et al. (2002) Lee et al. (2004b) Zeng et al. (2000) Akita et al. (2002)
Sf9 vesicle Sf9 vesicle
Rat Rat
Not determined KI ∼ 2.5 M
Akita et al. (2002) Akita et al. (2002)
LLC-PK1 vesicle
Rat
IC50 ∼ 3.3 M
Hirohashi et al. (1999)
HeLa vesicle
Rat
IC50 >1 M
Hirohashi et al. (1999)
Deoxyprostaglandin J2 -SG
MCF7 vesicle
Human
Modulation of E217G uptake Direct transport Direct transport Direct transport E2 17G uptake inhibition Direct transport E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition Direct transport
KM ∼ 2.9 M
Paumi et al. (2003)
Dinitrophenol-SG
Sf9 vesicle
Human
Direct transport
Zelcer et al. (2001)
HEK293 vesicle MDCKII cells Sf9 vesicle Sf9 vesicle
Human Human Human Human
Zeng et al. (2000) Kool et al. (1999) Akita et al. (2002) Akita et al. (2002)
Sf9 vesicle LLC-PK1 vesicle Sf9 vesicle
Rat Rat Rat
Not determined Not determined KI 83.8 ± 2.7 M
Akita et al. (2002) Hirohashi et al. (1999) Akita et al. (2002)
LLC-PK1 vesicle
Rat
IC50 ∼ 83 M
Hirohashi et al. (1999)
HeLa vesicle
Rat
IC50 ∼ 57 M
Hirohashi et al. (1999)
HEK293 Vesicles
Human
Direct transport Direct transport Direct transport E2 17G uptake inhibition Direct transport Direct transport E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition
Very poor, uptake ∼3× background KM 5.7 ± 1.7 M Not determined Not determined KI 337 ± 41 M
Not observed 6 M
Liu et al. (2001a)
LLC-PK1 vesicle
Rat
Hirohashi et al. (1999)
Abcc3−/− mouse liver perfusion
Mouse
No effect (0–500 M) Not observed
Manautou et al. (2005)
Abcc3−/− mouse
Mouse
∼60%
Manautou et al. (2005)
Abcc3−/− mouse liver perfusion
Mouse
Not observed
Manautou et al. (2005)
Abcc3−/− mouse
Mouse
Slight decrease, not significant
Manautou et al. (2005)
Leukotriene C4
Dinitrophenolmercapturate Acetaminophen-SG
Acetaminophencysteinylglycine/cysteine
biliary excretion of unconjugated and glycine- and taurineconjugated bile acids (Kullak-Ublick et al., 2000; Meier, 1995). While Bsep is not thought to transport phase II metabolites of drugs, numerous xenobiotics, including cyclosporin A, rifampicin, troglitazone, bosentan, and glibenclamide recently have been reported to inhibit Bsep function (Byrne et al., 2002; Fattinger et al., 2001), leading to drug-induced cholestasis and hepatotoxicity (Bohan and Boyer, 2002). Multidrug resistance protein (Mdr)2 (Abcb4, MDR3 in humans) acts as a flippase for phosphatidylcholine, which is an important component
E2 17G uptake inhibition Impaired basolateral excretion Lower plasma concentrations Impaired basolateral excretion Lower plasma concentrations
of micelles that solubilize bile acids in the lumen of the bile canaliculus (Carrella and Roda, 1999; Elferink et al., 1997). The high percent homology of MDR2 with P-glycoprotein allows Mdr2 to transport some organic cations (e.g. digoxin, paclitaxel, and vinblastine), albeit at a much lower rate than P-glycoprotein (Smith et al., 2000). Other than transporting an essential constituent of bile into the canalicular lumen, Mdr2 is not thought to be responsible for direct transport of phase II conjugates. In fact biliary excretion of estradiol17-(-d-glucuronide) is enhanced ∼30% in Mdr2 knockout
457
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 2A – Summary of reported interactions between sulfate conjugates and Mrp4 X-sulfate
Experimental system
Species of Mrp4 origin
Interaction with Mrp4
Affinity
Reference
Dehydroepiandrosterone-S
Sf9 vesicles HEK-293 vesicles V79 vesicles
Human Human Human
KM 1.9 ± 0.2 M IC50 ∼ 3 M ∼65% at 5 M
Zelcer et al. (2003b) Zelcer et al. (2003b) Rius, 2003
Lithocholate-S
HEK-293 vesicles
Human
Direct transport E2 17G uptake inhibition Cholyltaurine uptake inhibition E2 17G uptake inhibition
IC50 ∼ 10 M
Zelcer et al. (2003b)
Taurolithocholate-S
HEK-293 vesicles
Human
E2 17G uptake inhibition
Zelcer et al. (2003b)
Glycolithocholate-S
HEK-293 vesicles
Human
E2 17G uptake inhibition
IC50 ∼ 10 M competitive IC50 ∼ 10 M
Estrone-3-S
HEK-293 vesicles HEK-293 vesicles
Human Human
IC50 ∼ 45 M IC50 ∼ 95 M
Zelcer et al. (2003b) Zelcer et al. (2003b)
Estradiol-3-S
HEK-293 vesicles HEK-293 vesicles
Human Human
IC50 ∼ 50 M IC50 ∼ 70 M
Zelcer et al. (2003b) Zelcer et al. (2003b)
Estradiol-3,17-diS
HEK-293 vesicles
Human
E2 17G uptake inhibition DHEAS uptake inhibition E2 17G uptake inhibition DHEAS uptake inhibition E2 17G uptake inhibition
Zelcer et al. (2003b)
HEK-293 vesicles
Human
IC50 ∼ 2 M competitive IC50 ∼ 0.2 M
Acetaminophen-S
Abcc4−/− mouse liver perfusion
Mouse
∼35%
Zamek-Gliszczynski al. (2006d, in press)
et
4-Methylumbelliferone-S
Abcc4−/− mouse liver perfusion
Mouse
Impaired basolateral excretion
∼35%
Zamek-Gliszczynski al. (2006d, in press)
et
Harmol-S
Abcc4−/− mouse liver perfusion
Mouse
Impaired basolateral excretion
∼45%
Zamek-Gliszczynski al. (2006d, in press)
et
mice (Huang and Vore, 2001). In addition, the ATP-dependent half-transporters Abcg5 and Abcg8, form a heterodimer, that functions to excrete cholesterol from hepatocytes into bile (Wittenburg and Carey, 2002). At present the ability of the Abcg5/Abcg8 heterodimer to transport anything other than cholesterol has not been reported. Xenobiotics may inhibit biliary excretion of phospholipids and cholesterol [e.g. bosentan (Fouassier et al., 2002)], but the possibility that certain phase II conjugates may inhibit these transporters remains to be investigated. The ATP-dependent multidrug resistance protein 1 (Mdr1; P-glycoprotein; P-gp; Abcb1) arguably is the most studied ATP-binding cassette transporter due to its notorious role in limiting oral bioavailability and CNS penetration of substrates: bulky, lipophilic and amphiphilic organic cations (Golden and Pollack, 2003; Wacher et al., 2001). In the liver, P-gp is localized to the canalicular membrane, where it functions as the major mechanism for translocation of organic cations from hepatocytes into bile (Kusuhara et al., 1998a; Meijer et al., 1997; Silverman and Schrenk, 1997). Under normal conditions, P-gp does not appear to be involved in the biliary excretion of phase II conjugates; the hydrophilic anionic nature of these metabolites makes them unlikely P-gp substrates. One of the few exceptions is estradiol-17-(-d-glucuronide) (E2 17G), which has affinity for recombinant P-gp. However, in P-gp knockout mice biliary excretion was not altered (Huang et al., 1998; Huang et al., 2000). Recent work by Zamek-Gliszczynski et al. (2006c) utilizing Mdr1a/Mdr1b double gene knockout mice failed to demonstrate any impairment in the biliary excretion of the sulfate and glucuronide conjugates of acetaminophen, 4-methylumbelliferone, or harmol relative to wild-type control mice.
DHEAS uptake inhibition Impaired basolateral excretion
Zelcer et al. (2003b)
Zelcer et al. (2003b)
Animals with hereditary conjugated hyperbilirubinemia (TR− and EHBR rats, Corriedale sheep) and patients with Dubin–Johnson syndrome exhibit normal bile acid output, but impaired biliary excretion of most organic anions (Keppler and Konig, 1997; Thompson and Strautnieks, 2000). The multidrug resistance-associated protein 2 (Mrp2; Abcc2) is an ATPdependent canalicular transporter responsible for the biliary excretion of many drugs (e.g., ceftriazone, ampicillin, dibromosulfophthalein), as well as their glucuronide, sulfate, and glutathione conjugates (Homolya et al., 2003; Keppler and Konig, 1997; Oude Elferink and Jansen, 1994). In addition, Mrp2 also transports sulfated and glucuronidated bile acids (Meier, 1995). Aside from in vitro characterization of recombinant Mrp2, the majority of studies examining the hepatic relevance of Mrp2 have utilized Mrp2-deficient rats. Livers of Mrp2-deficient rats exhibit negligible biliary excretion of most glucuronide and glutathione conjugates, whereas the biliary excretion of sulfate metabolites is impaired only partially. However, recent investigations indicated that rat livers contain much more Mrp2 protein than dog livers, and may therefore overestimate the importance and kinetic efficiency (i.e. the intrinsic clearance) of this transporter in biliary excretion (Ninomiya et al., 2005). Furthermore, studies with Abcc2 gene knockout mice indicated that Mrp2 plays a less important role in the biliary exceretion of phase II conjugates in mice than in rats (Zamek-Gliszczynski et al., 2005, 2006b,c). The breast cancer resistance protein (Bcrp; Abcg2) is the most recently identified hepatic canalicular drug transport protein. The importance of Bcrp in the biliary excretion of phase II conjugates is just emerging. Bcrp is an ATP-dependent half-transporter, which presumably forms a dimer or an even
458
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 2B – Summary of reported interactions between glucuronide and glutathione conjugates and Mrp4 Conjugate
Experimental system
Species of Mrp4 origin
Interaction with Mrp4
Affinity
Reference
Sf9 vesicles Sf9 vesicles Erythrocyte vesicles HEK-293 vesicles Sf9 vesicles
Human Human Human
Direct transport Direct transport cGMP uptake modulation
KM 30.3 ± 6.2 M Not determined ∼90% at 65 M
Chen et al. (2001) van Aubel et al. (2002) Klokouzas et al. (2003)
Human Human
IC50 ∼ 30 M ∼60% at 30 M
Zelcer et al. (2003b) Chen et al. (2002)
Sf9 vesicles
Human
∼25% at 100 M
van Aubel et al. (2002)
Dehydroepiandrosterone-G
HEK-293 vesicles HEK-293 vesicles
Human Human
DHEAS uptake inhibition Methotrexate uptake inhibition Methotrexate uptake inhibition E2 17G uptake inhibition DHEAS uptake inhibition
IC50 ∼ 80 M IC50 ∼ 80 M
Zelcer et al. (2003b) Zelcer et al. (2003b)
Estradiol-3-G
HEK-293 vesicles HEK-293 vesicles
Human Human
E2 17G uptake inhibition DHEAS uptake inhibition
IC50 ∼ 120 M IC50 ∼ 80 M
Zelcer et al. (2003b) Zelcer et al. (2003b)
Napththol-G
Sf9 vesicles
Human
IC50 ∼ 17 M
van Aubel et al. (2002)
Nitrophenol-G
Sf9 vesicles
Human
IC50 ∼ 341 M
van Aubel et al. (2002)
Acetaminophen-G
Abcc4−/− mouse liver perfusion
Mouse
Methotrexate uptake inhibition Methotrexate uptake inhibition Impaired basolateral excretion
Not observed
Zamek-Gliszczynski al. (2006d, in press)
et
4-Methylumbelliferone-G
Abcc4−/− mouse liver perfusion
Mouse
Impaired basolateral excretion
Not observed
Zamek-Gliszczynski al. (2006d, in press)
et
Harmol-G
Abcc4−/− mouse liver perfusion
Mouse
Impaired basolateral excretion
∼20%
Zamek-Gliszczynski al. (2006d, in press)
et
V79 vesicles Erythrocyte vesicles V79 vesicles
Human Human
Direct transport cGMP uptake modulation
Rius et al. (2003) Klokouzas et al. (2003)
Human
HEK293 cells HEK293 cells
Human Human
Cholyltaurine uptake stimulation cAMP efflux modulation cGMP efflux modulation
KM 2.7 ± 0.2 mM Not observed (0.5–4 mM) ∼60× at 5 mM Not observed Not observed
Wielinga et al. (2003) Wielinga et al. (2003)
GSSG
V79 vesicles
Human
∼50% at 5 mM
Rius et al. (2003)
Methyl-SG
V79 vesicles V79 vesicles
Human Human
KM 1.2 ± 0.2 mM ∼22× at 5 mM
Rius et al. (2003) Rius et al. (2003)
Decyl-SG
V79 vesicles
Human
∼50% at 5 mM
Rius et al. (2003)
Leukotriene C4
Sf9 vesicles
Human
van Aubel et al. (2002)
Bimane-SG
HepG2 cells
Human
Not observed (1 M) Not determined
Dinitrophenol-SG
HepG2 cells
Human
Conc. dependent
Bai et al. (2004)
Sf9 vesicles
Human
IC50 ∼ 13 M
van Aubel et al. (2002)
Sf9 vesicles
Human
IC50 ∼ 5 M
van Aubel et al. (2002)
X-glucuronide Estradiol-17-(DG)
X-Glutathione GSH
Dinitrophenol-mercapturate
larger homo-complex to become functional. BCRP excrete an anthracyclines, the active metabolite of CPT-11 (SN-38), as well as many sulfate and glucuronide conjugates into bile (Bates et al., 2001; Ejendal and Hrycyna, 2002; Suzuki et al., 2003). Reported interactions between phase II conjugates and Bcrp are summarized in Tables 4A and 4B. Bcrp appears to be responsible for the non-Mrp2-mediated component of biliary excretion of sulfate metabolites. The role of Bcrp in the biliary excretion of sulfate conjugates has been demonstrated
Cholyltaurine uptake inhibition Direct transport Cholyltaurine uptake modulation Cholyltaurine uptake inhibition Methotrexate uptake modulation Direct transport Bimane-SG efflux inhibition Methotrexate uptake inhibition Methotrexate uptake inhibition
Rius et al. (2003)
Bai et al. (2004)
in vitro, as well as in the whole organ by using GF120918 (an inhibitor of both P-gp and Bcrp); GF120918 partially impairs the biliary excretion of sulfate conjugates in the wild-type rat liver, and nearly completely abolishes sulfate metabolite excretion in the bile of livers from Mrp2-deficient rats (Suzuki et al., 2003; Zamek-Gliszczynski et al., 2005, 2006b). Subsequent liver perfusion studies with Abcg2 gene knockout mice provided the definitive proof for the involvement of Bcrp in the biliary excretion of sulfate metabolites (Zamek-Gliszczynski et
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
al., 2006c). Although Suzuki et al. (2003) reported that recombinant human BCRP interacted with glucuronide conjugates, data generated in Mrp2-deficient rats indicated that the biliary excretion of some glucuronide conjugates was negligible in the absence of Mrp2 (Patel et al., 2003; Takenaka et al., 1995b; Xiong et al., 2000). Subsequent work utilizing Abcg2 gene knockout mice demonstrated clearly that Bcrp mediated the biliary excretion of several model glucuronide conjugates (ZamekGliszczynski et al., 2006c). As previously mentioned, rat livers contain high levels of Mrp2 protein and may exaggerate the importance of Mrp2 in biliary excretion (Ninomiya et al., 2005). The role of Bcrp in biliary excretion of glutathione conjugates remains to be elucidated. In vitro recombinant Bcrp appears to have some transport activity for dinitrophenyl-S-glutathione. However, Bcrp function is not impaired by leukotriene C4 and is very poorly impaired by dinitrophenyl-S-glutathione, suggesting that the affinity of glutathione conjugates for Bcrp is weak (Suzuki et al., 2003). Furthermore, in Mrp2-deficient rat livers, biliary excretion of glutathione conjugates is negligible, despite the presence of functional Bcrp (Chen et al., 2003a; Zamek-Gliszczynski et al., 2005). Therefore, it is unlikely that Bcrp plays a major role in the biliary excretion of glutathione conjugates.
4.
Discussion
4.1.
Co-modulation examples
Modulators of transport and/or metabolism may alter both processes. This statement is especially true for inducers, which typically exert their action by binding to receptors controlling gene transcription. Thus, activation of a nuclear receptor, such as the pregnane X receptor, results in activation of numerous genes, some of which encode phase II metabolic enzymes and drug transporters. Unlike inducers, prototypical “selective” inhibitors usually have adequate separation in potencies to avoid non-specific interactions with other processes. However, as “selective” inhibitors become better characterized, it often becomes apparent that they inhibit more than one process, sometimes interacting with both metabolism and transport. Two examples of metabolic and transport co-modulators are discussed below. Phenobarbital is a prototypical activator of the constitutive androstane receptor (CAR), and the effects of phenobarbital on both metabolism and transport have been recognized (Xu et al., 2005). In addition to inducing certain phase I oxidative enzymes, phenobarbital is an inducer of Mrp3 and UGTs (Sugatani et al., 2001; Xiong et al., 2002a). Immediately following chronic exposure to phenobarbital, Mrp2 expression may be induced (less than two-fold), but Mrp2 protein levels decrease below baseline levels 48 h after cessation of phenobarbital exposure (Patel et al., 2003; Slitt et al., 2003). Phenobarbital glucuronide is excreted into bile by Mrp2 and has been shown in vitro to inhibit Mrp2 function, so phenobarbital glucuronide may act as a competitive Mrp2 inhibitor (Patel et al., 2003; Xiong et al., 2002b). Thus, phenobarbital exposure enhances the clearance by glucuronidation and redirects the route of excretion of the glucuronide conjugates by enhancing Mrp3-mediated basolateral excretion and impair-
459
ing biliary excretion via Mrp2. Following phenobarbital exposure, glucuronidated substrates are eliminated more rapidly, and recovery of glucuronide conjugates in urine is enhanced, whereas biliary excretion of glucuronide conjugates may be diminished, resulting in an enhanced urine/bile glucuronide recovery (Brouwer and Jones, 1990; Gregus et al., 1990; Loeser and Siegers, 1985; Watkins and Klaassen, 1982; Xiong et al., 2002b). Probenecid is a prototypical non-specific competitive inhibitor of organic anion transport, which may impair the transport of substrates for organic anion transporters (Oats), organic anion transporting polypeptides (Oatps), and multidrug resistance-associated proteins (Mrps) (Beyer et al., 1951; Sugiyama et al., 2001; Zamek-Gliszczynski et al., 2003). Due to its low affinity as a competitive inhibitor, probenecid is administered at high concentrations to impair organic anion transport; because probenecid is glucuronidated, it also behaves as a competitive inhibitor of glucuronidation (Abernethy et al., 1985; Guarino et al., 1969; Kamali, 1993; Smith et al., 1985). In addition to competitively inhibiting glucuronidation, probenecid also impairs the transport of UDP-GA into the lumen of the endoplasmic reticulum, inhibiting glucuronide conjugation directly and by limiting the co-factor available to the enzyme (Hauser et al., 1988). As exemplified by acetaminophen glucuronide, probenecid co-administration impairs glucuronidation, and also retards subsequent hepatic excretion (Savina and Brouwer, 1992; Turner and Brouwer, 1997).
4.2.
Cholestasis
The interplay between phase II metabolism and transport is perhaps most evident under cholestatic conditions. When hepatocytes are exposed to potentially toxic levels of bile salts that are forced to adapt their metabolism and transport to deal with the impaired biliary excretion of unconjugated and/or conjugated bile acids. Cholestasis can be induced by certain xenobiotics, disease states, as well as physical ligation of the bile duct, representing obstructive cholestasis, or can result from a variety of gene deficiencies. Mrp2 deficiency, which results in conjugated hyperbilirubinemia, is perhaps the most relevant to the focus of this review due to the major role that this transporter plays in the biliary excretion of phase II metabolites. Changes in hepatic transport that occur during cholestasis have been studied extensively in bile-duct-ligated rodents. In models of obstructive jaundice, hepatic Mrp2 expression is decreased ∼3–14-fold and ∼5-fold at the protein and mRNA levels, respectively, depending on the time elapsed since ligation. More pronounced downregulation occurs at later times since organic anions excreted into the bile canaliculi cannot proceed to the duodenum and remain trapped in the bile ducts (Donner and Keppler, 2001; Tanaka et al., 2002). To compensate for the inability to excrete bile acids and other organic anions into bile, basolateral Mrp3 is markedly induced, ∼6–50-fold and ∼6–30-fold at the protein and mRNA levels, respectively, depending on the time elapsed since ligation. Upregulation of Mrp3 increases with time, presumably to enhance excretion of potentially toxic anions into sinusoidal blood for clearance by the kidneys thus avoiding hepatic accumulation (Ogawa et
460
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
al., 2000; Soroka et al., 2001; Tanaka et al., 2002). To accommodate the increased hepatic basolateral excretion of organic anions into blood, Mrp2 expression is upregulated in kidneys resulting in increased renal clearance of organic anions following bile duct ligation (Tanaka et al., 2002). In addition to alterations in transport, glucuronidation of phenolic-type molecules appears to be modestly decreased, presumably to accommodate the liver’s inability to secrete metabolites into bile (Desmond et al., 1994). Mrp2-deficient rats (GY/TR− and EHBR) are the most extensively studied animal model of hereditary conjugated hyperbilirubinemia. Livers from these mutant rats exhibit altered phase II metabolism and hepatic transport; these changes protect the liver from toxic injury that might otherwise be caused by the absence of functional Mrp2. Hepatic glucuronidation and sulfation appear to be functionally upregulated in Mrp2deficient rats, which can result in more efficient clearance of compounds that undergo direct phase II conjugation, such as acetaminophen (Nishino et al., 2000; Seitz et al., 1998; Xiong et al., 2000; Zamek-Gliszczynski et al., 2005). Since glutathione biliary excretion is mediated primarily by Mrp2, Mrp2-deficient rats have negligible biliary glutathione output, resulting in increased hepatic glutathione concentrations (∼50–150% in reduced glutathione and ∼3-fold in oxidized glutathione) which protects hepatocytes from toxicity of potent electrophiles, such as the oxidative metabolite of acetaminophen, N-acetyl-p-quinoneimine (Elferink et al., 1989; Ji et al., 2004; Johnson et al., 2002). Interestingly, Abcc2 gene knockout mice are protected from acetaminopheninduced hepatotoxicity at doses that are toxic in wild-type mice (Raub et al., 2005), presumably due to elevated hepatic glutathione concentrations resulting from impaired biliary excretion of glutathione. Glutathione synthetase activity is not increased in the livers of Mrp2-deficient rats and ␥glutamylcysteine synthetase activity has been reported to be unchanged or slightly increased (Lu et al., 1996; Sugawara et al., 1996). Basolateral Mrp3 expression in livers of Mrp2deficient rats is an order of magnitude greater than in wildtype rats, allowing for efficient basolateral excretion of phase II conjugates and other organic anions whose biliary excretion is fully or partially impaired. Taken together, upregulated phase II metabolism and basolateral Mrp3 allow Mrp2-deficient livers to quickly inactivate and detoxify certain xenobiotics, and subsequently efficiently excrete their metabolites into sinusoidal blood for clearance by the kidneys. As in obstructive jaundice, upregulation of hepatic Mrp3 is complemented by upregulation of Mrp3 and to a lesser extent Mrp4 in the kidneys of Mrp2-deficient rats (Chen et al., 2005; Kuroda et al., 2004). Alterations in compensatory basolateral efflux mechanisms have focused traditionally on Mrp3 due to the highly inducible nature of this protein under cholestatic conditions. However, recently Mrp4 also has been implicated in the hepatic basolateral excretion of sulfated bile acids and also in hepatic response to cholestasis (Assem et al., 2004; Schuetz et al., 2001; Zelcer et al., 2003b). In bile duct ligated rats, Mrp4 protein is progressively upregulated after surgery to a maximum of ∼7-fold (Denk et al., 2004). In addition, expression of the bile salt export pump is downregulated in farnesoid X receptor gene knockout mice, resulting in elevated hepatic bile acid
concentrations and upregulation of Mrp4 (Schuetz et al., 2001). Furthermore, Mrp4 and Sult2a1, the bile acid sulfotransferase, are coordinately regulated by the constitutive androstrane receptor; thus, prototypical activators of this nuclear receptor induce both the enzyme and transporter (Assem et al., 2004). In Abcc4 gene knockout mice, Sult2a1 constitutive expression is downregulated, demonstrating the sulfotransferase-efflux transporter interplay (Assem et al., 2004). Mrp4 is upregulated and bile acid sulfation is increased secondary to Bsep downregulation, suggesting that sulfation and subsequent basolateral excretion act as an overflow detoxification pathway when biliary excretion of bile acids is impaired (Schuetz et al., 2001; Zelcer et al., 2003b).
4.3.
Pharmacodynamic consequences
Not all phase II conjugates lack pharmacological activity, and for those metabolites, alterations in hepatic metabolism and/or transport can have profound pharmacodynamic implications. A discussion of two examples of pharmacological consequences of modulation of hepatic metabolism and transport follows. The opioid analgesic, morphine, forms two glucuronide conjugates in humans: morphine-3- and morphine-6-glucuronide. Whereas morphine-3-glucuronide lacks pharmacological activity, morphine-6-glucuronide is equally or more potent than the parent compound (Moran and Smith, 2002; Romberg et al., 2004). Both glucuronide conjugates of morphine are formed primarily in the liver, and subsequently are excreted predominantly across the basolateral membrane into sinusoidal blood (Yeh, 1975). Following excretion into sinusoidal blood, morphine glucuronides may gain access to the CNS. Recombinant Mrp3 transports morphine glucuronides in vitro (Zelcer et al., 2005). In Abcc3 gene knockout mice, appearance of intrahepatically-formed morphine3-glucuronide in blood was decreased markedly (∼50-fold), with a resulting shift in elimination of this metabolite from urine to feces (Zelcer et al., 2005). Unlike humans, mice do not form the active morphine-6-glucuronide metabolite, so the pharmacokinetic/dynamic consequences of the absence of Mrp3 were evaluated after direct i.p. injection of this metabolite in mice. Plasma concentrations of morphine-6glucuronide were ∼50% lower at 60 min and the antinociceptive effect also was decreased in the absence of Mrp3. Zelcer et al. (2005) proposed that morphine-6-glucuronide undergoes carrier-mediated uptake by the liver, and that in the absence of Mrp3, hepatic basolateral excretion of this active metabolite is diminished, resulting in decreased systemic exposure and effect. Modulation of hepatic excretion of active phase II conjugates may have noticeable pharmacodynamic consequences, but meaningful changes also can be observed with direct modulation of phase II metabolism that results in a pharmacologically active metabolite. Minoxidil requires activation through sulfation to become active topically as a hair growth stimulant and systemically as a peripheral vasodilator (Buhl et al., 1990; Meisheri et al., 1993). Duanmu et al. (2000) demonstrated that both inhibition and induction of SULT1A1 resulted in meaningful changes in the effect of minoxidil as a peripheral vasodilator. Co-admininstration of the SULT1A1 inhibitor,
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
pentachlorophenol, obliterated minoxidil-induced decreases in mean arterial pressure. In contrast, ∼2.5-fold induction of SULT1A1 with the glucocorticoid, triamcinolone acetonide, enhanced minoxidil’s blood pressure lowering effect ∼2-fold. Although the pharmacodynamic consequences of hepatic efflux modulation of minoxidil sulfate have not been examined to date, it is likely that the hypotensive effect could be attenuated if hepatic efflux was impaired and the metabolite was trapped inside the liver.
4.4.
Toxicity
Although phase II conjugates are typically water-soluble detoxification and/or inactivation products ready for basolateral or canalicular excretion, some metabolites are toxic, and modulation of their hepatic formation and/or excretion may have important implications with respect to adverse effects. Two specific examples demonstrating the cumulative contributions of hepatic metabolism and transport to toxicity are troglitazone and SN-38-glucuronide. Troglitazone was a blockbuster thiazolidinedione for the treatment of diabetes until it was withdrawn from the market due to drug-induced liver injury. Several hypotheses explaining the idiosyncratic hepatotoxicity observed during troglitazone treatment have been suggested (Smith, 2003). Troglitazone and/or its metabolite(s) inhibit Bsep causing impaired biliary secretion of unconjugated bile acids, which subsequently accumulate inside the hepatocyte. Bile acids have detergent-like properties and can cause toxicity at higher concentrations. Unconjugated bile acids are usually more toxic than conjugated bile acids, as is demonstrated by progressive intrahepatic familial cholestasis (absence of functional Bsep), which is much more serious and lethal at an earlier age than Dubin–Johnson syndrome (Strautnieks et al., 1998). The sulfate conjugate of troglitazone is a much more potent Bsep inhibitor than the parent drug (Funk et al., 2001). Therefore, sulfation of troglitazone may represent a toxification mechanism for this xenobiotic; if hepatic export is impaired, troglitazone sulfate may accumulate in hepatocytes with increased toxicity to the liver. In fact, Kostrubsky et al. (2001) demonstrated that in the Mrp2-deficient TR− rat, biliary excretion of troglitazone sulfate exhibited an ∼2-h delay; blood concentrations and urinary excretion were markedly increased, with an ∼2-fold increase in serum bilirubin over baseline 2 and 36 h following troglitazone administration. In contrast, serum bilirubin was not altered in wild-type rats. Troglitazone exemplifies how a phase II metabolite can exert its toxic effect at the transport level, and how impaired hepatic excretion of the toxic metabolite can exacerbate the toxicity. Another example of a phase II conjugate whose hepatic metabolism and subsequent carrier-mediated export has generated considerable interest is SN-38-glucuronide, the conjugate of the active metabolite of irinotecan. Many cancer patients receiving irinotecan chemotherapy experience severe diarrhea. Several hypotheses have been proposed for the exact mechanism(s) of irinotecan GI toxicity. One explanation is that SN-38 and its glucuronide conjugate are excreted in bile primarily by Mrp2; in the intestine, SN-38 glucuronide is deconjugated to SN-38, which causes the GI toxicity (Chu et al., 1997a,b; Kato et al., 2002). Horikawa et al. (2002a) demon-
461
strated that by co-administering probenecid, an inhibitor of glucuronidation and organic anion transport, the normal irinotecan dose for rats could be decreased by 50%, diarrhea was ameliorated, and plasma concentrations of SN-38 were maintained at efficacious levels.
4.5.
Species differences
While much effort has been devoted to the study of species differences in drug metabolism and drug–drug interactions at the metabolic level in order to more accurately predict human metabolism from pre-clinical data, differences in hepatic transport are just beginning to be recognized as an important contributor to inter-species variability in drug disposition. Species differences in drug/metabolite transport may be an important point to consider in the design and interpretation of drug disposition studies. Rats traditionally have been the species of choice for hepatobiliary drug disposition studies due to their convenient size, ease with which the common bile duct can be cannulated, and the absence of a gallbladder, which may complicate the experimental design and/or confound data interpretation. Mice are a common pre-clinical species for drug disposition studies, and the increasing availability of transport protein, metabolic enzyme, nuclear receptor, or pharmacological target gene knockout mouse models makes this species particularly amenable to investigations of hepatic disposition. However, recent data suggest that species differences in key hepatic efflux transporters are sufficiently profound to warrant careful re-examination of conclusions based on existing data, and to design future studies with caution. Rats have long been recognized as unusually efficient in the biliary excretion of organic anions, but the molecular mechanism(s) underlying these observations are only now being elucidated. Generally, it was assumed that rat Mrp2 exhibited a higher affinity for substrates than Mrp2 of other species. However, recent data have revealed that rat livers contain much more (∼10-fold) Mrp2 protein resulting in a much higher capacity for the biliary excretion of organic anions in rats than humans or other pre-clinical species (Ishizuka et al., 1999; Ninomiya et al., 2005). Species differences in drug transport can have profound implications on both the kinetic and mechanistic interpretation of data obtained from rats, and especially on the contribution of Mrp2 to the biliary excretion of an organic anion. Ishizuka et al. (1999) demonstrated that uptake of the Mrp2 substrate, dinitrophenyl-Sglutathione, in rat liver canalicular plasma membrane vesicles yielded a maximal velocity approximately an order of magnitude greater than in other species, while affinities of this substrate for various Mrp2s were fairly comparable. Furthermore, the unbound biliary in vivo excretion clearance (calculated relative to hepatic unbound drug concentrations) of the Mrp2 substrate, temocaprilat, were ∼4–50-fold greater in rats than in other pre-clinical species (Ishizuka et al., 1997; Ishizuka et al., 1999). Liver perfusion studies by Zamek-Gliszczynski et al., 2005, 2006b,c, see Tables 3A–3C, 4A and 4B) indicated that the role of Mrp2 in the biliary excretion of sulfate and glucuronide metabolites may be overemphasized based on comparisons between Mrp2-deficient and wild-type rats. In subsequent mouse liver perfusion studies, Zamek-Gliszczynski
462
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3A – Summary of reported interactions between sulfate conjugates and Mrp2 X-sulfate
Experimental system
Acetaminophen-S
TR− rat
Rat
TR− rat liver perfusion TR− rat liver perfusion TR− rat liver perfusion Abcc2−/− mouse liver perfusion
Rat
S.D. Rat CMVs
Rat
EHBR rat perfused intestine TR− rat liver perfusion Abcc2−/− mouse liver perfusion
Rat
4-Methylumbelliferone-S
Species of Mrp2 origin
Rat Rat Mouse
Rat Mouse
TR− rat liver perfusion Abcc2−/− mouse liver perfusion
Rat
EHBR rat
Rat
EHBR liver perfusion EHBR liver perfusion EHBR CMVs EHBR rat perfused intestine S.D. rat CMVs
Rat
Phenolphthalein-diS
EHBR rat
Rat
Indocyanine green
EHBR rat
Rat
EHBR rat
Rat
EHBR rat
Rat
Benzo[a]pyrene-1-S
MDCKII cells
Human
Benzo[a]pyrene-3-S
MDCKII cells
Human
PhIP-S
TR− rat
Rat
Ethinylestradiol-S
Sf9 Vesicles Sf9 Vesicles
Human Human
Sf9 Vesicles
Human
Sf9 Vesicles
Human
TR− rat
Rat
Harmol-S
E3040-S
Troglitazone-S
Mouse
Rat Rat Rat
Rat
Interaction with Mrp2
Affinity
Reference
Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion
>30%
Chen et al. (2003b)
∼81%
Xiong et al. (2000)
∼70%
Xiong et al. (2000)
∼80%
Zamek-Gliszczynski (2005) Zamek-Gliszczynski et al. (2006a,b,c,d, in press)
Stimulated DNP-SG uptake Impaired luminal secretion
Conc. dependent ∼3× at 500 M Not observed
Niinuma et al. (1997)
Impaired biliary excretion Impaired biliary excretion
∼60%
Zamek-Gliszczynski et al. (2006c, in press) Zamek-Gliszczynski et al. (2006c, in press)
Impaired biliary excretion Impaired biliary excretion
∼65%
Impaired biliary excretion Enhanced biliary excretion Impaired biliary excretion Impaired uptake Impaired luminal secretion
∼30%
Takenaka et al. (1995)
∼1.5×
Takenaka et al. (1995)
Not observed
Takenaka et al. (1995)
∼25% Not observed
Takenaka et al. (1995) Adachi et al. (2005)
Stimulation of DNP-SG uptake Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Enhanced apical excretion Enhanced apical excretion Impaired biliary excretion Direct transport Modulation of ethacrynic acid-SG uptake Stimulation of E217BG uptake Stimulation of EEG uptake
100 M: ∼2× decreases DNP-SG KM ∼ 3× ∼85%
Niinuma et al. (1997) Tanaka et al. (2003)
∼95%
Yamaguchi et al. (1997)
∼95%
Hamaguchi et al. (1994)
∼70%
Takikawa et al. (1995)
Not observed
Buesen et al. (2002)
Not observed
Buesen et al. (2002)
Not observed
Dietrich et al. (2001b)
Not observed 1–20 M: >50% Stimulation; 20–100 M: >50% inhibition Conc. dependent ∼16× at 50–100 M Conc. dependent ∼25× at 100 M 20 M: decreased EEG KM ∼ 5× 0–2 h∼90% decreased; 2–36 h normal
Chu et al. (2004) Chu et al. (2004)
Delayed biliary excretion
Not observed
Not observed
Not observed
Adachi et al. (2005)
Zamek-Gliszczynski et al. (2006c, in press) Zamek-Gliszczynski et al. (2006c, in press)
Chu et al. (2004) Chu et al. (2004)
Kostrubsky et al. (2001)
463
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3A (Continued) X-sulfate
Experimental system
Hydroxyphenobarbital-S
TR− rat liver perfusion EHBR rat
Rat
MDCKII cells HEK293 vesicles Wistar rat CMVs
Human Human Rat
Wistar rat CMV TR− rat CMV S.D. rat CMVs
Rat Rat Rat
EHBR rat
Rat
EHBR rat
Rat
EHBR rat
Rat
EHBR rat
Rat
S.D. rat
Rat
S.D. rat
Rat
Dibromosulfophthalein
EHBR rat
Rat
Taurochenodeoxycholate-S
S.D. CMVs EHBR CMVs
Rat Rat
Tauroursodeoxycholate-S
Wistar rat erythrocyte vesicles MDCKII cells
Rat
Grepafloxacin-S Sulfobromophthalein
Estrone-S
Taurocholate-S
Dehydroepiandrosterone-S
Ursodeoxycholate-diS
Lithocholate-S
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Impaired biliary excretion Impaired biliary excretion Direct transport Direct transport Impaired bilirubin-diG uptake Uptake Impaired uptake Inhibition of DNP-SG uptake Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Inhibition of SN-38-G biliary excretion Inhibition of E217G biliary excretion Impaired biliary excretion Direct transport Direct transport
∼70%
Patel et al. (2003)
Not observed
Sasabe et al. (1998)
Not determined KM ∼ 12 M ∼35% at 50 M
Cui et al. (2001) Cui et al. (2001) Nishida et al. (1992b)
KM 31 ± 4 M Complete obliteration KI ∼ 2.18 M
Nishida et al. (1992a) Nishida et al. (1992a) Horikawa et al. (2002b)
∼95%
Yamaguchi et al. (1997)
∼85%
Takikawa et al. (1991)
∼95%
Hamaguchi et al. (1994)
>95%
Yamashita et al. (1993)
∼65%
Horikawa et al. (2002a)
∼75%
Takikawa et al. (1996)
∼80%
Takikawa et al. (1995)
KM 8.8 ± 1.3 M Not observed
Akita et al. (2001) Akita et al. (2001)
Impaired GSSG uptake
∼40% at 10 M
Heijn et al. (1992)
Human
Direct transport
Matsushima et al. (2005)
LLC-PK1 cells
Human
MDCKII cells
Human
Not observed
Sasaki et al. (2002)
Wistar rat erythrocyte vesicles MDCKII cells LLC-PK1 Cells
Rat
Enhanced apical efflux Enhanced apical efflux Impaired GSSG uptake
Cl = 0.268 ± 0.013 L/ min/mg protein ∼5×
Not observed 10 M
Heijn et al. (1992)
Human Human
Not determined ∼2×
Cui et al. (2001) Spears et al. (2005)
Sf9 vesicles
Human
Zelcer et al. (2003b)
MDCKII cells
Human
Not observed (ATP or GSH) Not observed
EHBR rat
Rat
∼70%
Takikawa et al. (1998)
Wistar rat
Rat
Not observed
Kitaura et al. (1997)
EHBR rat
Rat
∼35%
Takikawa et al. (1991)
EHBR rat
Rat
∼70%
Takikawa et al. (1995)
Wistar Rat Erythrocyte Vesicles
Rat
∼50% at 10 M
Heijn et al. (1992)
Rat
Direct transport Enhanced apical efflux Direct transport Enhanced apical efflux Impaired biliary excretion Impaired LTC4 biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired GSSG uptake
Spears et al. (2005)
Sasaki et al. (2002)
464
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3A (Continued) X-sulfate
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Glycolithocholate-S
Nordeoxycholate-3-S
Wistar Rat Erythrocyte Vesicles TR− rat
Rat
Impaired GSSG uptake
Competitive KI 2.9 ± 2.1 M
Heijn et al. (1992)
Rat
Impaired biliary excretion Impaired biliary excretion
∼85%
Oude Elferink et al. (1989) Oude Elferink et al. (1989)
Taurinenordeoxycholate-3-S
TR− rat
Rat
Taurolithocholate-S
HEK293 vesicles MDCKII cells
Human Human
Direct transport Enhanced apical efflux Direct transport Direct transport Direct transport Impaired biliary excretion Direct transport Impaired GSSG uptake
KM ∼ 12 M ∼4×
Cui et al. (2001) Sasaki et al. (2002)
S.D. CMVs EHBR CMVs Sf9 Vesicles EHBR Rat
Rat Rat Rat Rat
KM 1.5 ± 0.3 M Not observed KM 3.9 ± 0.4 M Not Observed
Akita et al. (2001) Akita et al. (2001) Akita et al. (2001) Takikawa et al. (1991)
Sf9 vesicles Wistar erythrocyte vesicles Sf9 vesicles
Rat Rat
Not determined ∼90% at 10 M
Stieger et al. (2000) Heijn et al. (1992)
Not determined
Ito et al. (2001b)
Rat
Direct transport
et al. (2006c) demonstrated that Abcg2 gene knockout mice exhibit a more profound alteration in the biliary excretion of intrahepatically formed sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol compared to Abcc2 gene knockout mice. These differences may be attributed in large part to the fact that rats have more Mrp2 protein than other species (Ninomiya et al., 2005), and this must be taken into consideration in study design and data interpretation, as well as in interspecies scaling. In mice, the constitutive expression level of Mrp3 is much higher than in other species (Belinsky et al., 2005; Donner and Keppler, 2001; Soroka et al., 2001). Furthermore, mouse Mrp3 is not as inducible as rat Mrp3 or human MRP3 under conditions that result in profound increases in hepatic Mrp3 expression such as bile duct ligation (Belinsky et al., 2005). Therefore, hepatic basolateral excretion of Mrp3 substrates in mice may be more representative of the induced Mrp3 state in other species, such as in cholestasis or following chronic exposure to phenobarbital. In scaling hepatic clearance of Mrp3 substrates, such as glucuronide conjugates, from mice to other species, care should be taken to account for interspecies variability in Mrp3 expression and inducibility. Mrp2 and Mrp3 have arguably been the most intensively studied hepatic efflux transporters for organic anions such as sulfate, glucuronide, and glutathione metabolites. Thus, much is known about species differences in these two proteins. However, it is possible that other transport proteins relevant to the hepatic excretion of phase II conjugates, such as Bcrp and Mrp4, exhibit some degree of species variation. The field of drug transport is still in its infancy, and current efforts have focused primarily on elucidation of the physiological role of transport proteins in the liver. More detailed information with respect to species differences in trans-
∼75%
porters such as Bcrp and Mrp4 undoubtedly will be forthcoming.
4.6.
Transporter multiplicity
Prior to the 21st century, transport proteins were thought to accept a specific set of substrates based primarily on particular physicochemical properties (typically size, charge, and lipohilicity), with little or no substrate overlap between transporters. However, more recent studies have indicated that considerable substrate overlap exists between transporters mediating translocation in the same direction and localized to the same plasma membrane domain. Mounting evidence for transporter multiplicity suggests that it is insufficient to demonstrate that a compound of interest can be transported by a single recombinant transport protein in vitro. In vivo or whole organ inhibition studies and/or investigations in transporter gene knockout animal models are necessary to accurately determine whether a single transport protein is involved in translocation of a compound across a specific membrane, or whether multiple transport processes are involved, and to precisely determine the relative contribution of each process (Hoffmaster et al., 2004; Zamek-Gliszczynski et al., 2005, 2006b). Development of more comprehensive in vitro recombinant models, where transport by all relevant proteins on a given plasma membrane domain is evaluated, and the relative contribution of each candidate transport protein to the overall vectorial flux is predicted, has been proposed (Hirano et al., 2004; Kopplow et al., 2005; Matsushima et al., 2005). Biliary excretion of sulfate conjugates in rats exemplifies substrate overlap between Mrp2 and Bcrp (ZamekGliszczynski et al., 2005, 2006b). In the Mrp2-deficient rat and in the wild-type rat in the presence of the Bcrp and P-glycoprotein inhibitor, GF120918, biliary excretion of sul-
465
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3B – Summary of reported interactions between glucuronide conjugates and Mrp2 X-glucuronide
Experimental system
E3040-G
EHBR rat perfused intestine Sf9 vesicles S.D. rat CMVs EHBR rat
Harmol-G
Bilirubin-monoG
Bilirubin-diG
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Rat
Impaired luminal secretion
∼50%
Adachi et al. (2005)
Rat Rat Rat
Direct transport Uptake Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired uptake Inhibition of DNP-SG uptake Impaired uptake
Not determined KM 5.7 ± 4.0 M ∼75%
Ito et al. (2001b) Niinuma et al. (1997) Takenaka et al. (1995)
∼95%
Takenaka et al. (1995)
∼97%
Takenaka et al. (1995)
∼60% Competitive KI 3.84 ± 0.34 M ∼95% KM ∼ 44.6 M
Takenaka et al. (1995) Niinuma et al. (1997)
Impaired biliary excretion Impaired biliary excretion
∼65%
EHBR rat liver perfusion EHBR rat liver perfusion EHBR CMVs S.D. rat CMVs
Rat
EHBR rat CMVs
Rat
−
TR rat liver perfusion Abcc2−/− mouse liver perfusion
Rat Rat Rat
Rat Mouse
TR− rat CMVs
Rat
Impaired uptake
Wistar rat CMVs
Rat
TR− rat CMVs
Rat
Inhibition of LTC4 uptake Impaired uptake
Wistar rat CMVs
Rat
Wistar rat CMVs TR− rat CMVs
Rat Rat
Inhibition of LTC4 uptake Uptake Impaired uptake
Wistar rat CMVs
Rat
Impaired BSP uptake
EHBR rat CMVs
Not observed
Niinuma et al. (1997) Zamek-Gliszczynski et al. (2006a, in press) Zamek-Gliszczynski et al. (2006a, in press)
Complete obliteration IC50 ∼ 0.12 M
Jedlitschky et al. (1997)
Complete obliteration IC50 ∼ 0.10 M
Jedlitschky et al. (1997)
KM 65 ± 15 M Complete obliteration KI ∼ 4.2 M competitive Not observed
Nishida et al. (1992b) Nishida et al. (1992b)
Oude Elferink et al. (1989) Oude Elferink et al. (1989)
Jedlitschky et al. (1997)
Jedlitschky et al. (1997)
Nishida et al. (1992b)
Rat
Impaired uptake
Nordeoxycholate-3-G
−
TR rat
Rat
∼99.5%
Nordeoxycholate-23-G
TR− rat
Rat
Impaired biliary excretion Enhanced biliary excretion
Acetaminophen-G
Sf9 Vesicles
Human
TR− rat
Rat Rat
Conc. dependent ∼4× at 10 mM Complete obliteration ∼99.7%
Chen et al. (2003b)
TR− rat liver perfusion TR− rat liver perfusion Sf9 vesicles
∼99.8%
Xiong et al. (2000)
KI ∼ 4–5 mM
Xiong et al. (2000)
TR− rat liver perfusion Abcc2−/− mouse liver perfusion
Rat
Stimulation of E217G uptake Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Inhibition of CDF uptake Impaired biliary excretion Impaired biliary excretion
∼99.8%
Zamek-Gliszczynski (2005) Zamek-Gliszczynski et al. (2006c, in press)
2 Binding sites IC50 70.1 ± 51.8 M IC50 1.54 ± 0.16 mM ∼99.5%
4-Methylumbelliferone-G
Rat Rat
Mouse
Sf9 vesicles
Dog
Inhibition of E217G transport
TR− rat liver perfusion Sf9 vesicles
Rat
Impaired biliary excretion Inhibition of E217G transport
Rat
∼3.5×
Not observed
IC50 452 ± 28 M
Adachi et al. (1993)
Zelcer et al. (2003c)
Xiong et al. (2000)
Ninomiya (2005)
Zamek-Gliszczynski et al. (2006b, in press) Ninomiya (2005)
466
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3B (Continued ) X-glucuronide
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Inhibited DNP-SG uptake Impaired luminal secretion
Conc. dependent ∼75% at 500 M Not observed
Niinuma et al. (1997)
Mouse
Impaired biliary excretion
∼40%
Zamek-Gliszczynski et al. (2006c, in press)
Impaired biliary excretion Impaired biliary excretion Impaired uptake Inhibition of DNP-SG uptake Impaired biliary excretion Impaired uptake Inhibition of DNP-SG uptake Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Direct transport Inhibition of ethacrynic acid-SG uptake EES uptake modulation Impaired biliary excretion Impaired biliary excretion Direct transport
∼99.5%
Shimamura et al. (1996)
∼90% 10 mg/kg ∼70% 40 mg/kg ∼80% KI 1.03 ± 0.05 M
Chu et al. (1997b)
S.D. rat CMVs
Rat
EHBR rat perfused intestine Abcc2−/− mouse liver perfusion
Rat
Glycyrrhizin
EHBR rat
Rat
SN-38-G (carboxylate)
EHBR rat
Rat
EHBR rat CMVs S.D. rat CMVs
Rat Rat
EHBR rat
Rat
EHBR rat CMVs S.D. rat CMVs
Rat Rat
hydroxyPhIP-G
TR− rat
Rat
N-hydroxyPhIP-N2-G
TR− rat
Rat
N-hydroxyPhIP-N3-G
TR− rat
Rat
Ethinylestradiol-G
Sf9 vesicles Sf9 vesicles
Human Human
Sf9 vesicle
Human
Bisphenol A-G
EHBR rat
Rat
Indomethacin-G
EHBR rat
Rat
4-
HEK293T vesicles
Human
(methylnitrosamino)1-(3-pyridyl)-1butanol-G Nicotine-N-G
HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
Troglitazone-G
TR− rat
Rat
HSR-903-G R-isomer
EHBR rat
Rat
HSR-903-G S-isomer
EHBR rat
Rat
Hydroxyphenobarbital-G
TR− rat liver perfusion Sf9 vesicles
Rat
SN-38-G (lactone)
Cotinine-N-G
Hydroxycotinine-O-G
Rat
E2 17G uptake inhibition Methotrexate uptake inhibition E2 17G uptake inhibition Methotraxate uptake inhibition Methotrexate uptake inhibition Methotrexate uptake inhibition Delayed biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Inhibition of CDF uptake
∼85% 10 mg/kg ∼60% 40 mg/kg ∼90% KI 1.62 ± 0.05 M
Adachi et al. (2005)
Chu et al. (1997a) Chu et al. (1997a) Chu et al. (1997b) Chu et al. (1997a) Chu et al. (1997a)
Complete obliteration Complete obliteration ∼90%
Dietrich et al. (2001b)
KM 35.1 ± 3.5 M KI 20 ± 1 M
Chu et al. (2004) Chu et al. (2004)
No effect (0–100 M)
Chu et al. (2004)
Complete obliteration ∼50%
Inoue et al. (2005) Kouzuki et al. (2000)
Not determined
Leslie et al. (2001)
Not observed at 100 M Not observed at 100 M Not observed at 100 M Not observed at 100 M Not observed at 100 M Not observed at 100 M Decreased 0–4 h >75%; 4–36 h normal ∼98%
Letourneau et al. (2005)
Murata et al. (1998)
∼99%
Murata et al. (1998)
Complete obliteration IC50 0.68 ± 0.02 mM
Patel et al. (2003)
Dietrich et al. (2001b) Dietrich et al. (2001b)
Letourneau et al. (2005) Letourneau et al. (2005) Letourneau et al. (2005) Letourneau et al. (2005) Letourneau et al. (2005) Kostrubsky et al. (2001)
Xiong et al. (2002)
467
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3B (Continued ) X-glucuronide
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Phenolphthalein-G
Sf9 vesicles
Rabbit
∼95% at 1 mM
van Aubel et al. (1998)
EHBR rat
Rat
Inhbition of E217G uptake Impaired biliary excretion
Complete obliteration
Ogasawara and Takikawa (2001)
Telmisaltan-G
EHBR rat
Rat
∼50%
Nishino et al. (2000)
Grepafloxacin-G
EHBR rat
Rat
∼99.4%
Sasabe et al. (1998)
S.D. rat CMVs S.D. rat CMVs
Rat Rat
KM 7.2 ± 2.4 M KI 9.2 ± 1.7 M
Sasabe et al. (1998) Sasabe et al. (1998)
EHBR CMVs
Rat
∼85%
Sasabe et al. (1998)
PKI166-G (ACU154)
MDCKII cells
Human
∼5×
Takada et al. (2004)
PKI166-G (ACU154) PKI166-G (ACU154)
Wistar rat CMVs TR− rat CMVs
Rat Rat
Takada et al. (2004) Takada et al. (2004)
PKI166-G (ACU154)
Wistar rat CMVs
Rat
Naphtol-G
Sf9 vesicles
Rabbit
KM ∼ 1 M Completely obliterated Conc. dependent ∼45% at 20 M ∼5% at 1 mM
Rat
Nitrophenol-G
TR− liver perfusion Sf9 vesicles
Rabbit
Valproate-G
TR− rat
Rat
UFX-G
EHBR rat
Rat
Estriol-16␣-G
Sf9 vesicles
Rat
Estradiol-3-G
Sf9 vesicles Sf9 vesicles
Rat Rat
Estradiol-3-S-17G
Sf9 vesicles
Rat
Sf9 vesicles
Rat
EHBR rat
Rat
Wistar erythrocyte vesicles EHBR rat
Rat
Rat
Biliary excretion modulation
EHBR rat
Rat
Ursodeoxycholate-G
EHBR rat
Rat
Taurolithocholate-G
EHBR rat
Rat
Chenodeoxycholate-G
EHBR rat
Rat
Estradiol-17-(DG)
MDCKII cells Sf9 vesicles Sf9 vesicles HEK293T vesicles
Human Human Rat Human
Impaired biliary excretion Impaired biliary excretion Enhanced biliary excretion Impaired biliary excretion Direct transport Direct transport Direct transport Direct transport
Cholate-G
Lithocholate-G
Impaired biliary excretion Impaired biliary excretion Uptake Inhibition of DNP-SG uptake Impaired uptake Enhanced apical excretion Uptake Impaired uptake Inhibition of E217G uptake Inhbition of E217G uptake Impaired biliary excretion Inhbition of E217G uptake Impaired biliary excretion Impaired biliary excretion Inhibition of E-3-G uptake Direct transport Inhibition of E217G uptake Inhibition of E217G uptake Inhibition of E-3-G uptake Impaired biliary excretion Impaired GSSG uptake
Takada et al. (2004) van Aubel et al. (1998)
∼90%
de Vries et al. (1989)
Not observed (1 mM)
van Aubel et al. (1998)
∼97%
Wright and Dickinson (2004) Yagi et al. (2003)
Complete obliteration IC50 ∼ 2 M KM ∼ 56 M Competitive IC50 ∼ 14 M Conc. dependent 20–50 M: >90% Competitive 5 M: increased E-3-G KM ∼ 2× Complete obliteration ∼5% at 10 M
∼40% decrease (1 nmol/min/g) ∼1.5× increase (1 nmol/min/g) ∼50–100% Complete obliteration ∼15.5× Complete obliteration Not determined KM >0.5 mM KM >160 M Not determined GSH independent
Gerk et al. (2004) Gerk et al. (2004) Gerk et al. (2004) Gerk et al. (2004) Gerk et al. (2004)
Morikawa et al. (2000) Heijn et al. (1992)
Takikawa et al. (1993)
Takikawa et al. (1991) Takikawa et al. (1992) Takikawa et al. (1991) Takikawa et al. (1991) Cui et al. (2001) Bodo et al. (2003) Gerk et al. (2004) Letourneau et al. (2005)
468
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3B (Continued ) X-glucuronide
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Stimulation of E217G uptake Inhibition of E-3-G uptake
Positive cooperativity Competitive IC50 ∼ 33 M 5–125 M: Increased E-3-G KM ∼ 50% IC50 13.3 ± 2.3 M
Gerk et al. (2004)
IC50 0.65 ± 0.12 M
Ito et al. (2001b)
Not determined KM 3.91 ± 0.73 M KM 7.46 ± 3.39 M KM 3.91 ± 0.93 M KM 4.81 ± 1.21 M 2 Binding sites KM 3.25 ± 0.10 M KM 75 M ∼5×
Ito et al. (2001c) Ito et al. (2005) Ito et al. (2001a) Ito et al. (2001b) Ninomiya et al. (2005) Ninomiya et al. (2005)
∼50% at 0.1 M ATP-dependent Not observed at 5 M
van Aubel et al. (1999) Zelcer et al. (2003c)
>20×
Spears et al. (2005)
Competely obliterated KM 6.32 ± 2.39 M Competitive KI 5.78 ± 1.20 M Dose dependent 180 pmol/g ∼90% 10 mol/g ∼65% Not determined Not determined Conc. dependent ∼85% at 200 M
Morikawa et al. (2000)
Sf9 vesicles
Rat
Sf9 vesicles
Rat
Sf9 vesicles
Rat
Sf9 vesicles
Rat
Sf9 vesicles Sf9 vesicles Sf9 vesicles Sf9 vesicles Sf9 Vesicles Sf9 vesicles
Human Rat Rat Rat Rat Dog
MDCKII cells
Human
Sf9 vesicles
Rabbit
Sf9 vesicles
Human
LLC-PK1 cells
Human
EHBR CMVs
Rat
S.D. rat CMVs S.D. rat CMVs
Rat Rat
EHBR rat
Rat
Sf9 vesicles Sf9 vesicles Sf9 vesicles
Rat Rat Human
Sf9 vesicles
Human
Yeast vesicles
Arabidopsis
Stimulation of DNP-SG uptake
Yeast vesicles
Arabidopsis
Yeast vesicles EHBR rat
Arabidopsis Rat
MDCKII Cells
Human
Inhibition of GSH uptake Direct transport Impaired biliary excretion Direct transport
Sf9 vesicles
Rat
Sf9 vesicles Sf9 vesicles Wistar CMVs
Rat Rabbit Rat
EHBR rat
Rat
HepG2 Cells
Human
Inhibition of DNP-SG uptake Inhibition of E217G uptake Direct transport Direct transport Direct transport Direct transport Direct transport Direct transport
Enhanced apical efflux Inhibition of GSH uptake Modulation of E217G uptake Enhanced apical efflux Impaired uptake Uptake Impaired DNP-SG uptake Impaired biliary excretion Direct transport Direct transport Inhibition of methotrexate uptake Direct transport
Inhibition of E217G uptake Direct transport Direct transport Inhibition of LTC4 uptake Impaired biliary excreion Inhibition of LTC4 transport
Gerk et al. (2004)
Ito et al. (2001b)
Sasaki et al. (2002)
Morikawa et al. (2000) Morikawa et al. (2000) Morikawa et al. (2000)
Ito et al. (2004) Xiong et al. (2002) Zelcer et al. (2003a,c)
KM ∼ 120 M homotropic cooperativity ∼5× decrease DNP-SG KM ∼ 6× cis stimulation Complete at 100 M
Zelcer et al. (2003c)
KM 752 ± 220 M ∼85%
Liu et al. (2001a,b) Takikawa et al. (1996)
Cl 3.56 ± 0.07 L/min/mg protein Competitive IC50 ∼ 14 M Not determined Not determined IC50 ∼ 0.10 M
Matsushima (2005)
Stieger et al. (2000) van Aubel et al. (1998) Jedlitschky et al. (1997)
∼80%
Sano et al. (1993)
IC50 ∼ 0.40 M
Jedlitschky et al. (1997)
Liu et al. (2001a)
Liu et al. (2001a)
Gerk et al. (2004)
469
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3C – Summary of reported interactions between glutathione conjugates and Mrp2 X-glutathione
Experimental system
Acetaminophen-SG
TR− rat
Rat
TR− rat liver perfusion
Rat
TR− rat
Rat
TR− rat liver perfusion
Rat
Acetaminophencysteinylglycine/cysteine
Acetaminophen-mercapturate TR− rat
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Impaired biliary excretion Impaired biliary excretion
Complete obliteration
Chen et al. (2003b)
Complete obliteration
Zamek-Gliszczynski et al. (2005)
Impaired biliary excretion Impaired biliary excretion
Not observed
Chen et al. (2003b)
∼90%
Zamek-Gliszczynski et al. (2005)
Rat
Metolachlor-SG Ethacrynic Acid-SG
Yeast vesicles Sf9 vesicles
Impaired biliary excretion Arabidopsis Direct transport Human Direct transport
Hydroxynonenal-SG
MDCKII Cells EHBR rat
Human Rat
N-ethylmaleimide-SG
Sf9 Vesicles Sf9 Plasma membranes
Human Human
Methylfluorescein-SG MDCKII cells Dinitrophenol-cysteinylglycine EHBR rat
Human Rat
Dinitrophenol-cysteine
EHBR rat
Rat
Dinitrophenol-mercapturate
EHBR rat
Rat
Curcumin-SG
MDCKII cells Sf9 Vesicles
Human Human
Methylmercury-SG
EHBR rat
Rat
Arsenite-SG
TR− rat
Rat
Decyl-SG
SD rat CMVs
Rat
Sulfobromophthalein-SG
TR−
Rat
S.D. rat CMVs
Rat
S.D. rat CMVs
Rat
Wistar rat CMVs EHBR rat
Rat Rat
Wistar rat erythrocyte vesicles EHBR rat liver perfusion MDCKII Cells S.D. Rat CMVs
Rat
Human Rat
EHBR rat CMVs
Rat
HEK293 vesicles LLC-PK1 vesicles Sf9 vesicles Sf9 vesicles HEK293T vesicles
Human Human Rat Human Human
Leokotriene C4
Rat
Enhanced apical efflux Impaired biliary excretion Direct transport Vanadate-sensitive ATPase stimulation
Complete obliteration
Chen et al. (2003b)
Not determined Not determined
Liu et al. (2001a) Wortelboer et al. (2003)
∼10× Complete obliteration
Ji et al. (2002) Ji et al. (2002)
KM ∼ 1.5 mM Concentrationdependent ∼3× at 10 mM EC50 ∼3–4 mM Enhanced cellular efflux Not determined Impaired biliary ∼85% excretion Impaired biliary ∼60% excretion Impaired biliary ∼70% excretion Enhanced apical efflux ∼3.5× Inhibition of ethacrynic IC50 ∼ 30 M acid-SG uptake Impaired biliary >98% excretion Impaired biliary ∼99.5% excretion (measured as As) Inhibition of DNP-SG KI ∼ 0.86 M uptake Impaired biliary ∼85% excretion Inhibition of DNP-SG KI ∼ 0.0461 M uptake cis and trans modulation Not observed 0–1 mM of GSH uptake Impaired BSP uptake ∼90% at 25 M Impaired biliary >95% excretion Impaired GSSG uptake Complete obliteration 1–10 M Impaired biliary excretion Direct transport MK-571 sensitive direct transport MK-571 Sensitive direct transport Direct transport Direct transport Direct transport Direct transport Direct transport
Bakos et al. (2000) Bakos et al. (2000)
Bogman et al. (2003) Gotoh et al. (2000) Gotoh et al. (2000) Gotoh et al. (2000) Wortelboer et al. (2003) Wortelboer et al. (2003) Ballatori et al. (1995) Dietrich et al. (2001a)
Horikawa et al. (2002a,b) Jansen et al. (1993) Horikawa et al. (2002a,b) Fernandez-Checa et al. (1992) Nishida et al. (1992a,b) Yamashita et al. (1993) Heijn et al. (1992)
Complete obliteration
Geng et al. (1998)
Not determined Not determined
Cui et al. (2001) Keppler et al. (1997)
Not observed
Keppler et al. (1997)
Not determined KM 0.26 ± 0.05 M Not determined Not determined Not determined GSH independent
Hashimoto et al. (2002) Chen et al. (1999) Ito et al. (2005) Ito et al. (2001c) Letourneau et al. (2005)
470
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3C (Continued ) X-glutathione
Dinitrophenol-SG
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Sf9 vesicles Sf9 vesicles
Rabbit Rabbit Human Human
MDCKII cells Sf9 vesicles Sf9 vesicles Sf9 vesicles
Human Rat Rabbit Rabbit
Not determined ∼75% at 5 M ATP dependent KM ∼ 1–1.4 M Concentrationdependent ∼1.5× at 20 mM ∼2× Not determined Not determined ∼80% at 10 M
van Aubel et al. (1999) van Aubel et al. (1999)
Sf9 vesicles Sf9 plasma membranes
Direct transport Inhibition of GSH uptake Direct transport Vanadate-sensitive ATPase stimulation
Wistar rat erythrocyte vesicles EHBR rat CMVs
Rat
∼20% at 1 M
Heijn et al. (1992)
Rat
Impaired uptake
Completely obliterated
Sf9 vesicles Sf9 vesicles EHBR rat
Rat Dog Rat
KM 2.05 ± 0.41 M KM 0.53 ± 0.03 M ∼80%
Xenopus laevis oocytes EHBR rat CMVs Sf9 vesicles
Rat
Direct transport Direct transport Impaired LTC4 biliary excretion Enhanced efflux
Fernandez-Checa et al. (1992) Ninomiya et al. (2005) Ninomiya et al. (2005) Kitaura et al. (1997)
∼2×
Madon et al. (1997)
Rat Rat
Impaired uptake Direct transport
∼98% Not determined
Keppler et al. (1997) Ito et al. (2001b)
MDCKII cells
Human Rat
Concentration dependent ∼75%
Cui et al. (2001)
EHBR rat CMVs
Hirouchi et al. (2005)
EHBR ratCMVs COS-7 cells Xenopus laevis oocytes S.D. rat CMVs
Rat Rat Rat
Inhibition of BSP apical excretion Impaired direct transport Impaired uptake Enhanced efflux Enhanced efflux
∼95% ∼9× ∼4×
Takenaka et al. (1995) Madon et al. (1997) Madon et al. (1997)
Conc. dependent ∼95% at 1 mM
Chu et al. (1997a)
KM 80.8 ± 7.0 M KM 62.6 ± 10.6 M IC50 19.3 ± 3.5 M
Ito et al. (2001b) Ito et al. (2001a) Ito et al. (2001b)
Conc. dependent ∼60% at 0.5 mM KM 126 ± 53 M ∼4× decrease E217G KM ∼ 3× cis stimulation ∼5–10× EC50 ∼ 1–7 M
Zelcer et al. (2003c)
KM 70 ± 12 M Not determined ∼3×
Paulusma et al. (1999) Zelcer et al. (2003c) Wortelboer et al. (2003)
∼95%
Gotoh et al. (2000)
∼50%
Gotoh et al. (2000)
Sf9 vesicles Sf9 vesicles Sf9 vesicles Sf9 vesicles Yeast vesicles Yeast vesicles Yeast vesicles MDCKII vesicles Sf9 vesicles MDCKII cells EHBR rat EHBR rat jejunum everted sac EHBR rat jejunum ussing chamber TR− rat liver perfusion
Enhanced apical efflux Direct transport Direct transport Inhibition of E217G uptake Inhibition of GSSG uptake
Inhibition of 5 M SN-38-G carboxylate uptake Rat Direct transport Rat Direct transport Rat Inhibition of E217G uptake Human Inhibition of E217G uptake Arabidopsis Direct transport Arabidopsis Stimulation of E217G uptake Arabidopsis Stimulation of E217G uptake Human Direct transport Human Direct transport Human Enhanced apical excretion Rat Impaired biliary excretion Rat Impaired secretion Rat
Bakos et al. (2000) Bakos et al. (2000)
Sasaki et al. (2002) Stieger et al. (2000) van Aubel et al. (1998) van Aubel et al. (1998)
Liu et al. (2001a) Liu et al. (2001a) Liu et al. (2001a)
Rat
Decreased BtoA/AtoB flux ratio
Decreased to ∼1
Gotoh et al. (2000)
Rat
Impaired biliary excretion
∼98%
Oude Elferink et al. (1989)
471
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3C (Continued ) X-glutathione
GSH
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Rat
Impaired efflux
∼80%
Oude Elferink et al. (1989) Oude Elferink et al. (1990) Nishida et al. (1992b)
TR− rat hepatocytes TR− rat hepatocytes Wistar rat CMVs
Rat
Impaired efflux
∼65%
Rat
Wistar rat CMVs Sf9 vesicles S.D. rat CMVs S.D. rat CMVs
Rat Rat Rat Rat
Impaired bilirubin-diG uptake Impaired BSP uptake Direct transport Uptake Inhibition of E3040G uptake
EHBR rat CMVs
Rat
∼40% at 200 M competitive KI ∼ 41 M competitive Not determined KM 17.6 ± 4.9 M Competitive, KI 17.1 ± 5.3 M Inhibition incomplete Not observed
EHBR rat CMVs Wistar rat erythrocyte vesicles S.D. rat CMVs
Rat Rat
Rat
S.D. Rat CMVs
Rat
S.D. Rat CMVs
Rat
Dubin–Johnson erythrocute vesicles TR− rat erythrocyte vesicles LLC-PK1 vesicles S.D. rat CMVs HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
TR− rat
Rat
TR− rat
Rat
MDCKII vesicles
Human
MDCKII cells Sf9 vesicles
Human Rabbit
Sf9 vesicles
Rabbit
Sf9 vesicles
Rabbit
MDCKII cells
Human
Sf9 vesicles
Human
MDCKII cells Sf9 vesicles Wistar rat CMVs
Human Human Rat
Inhibition of E3040G uptake Impaired uptake Impaired GSSG uptake
Impaired temocaprilat uptake cis Stimulation of GSH uptake
Nishida et al. (1992b) Ito et al. (2004) Niinuma et al. (1997) Niinuma et al. (1997)
Niinuma et al. (1997)
Complete obliteration Competitive KI 2.6 ± 1.4 M
Niinuma et al. (1997) Heijn et al. (1992)
KI ∼ 25.8 M
Ishizuka et al. (1997)
Human
No ATP: conc. dependent stimulation >30% 0.25–1 mM trans stimulation of GSH Conc. dependent ∼3× at uptake 1 mM Modulation of transport Not observed
Fernandez-Checa et al. (1992) Board et al. (1992)
Rat
Modulation of transport Not observed
Board et al. (1992)
Human Rat
Direct transport Inhibition of 5-CH3 -H4 PteGlu uptake Inhibition of NNAL-G uptake Modulation of LTC4 uptake Modulation of E217G uptake Impaired biliary excretion Impaired biliary excretion Inhibition of DNP-SG transport Enhanced apical efflux Stimulation of vinblastine uptake Direct transport
Not determined KI 34.5 ± 4.2 M
Chen et al. (1999) Kusuhara et al. (1998b)
∼86% at 3 mM
Leslie et al. (2001)
Not observed at 3 mM
Letourneau et al. (2005)
Not Observed at 3 mM
Letourneau et al. (2005)
∼40%
Paulusma et al. (1999)
∼99.9%
Paulusma et al. (1999)
Competitive KI 20 ± 0.6 mM ∼11× ∼5× at 5 mM ED50 1.9 ± 0.1 mM Not determined, ATP-independent Conc. dependent (0.1–5 mM) >90% at 5 mM ∼6×
Paulusma et al. (1999)
Potentiated vinblastine inhibition of LTC4 uptake Enhanced apical excretion Stimulationn of E217G uptake Enhanced apical efflux Direct transport Impaired bilirubin-diG uptake
Fernandez-Checa et al. (1992)
Paulusma et al. (1999) van Aubel et al. (1999) van Aubel et al. (1999) van Aubel et al. (1999)
Wortelboer et al. (2003)
∼20% at 0.1–10 mM
Zelcer et al. (2003c)
∼60% Not determined ∼20% at 5 mM
Ito et al. (2004) Zelcer et al. (2003c) Nishida et al. (1992b)
472
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3C (Continued ) X-glutathione
GSSG
Methyl-SG
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Modulation of BSP uptake Impaired uptake
Not Observed 3 mM
Nishida et al. (1992a)
Not observed ATP-independent GSH trans stimulated same KM VMAX KM ∼ 16 mM ∼97%
Fernandez-Checa et al. (1992)
Complete obliteration Complete obliteration
Oude Elferink et al. (1989) Dietrich et al. (2001a,b)
>99%
Koeppel et al. (1998)
∼99.6%
Lu et al. (1996)
∼90%
Johnson et al. (2002)
>98%
Ballartori et al. (1995)
Not determined Not observed 1–10 mM
Liu et al. (2001a) Liu et al. (2001a)
Wistar rat CMVs
Rat
EHBR rat CMVs
Rat
EHBR rat
Rat
TR− rat
Rat
TR− rat
Rat
TR− rat liver perfusion EHBR rat
Rat
EHBR rat
Rat
EHBR rat
Rat
Yeast vesicles Yeast vesicles
Arabidopsis Arabidopsis
Yeast vesicles
Arabidopsis
Yeast vesicles
Arabidopsis
Yeast vesicles
Arabidopsis
Yeast vesicles Yeast vesicles
Arabidopsis Arabidopsis
Sf9 Vesicles MDCKII vesicles
Rat Human
Sf9 vesicles
Human
Sf9 vesicles
Human
TR− rat CMVs Wistar rat CMVs
Rat Rat
Wistar rat CMVs TR− rat
Rat Rat
Dubin–Johnson erythrocute vesicles TR− rat erythrocyte vesicles TR− rat erythrocyte vesicles EHBR rat CMVs
Human
Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Direct transport Modulation of DNP-SG uptake Stimulation of E217G uptake Inhibition of DNP-SG uptake Stimulation of E217G uptake Direct transport Inhibition of E217G uptake Direct transport Inhibition of DNP-SG transport Inhibition of E217G uptake Inhibition of methotrexate uptake Impaired uptake Impaired bilirubin-diG uptake Impaired BSP uptake Impaired biliary excretion Modulation of transport
Rat
Yeast vesicles Yeast vesicles
Arabidopsis Direct transport Arabidopsis Inhibition of DNP-SG uptake Arabidopsis Stimulation of E217G uptake Rabbit Stimulation of vinblastine uptake
Yeast vesicles Sf9 vesicles
Rat
Sugawara et al. (1996)
Conc. dependent ∼3× at Liu et al. (2001a) 10 mM EC50 4.7 ± 1.3 mM Not observed 1–10 mM Liu et al. (2001a) Conc. dependent ∼2.5× at 10 mM Not determined Conc. dependent ∼25% at 200 M Not determined Conc. dependent ∼25% at 100 M Conc. dependent ∼60% at 1 mM Conc. dependent ∼50% at 1 mM Complete obliteration ∼50% at 100 M ∼60% at 25 M >99.7%
Liu et al. (2001a) Liu et al. (2001a) Liu et al. (2001a) Stieger et al. (2000) Paulusma et al. (1999) Zelcer et al. (2003c) Zelcer et al. (2003c) Nishida et al. (1992a) Nishida et al. (1992b)
Not observed
Nishida et al. (1992a) Oude Elferink et al. (1989) Board et al. (1992)
Impaired uptake
Not observed
Board et al. (1992)
Rat
Impaired uptake
∼45%
Heijn et al. (1992)
Rat
Impaired uptake
Completely obliterated
Fernandez-Checa et al. (1992)
Not determined Not observed 1–10 mM
Liu et al. (2001a) Liu et al. (2001a)
Conc. dependent ∼2.5× Liu et al. (2001a) at 10 mM ∼3× at 5 mM van Aubel et al. (1999)
473
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 4A – Summary of reported interactions between sulfate conjugates and Bcrp X-sulfate
Experimental system
Species of Bcrp origin
Interaction with Bcrp
Affinity
Reference
Acetaminophen-S
MDCKII cells
Mouse
A/B ratio ∼6–8
MDCKII Cells
Mouse
Liver perfsuion
Rat
Abcg2−/− mouse liver perfusion
Mouse
Enhanced apical excretion GF120918 inhibition of apical excretion GF120918 inhibition of biliary excretion Impaired biliary excretion
Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005)
Caco-2 Cells
Human
TC7 (Caco-2 subclone) cells TC7 (Caco-2 subclone) cells
Human
Aminomethylphenylimidazopyridine-S
Estrone-3-S
Estradiol-3-S
Dehydroepiandrosterone-S
Taurolithocholate-S
4-Methylumbelliferone-S
Human
K562 vesicles Sf9 vesicles
Human Human
K562 vesicles P388 Vesicles LLC-PK1 cells
Human Human Human
Caco-2 cells
Human
Caco-2 cells
Human
MDCKII cells
Human
K562 vesicles
Human
P388 vesicles
Human
LLC-PK1 cells
Human
K562 vesicles
Human
P388 Vesicles P388 vesicles
Human Human
P388 vesicles P388 vesicles
Human Human
K562 vesicles
Human
P388 vesicles
Human
P388 vesicles P388 vesicles
Human Human
MDCKII cells
Mouse
MDCKII cells
Mouse
Abcg2−/− mouse perfused intestine Abcg2−/− mouse
Mouse
Wistar rat liver perfusion
Mouse Rat
Ko143 inhibition of apical efflux Ko143 inhibition of apical efflux Enhanced apical excretion after BCRP induction Direct transport Direct transport Direct transport Direct transport Enhanced apical excretion Enhanced apical excretion Ko143, GF120918, prazosin inhibition of apical efflux Direct transport
A/B ratio ∼1 ∼50% ∼90% ∼20% at 5 M Ko143
Ebert et al. (2005)
∼40% at 5 M Ko143
Ebert et al. (2005)
<2×
Ebert et al. (2005)
KM 6.8 ± 1.4 M KM ∼ 40 M Not determined KM 16.6 ± 3.4 M ∼2×
Imai et al. (2003) Krishnamurthy et al. (2004) Yanase et al. (2004) Suzuki et al. (2003) Imai et al. (2003)
A/B ratio ∼8–16
Xia et al. (2005)
A/B ratio ∼1
Xia et al. (2005)
Cl = 2.31 ± 0.02 L/min/mg Matsushima et al. protein (2005)
Estrone-3-sulfate uptake inhibition Estrone-3-sulfate uptake inhibition Enhanced apical excretion Estrone-3-sulfate uptake inhibition Direct transport Estrone-3-sulfate uptake inhibition Direct transport Estrone-3-sulfate uptake inhibition Estrone-3-sulfate uptake inhibition Direct transport
Conc. dependent ∼60% at 30 M IC50 ∼ 14 M
Imai et al. (2003)
<40%
Imai et al. (2003)
Conc. dependent ∼50% at 30 M Not determined IC50 ∼ 55 M
Imai et al. (2003) Suzuki et al. (2003) Suzuki et al. (2003)
Not observed IC50 ∼ 37 M
Suzuki et al. (2003) Suzuki et al. (2003)
Conc. dependent ∼70% at 30 M KM 12.9 ± 2.1 M
Imai et al. (2003)
Direct transport Estrone-3-sulfate uptake inhibition Enhanced apical excretion GF120918 inhibition of apical excretion Impaired luminal excretion
Not determined IC50 ∼ 6 M
Suzuki et al. (2003) Suzuki et al. (2003)
A/B ratio ∼2
Complete obliteration
Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005) Adachi et al. (2005)
Not observed
Mizuno et al. (2004)
∼50%
Zamek-Gliszczynski et al. (2005)
Renal clearance modulation GF120918 inhibition of biliary excretion
A/B ratio ∼1
Suzuki et al. (2003)
Suzuki et al. (2003)
474
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 4A (Continued ) X-sulfate
Experimental system
Species of Bcrp origin
tInteraction with Bcrp
Affinity
Reference
Abcg2−/− mouse liver perfusion
Mouse
Impaired biliary excretion
∼99.9%
Zamek-Gliszczynski et al. (2005)
Harmol-S
Abcg2−/− mouse liver perfusion
Mouse
Impaired biliary excretion
∼99%
Zamek-Gliszczynski et al. (2005)
E3040-S
P388 vesicles P388 vesicles P388 vesicles
Human Human Human
KM 26.9 ± 4.0 M Not determined IC50 ∼ 10 M
Suzuki et al. (2003) Suzuki et al. (2003) Suzuki et al. (2003)
Abcg2−/− mouse
Mouse
∼4× Lower
Mizuno et al. (2004)
P388 vesicles
Human
IC50 ∼ 53 M
Suzuki et al. (2003)
MDCKII cells
Mouse
A/B ratio ∼5
MDCKII cells
Mouse
Direct transport Direct transport Estrone-3-sulfate uptake inhibition Impaired renal clearance Estrone-3-sulfate uptake inhibition Enhanced apical excretion GF120918 inhibition of apical excretion
Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005)
p-Nitrophenol-S
fate conjugates is impaired, but partially maintained. Biliary excretion of sulfate conjugates of acetaminophen and 4-methylumbelliferone is reduced to negligible levels in Mrp2deficient rats with GF120918 co-administration. Subsequent in vitro assays in Abcg2 and Mdr1a/Mdr1b gene knockout mouse liver perfusions demonstrated that the GF120918-sensitive component of sulfate conjugate biliary excretion was mediated by Bcrp, and not P-gp (Zamek-Gliszczynski et al., 2005, 2006b). Phase II metabolites, such as acetaminophen- and 4methylumbelliferyl sulfate demonstrate how in vitro assays with a single recombinant transport protein, such as Mrp2 or Bcrp, could mislead the investigator into concluding that in the absence of one of these protein, the sulfate metabolite would not be excreted into bile, when in fact this process would be partially maintained. The potential pitfalls of extending recombinant in vitro and transport gene knockout data from other organs to the liver is perhaps best exemplified by two P-glycoprotein substrates. Estradiol-17-(-d-glucuronide) is transported by recombinant P-glycoprotein in vitro (Huang et al., 1998), but in the intact liver, the absence of P-glycoprotein has no impact on the biliary excretion of this conjugate (Huang et al., 2000). [d-Penicillamine]2,5 enkephalin is an opioid pentapeptide whose CNS penetration is limited by P-glycoprotein at the blood–brain barrier (Chen and Pollack, 1997b, 1998, 1999). Despite the importance of P-glycoprotein in limiting access of this opioid to the CNS, elimination via biliary excretion was not impaired in Mdr1a gene knockout mice or by coadministration of GF120918 (Chen and Pollack, 1997a, 1998, 1999). However, in Mrp2-deficient rat livers, biliary excretion of [d-penicillamine]2,5 enkephalin was partially impaired, and fully impaired in the presence of a P-glycoprotein inhibitor (Hoffmaster et al., 2004). Collectively, these studies exemplify the potential pitfalls associated with predicting mechanisms of biliary excretion in the intact liver based on in vitro or other organ findings, and indicate that a more comprehensive approach is needed to elucidate the complexities of hepatic transport.
A/B ratio ∼1
4.7. Model systems for studying hepatic excretion of sulfate, glucuronide, and glutathione conjugates The hepatic excretion of sulfate, glucuronide and glutathione conjugates was first investigated in vivo in humans and animals by measuring urinary excretion with the requisite assumption that all conjugates recovered in urine were formed in the liver and traversed the hepatic basolateral membrane, moving from blood perfusing the hepatic sinusoids to the kidney for ultimate excretion in the urine; conjugates recovered in feces were assumed to be excreted from the bile and/or intestines. When access to bile was possible (T-tube in patients; bile duct cannulation in animals), biliary excretion of conjugates was measured directly. As discussed above, diseases that involved loss of specific hepatic transport functions [e.g., patients with Dubin–Johnson syndrome that lack canalicular MRP2 and exhibit impaired biliary excretion of sulfate, glucuronide, or glutathione conjugates of drugs or endogenous compounds (Kartenbeck et al., 1996; Paulusma et al., 1997)] have provided important insights regarding the role of transport proteins in disposition of conjugates. Naturally-occurring mutant rats that are deficient in canalicular Mrp2 allowed for early characterization of the substrate specificity for Mrp2 (Keppler and Konig, 1997; Oude Elferink and Jansen, 1994). More recently, the generation of knockout mouse models to examine the role of specific transport proteins in the hepatobiliary disposition of conjugates has proved very useful. However, data generated from naturally-occurring or generated knockout models must be interpreted cautiously because compensatory upregulation of other genes encoding different proteins involved in hepatic metabolism or transport may occur [e.g., increased Mrp3 expression in Mrp2 knockout models (Xiong et al., 2002b)], or other indirect alterations in hepatic disposition of conjugates (accumulation of endogenous substrates that compete for other routes of conjugate excretion) may confound data interpretation. The lack of specific inhibitors for individual hepatic transport proteins has been a major limitation in elu-
475
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 4B – Summary of reported interactions between glucuronide and glutathione conjugates and Bcrp Conjugate
Experimental system
Species of Bcrp origin
Interaction with Bcrp
Affinity
Reference
K562 vesicles MDCKII cells
Human Human
Direct transport Direct transport
P388 vesicles HEK293 vesicles K562 vesicles
Human Human Human
Imai et al. (2003) Matsushima et al. (2005) Suzuki et al. (2003) Chen et al. (2003b) Imai et al. (2003)
P388 vesicles
Human
Estrone-3-G
K562 vesicles
Human
∼10% at 30 M
Imai et al. (2003)
Estradiol-3-G
K562 vesicles
Human
Not observed
Imai et al. (2003)
4-Methylumbelliferone-G
P388 vesicles
Human
Direct transport Direct transport Estrone-3-sulfate uptake inhibition Estrone-3-sulfate uptake inhibition Estrone-3-sulfate uptake inhibition Estrone-3-sulfate uptake inhibition Direct transport
Not observed Cl = 0.383 ± 0.059 L/min/mg protein Not determined KM 44.2 ± 4.3 M Conc. dependent ∼20% at 30 M ∼7% at 75 M
Not determined
Suzuki et al. (2003)
P388 vesicles
Human
∼16% at 500 M
Suzuki et al. (2003)
Abcg2−/− mouse perfused intestine Wistar rat liver perfusion Abcg2−/− mouse liver perfusion
Mouse
∼80% lower
Adachi et al. (2005)
Not observed
Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005)
X-Glucuronide Estradiol-17-(G)
Rat Mouse
Estrone-3-sulfate uptake inhibition Impaired luminal excretion GF120918 modulation of biliary excretion Impaired biliary excretion
∼60%
Suzuki et al. (2003)
Harmol-G
Abcg2−/− mouse liver perfusion
Mouse
Impaired biliary excretion
∼95%
Zamek-Gliszczynski et al. (2005)
E3040-G
P388 vesicles P388 vesicles
Human Human
Not determined ∼24% at 250 M
Suzuki et al. (2003) Suzuki et al. (2003)
Abcg2−/− mouse perfused intestine Wistar rat liver perfusion Abcg2−/− mouse liver perfusion
Mouse
Direct transport Estrone-3-sulfate uptake inhibition Impaired luminal excretion GF120918 inhibition of biliary excretion Impaired biliary excretion
∼50% lower
Adachi et al. (2005)
Not observed
Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005)
SN-38-G
PC-6 vesicles HEK293 vesicles
Human Human
Direct transport Direct transport
KM ∼ 26 M Not determined
Nakatomi et al. (2001) Yoshikawa et al. (2004)
Aminomethylphenylimidazopyridine-G
TC7 (Caco-2 subclone) cells
Human
<2×
Ebert et al. (2005)
TC7 cells
Human
Enhanced apical excretion after BCRP induction Ko143 inhibition of apical efflux
∼20% at 5 M Ko143
Ebert et al. (2005)
P388 vesicles
Human
Not observed (2 M)
Suzuki et al. (2003)
Dinitrophenol-SG
P388 vesicles P388 vesicles
Human Human
Not determined ∼22% at 80 M
Suzuki et al. (2003) Suzuki et al. (2003)
Acetaminophen-SG
TR− rat liver perfusion TR− rat liver perfusion
Rat
Not observed
Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005)
Acetaminophen-G
X-Glutathione Leukotriene C4
Acetaminophencysteinylglycine/cysteine
Rat Mouse
Rat
cidating the role of individual transporters in overall disposition of sulfate, glucuronide and glutathione conjugates in vivo or in the isolated organ system. These model systems, with intact metabolic machinery and physiologically-relevant expression levels of transport proteins, may provide the best
Estrone-3-sulfate uptake inhibition Direct transport Estrone-3-sulfate uptake inhibition GF120918 modulation of biliary excretion GF120918 modulation of biliary excretion
∼80%
Not observed
overall description of hepatic disposition and the kinetics of hepatobiliary excretion of conjugates despite the multiplicity of transporters. Hepatocytes cultured between two layers of gelled collagen in a sandwich configuration maintain liverspecific functions including induction of metabolic enzymes
476
european journal of pharmaceutical sciences
to levels representative of in vivo expression and function (LeCluyse et al., 1996), develop intact canaliculi, maintain hepatic transport protein expression and function, and reestablish polarized excretory function (Liu et al., 1999a,b,c). Hepatocytes may offer some advantages over the intact liver with respect to compound requirements and higher throughput. However, molecular and functional characterization of the transport systems involved in the hepatic excretion of conjugates is challenging for cellular systems due to numerous practical limitations. Accurate kinetic characterization requires knowledge of the intracellular concentrations, which often are difficult to alter without influencing normal cellular processes. For example, preloading hepatocytes or transfected/expressed cells at precise substrate and/or inhibitor concentrations for efflux studies is problematic. If the conjugates are not taken up readily by the cells, intracellular concentrations of conjugates may be dependent on the formation rate of conjugates. Of course, transfected/expressed systems require pre-formed conjugates, which may not be readily available. The development of cell lines transfected with multiple transport proteins to facilitate vectorial transport of conjugates may circumvent some of these problems. Recently, Kopplow et al. (2005) demonstrated the utility of quadruple-transfected cells to study the transcellular transport of estrone 3-sulfate. The expression level of transport proteins between the transfected cells and whole liver must be considered in order to quantitatively predict biliary or basolateral excretion of conjugates in these artificial systems (Sasaki et al., 2004). Isolated basolateral or canalicular membrane vesicles would appear to be the least useful in vitro system for studying hepatic transport of conjugates. These membranes not only express the full complement of transport proteins, which makes it challenging to identify the specific transporters primarily responsible for excretion, but lack the metabolic machinery necessary to form conjugates. Furthermore, the directionality of transport may be lost in membrane vesicle systems, and the sidedness of vesicles (inside-out versus right side-out) may confound data interpretation. Clearly, the appropriate selection of a model system to study the hepatic excretion of conjugates depends on the study objectives. Important considerations include species differences in the transport proteins and the availability of preformed conjugate. For a more complete discussion of hepatic clearance models the reader is referred to ZamekGliszczynski and Brouwer (2004). If the objective is to examine the overall hepatobiliary disposition of the generated conjugate, in vivo, isolated perfused liver or sandwich-cultured hepatocyte studies would be appropriate. Transfected/expressed systems or knockout models would be more useful to characterize the specific protein(s) involved in transport of conjugates. The next decade promises to be an exciting era in the field of hepatic transport. As our knowledge of drug transport proteins increases, model systems will continue to be developed and refined to determine the extent of hepatic excretion of sulfate, glucuronide and glutathione conjugates in humans, to explore the interplay between metabolism and transport, to elucidate the mechanisms involved in cellular processing of conjugates, and to predict drug–drug interactions. A greater understanding of the regulatory mechanisms
27
( 2 0 0 6 ) 447–486
that govern transport and metabolic processes, and how disease states alter these processes, will undoubtedly evolve. One of the greatest challenges appears to be the major species differences that exist in the hepatic handling of sulfate, glucuronide and glutathione conjugates. If potent inhibitors of specific transport processes can be identified, many important questions can be addressed in a systematic fashion in humans. This knowledge will be particularly useful for conjugates that exhibit therapeutic efficacy and/or toxicity.
Acknowledgments The authors would like to sincerely thank Dr. Philip C. Smith and Rong Zhao for their constructive and insightful comments, which were instrumental in the prepatration of this manuscript. This work was funded by grant R01 GM41935 from the National Institutes of Health. Maciej J. Zamek-Gliszczynski was supported by a pre-doctoral fellowship in pharmacokinetics and drug disposition from the Eli Lilly and Company Foundation.
references
Abernethy, D.R., Greenblatt, D.J., Ameer, B., Shader, R.I., 1985. Probenecid impairment of acetaminophen and lorazepam clearance: direct inhibition of ether glucuronide formation. J. Pharmacol. Exp. Ther. 234, 345–349. Adachi, Y., Suzuki, H., Schinkel, A.H., Sugiyama, Y., 2005. Role of breast cancer resistance protein (bcrp1/abcg2) in the extrusion of glucuronide and sulfate conjugates from enterocytes to intestinal lumen. Mol. Pharmacol. 67, 923–928. Adachi, Y., Kobayashi, H., Shouji, M., Kitano, M., Okuyama, Y., Yamamoto, T., 1993. Functional integrity of hepatocyte canalicular membrane transport of taurocholate and bilirubin diglucuronide in eisai hyperbilirubinuria rats. Life Sci. 52, 777–784. Akita, H., Suzuki, H., Hirohashi, T., Takikawa, H., Sugiyama, Y., 2002. Transport activity of human mrp3 expressed in sf9 cells: comparative studies with rat mrp3. Pharm. Res. 19, 34–41. Akita, H., Suzuki, H., Ito, K., Kinoshita, S., Sato, N., Takikawa, H., Sugiyama, Y., 2001. Characterization of bile acid transport mediated by multidrug resistance associated protein 2 and bile salt export pump. Biochim. Biophys. Acta 1511, 7–16. Ameen, M., Musthapa, M.S., Abidi, P., Ahmad, I., Rahman, Q., 2003. Garlic attenuates chrysotile-mediated pulmonary toxicity in rats by altering the phase I and phase II drug metabolizing enzyme system. J. Biochem. Mol. Toxicol. 17, 366–371. Assem, M., Schuetz, E.G., Leggas, M., Sun, D., Yasuda, K., Reid, G., Zelcer, N., Adachi, M., Strom, S., Evans, R.M., Moore, D.D., Borst, P., Schuetz, J.D., 2004. Interactions between hepatic mrp4 and sult2a as revealed by the constitutive androstane receptor and mrp4 knockout mice. J. Biol. Chem.. Bai, J., Lai, L., Yeo, H.C., Goh, B.C., Tan, T.M., 2004. Multidrug resistance protein 4 (mrp4/abcc4) mediates efflux of bimane-glutathione. Int. J. Biochem. Cell. Biol. 36, 247–257. Bakos, E., Evers, R., Sinko, E., Varadi, A., Borst, P., Sarkadi, B., 2000. Interactions of the human multidrug resistance proteins mrp1 and mrp2 with organic anions. Mol. Pharmacol. 57, 760–768.
european journal of pharmaceutical sciences
Ballatori, N., Gatmaitan, Z., Truong, A.T., 1995. Impaired biliary excretion and whole body elimination of methylmercury in rats with congenital defect in biliary glutathione excretion. Hepatology 22, 1469–1473. Bandurski, R.S., Wilson, L.G., Squires, C.L., 1956. The mechanism of ’active sulfate’ formation. J. Am. Chem. Soc. 78, 6408–6409. Barbier, O., Villeneuve, L., Bocher, V., Fontaine, C., Torra, I.P., Duhem, C., Kosykh, V., Fruchart, J.C., Guillemette, C., Staels, B., 2003. The UDP-glucuronosyltransferase 1a9 enzyme is a peroxisome proliferator-activated receptor alpha and gamma target gene. J. Biol. Chem. 278, 13975–13983. Bates, S.E., Robey, R., Miyake, K., Rao, K., Ross, D.D., Litman, T., 2001. The role of half-transporters in multidrug resistance. J. Bioenerg. Biomembr. 33, 503–511. Belinsky, M.G., Chen, Z.S., Shchaveleva, I., Zeng, H., Kruh, G.D., 2002. Characterization of the drug resistance and transport properties of multidrug resistance protein 6 (mrp6, abcc6). Cancer Res. 62, 6172–6177. Belinsky, M.G., Dawson, P.A., Shchaveleva, I., Bain, L.J., Wang, R., Ling, V., Chen, Z.S., Grinberg, A., Westphal, H., Klein-Szanto, A., Lerro, A., Kruh, G.D., 2005. Analysis of the in vivo functions of mrp3. Mol. Pharmacol. 68, 160–168. Beyer, K.H., Russo, H.F., Tillson, E.K., Miller, A.K., Verwey, W.F., Gass, S.R., 1951. ‘benemid,’ p-(di-n-propylsulfamyl)-benzoic acid; its renal affinity and its elimination. Am. J. Physiol. 166, 625–640. Board, P., Nishida, T., Gatmaitan, Z., Che, M., Arias, I.M., 1992. Erythrocyte membrane transport of glutathione conjugates and oxidized glutathione in the Dubin–Johnson syndrome and in rats with hereditary hyperbilirubinemia. Hepatology 15, 722–725. Boberg, E.W., Miller, E.C., Miller, J.A., Poland, A., Liem, A., 1983. Strong evidence from studies with brachymorphic mice and pentachlorophenol that 1 -sulfooxysafrole is the major ultimate electrophilic and carcinogenic metabolite of 1 -hydroxysafrole in mouse liver. Cancer Res. 43, 5163– 5173. Bodo, A., Bakos, E., Szeri, F., Varadi, A., Sarkadi, B., 2003. Differential modulation of the human liver conjugate transporters mrp2 and mrp3 by bile acids and organic anions. J. Biol. Chem. 278, 23529–23537. Bogman, K., Erne-Brand, F., Alsenz, J., Drewe, J., 2003. The role of surfactants in the reversal of active transport mediated by multidrug resistance proteins. J. Pharm. Sci. 92, 1250–1261. Bohan, A., Boyer, J.L., 2002. Mechanisms of hepatic transport of drugs: implications for cholestatic drug reactions. Semin. Liver Dis. 22, 123–136. Bosma, P.J., Seppen, J., Goldhoorn, B., Bakker, C., Oude Elferink, R.P., Chowdhury, J.R., Chowdhury, N.R., Jansen, P.L., 1994. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J. Biol. Chem. 269, 17960–17964. Bosma, P.J., Chowdhury, J.R., Bakker, C., Gantla, S., de Boer, A., Oostra, B.A., Lindhout, D., Tytgat, G.N., Jansen, P.L., Oude Elferink, R.P., et al., 1995. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in gilbert’s syndrome. N. Engl. J. Med. 333, 1171–1175. Brouwer, K.L., Jones, J.A., 1990. Altered hepatobiliary disposition of acetaminophen metabolites after phenobarbital pretreatment and renal ligation: evidence for impaired biliary excretion and a diffusional barrier. J. Pharmacol. Exp. Ther. 252, 657–664. Buesen, R., Mock, M., Seidel, A., Jacob, J., Lampen, A., 2002. Interaction between metabolism and transport of benzo[a]pyrene and its metabolites in enterocytes. Toxicol. Appl. Pharmacol. 183, 168–178.
27
( 2 0 0 6 ) 447–486
477
Buhl, A.E., Waldon, D.J., Baker, C.A., Johnson, G.A., 1990. Minoxidil sulfate is the active metabolite that stimulates hair follicles. J. Invest. Dermatol. 95, 553–557. Byrne, J.A., Strautnieks, S.S., Mieli-Vergani, G., Higgins, C.F., Linton, K.J., Thompson, R.J., 2002. The human bile salt export pump: characterization of substrate specificity and identification of inhibitors. Gastroenterology 123, 1649–1658. Cappiello, M., Giuliani, L., Pacifici, G.M., 1991. Distribution of UDP-glucuronosyltransferase and its endogenous substrate uridine 5 -diphosphoglucuronic acid in human tissues. Eur. J. Clin. Pharmacol. 41, 345–350. Cappiello, M., Franchi, M., Giuliani, L., Pacifici, G.M., 1989. Distribution of 2-naphthol sulphotransferase and its endogenous substrate adenosine 3 -phosphate 5 -phosphosulphate in human tissues. Eur. J. Clin. Pharmacol. 37, 317–320. Carrella, M., Roda, E., 1999. Evolving concepts in the pathophysiology of biliary lipid secretion. Ital. J. Gastroenterol. Hepatol. 31, 643–648. Chen, C., Pollack, G.M., 1997a. Extensive biliary excretion of the model opioid peptide [d-pen2,5] enkephalin in rats. Pharm. Res. 14, 345–350. Chen, C., Pollack, G.M., 1997b. Blood–brain disposition and antinociceptive effects of d-penicillamine2,5-enkephalin in the mouse. J. Pharmacol. Exp. Ther. 283, 1151–1159. Chen, C., Pollack, G.M., 1998. Altered disposition and antinociception of [d-penicillamine(2,5)] enkephalin in mdr1a-gene-deficient mice. J. Pharmacol. Exp. Ther. 287, 545–552. Chen, C., Pollack, G.M., 1999. Enhanced antinociception of the model opioid peptide [d-penicillamine] enkephalin by P-glycoprotein modulation. Pharm. Res. 16, 296–301. Chen, C., Hennig, G.E., Manautou, J.E., 2003a. Hepatobiliary excretion of acetaminophen glutathione conjugate and its derivatives in transport-deficient (TR− ) hyperbilirubinemic rats. Drug Metab. Dispos. 31, 798–804. Chen, C., Slitt, A.L., Dieter, M.Z., Tanaka, Y., Scheffer, G.L., Klaassen, C.D., 2005. Up-regulation of mrp4 expression in kidney of mrp2-deficient tr− rats. Biochem. Pharmacol. 70, 1088–1095. Chen, Z.S., Lee, K., Kruh, G.D., 2001. Transport of cyclic nucleotides and estradiol 17-beta-d-glucuronide by multidrug resistance protein. 4. Resistance to 6-mercaptopurine and 6-thioguanine. J. Biol. Chem. 276, 33747–33754. Chen, Z.S., Lee, K., Walther, S., Raftogianis, R.B., Kuwano, M., Zeng, H., Kruh, G.D., 2002. Analysis of methotrexate and folate transport by multidrug resistance protein 4 (abcc4): Mrp4 is a component of the methotrexate efflux system. Cancer Res. 62, 3144–3150. Chen, Z.S., Robey, R.W., Belinsky, M.G., Shchaveleva, I., Ren, X.Q., Sugimoto, Y., Ross, D.D., Bates, S.E., Kruh, G.D., 2003b. Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-d-glucuronide) by abcg2: effects of acquired mutations at r482 on methotrexate transport. Cancer Res. 63, 4048–4054. Chen, Z.S., Kawabe, T., Ono, M., Aoki, S., Sumizawa, T., Furukawa, T., Uchiumi, T., Wada, M., Kuwano, M., Akiyama, S.I., 1999. Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter. Mol. Pharmacol. 56, 1219–1228. Chu, X.Y., Kato, Y., Sugiyama, Y., 1997a. Multiplicity of biliary excretion mechanisms for irinotecan, cpt-11, and its metabolites in rats. Cancer Res. 57, 1934–1938. Chu, X.Y., Kato, Y., Niinuma, K., Sudo, K.I., Hakusui, H., Sugiyama, Y., 1997b. Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J.
478
european journal of pharmaceutical sciences
Pharmacol. Exp. Ther. 281, 304–314. Chu, X.Y., Huskey, S.E., Braun, M.P., Sarkadi, B., Evans, D.C., Evers, R., 2004. Transport of ethinylestradiol glucuronide and ethinylestradiol sulfate by the multidrug resistance proteins mrp1, mrp2, and mrp3. J. Pharmacol. Exp. Ther. 309, 156–164. Clarke, D., Burchell, B., 1994. The uridine diphosphate glucuronosyltransferase multigene family: function and regulation. In: Kauffman, F. (Ed.), Conjugation–Deconjugation Reactions in Drug Metabolism and Toxicity. Springer-Verlag, Berlin, pp. 3–43. Coffman, B.L., Rios, G.R., King, C.D., Tephly, T.R., 1997. Human ugt2b7 catalyzes morphine glucuronidation. Drug Metab. Dispos. 25, 1–4. Court, M.H., Duan, S.X., von Moltke, L.L., Greenblatt, D.J., Patten, C.J., Miners, J.O., Mackenzie, P.I., 2001. Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J. Pharmacol. Exp. Ther. 299, 998–1006. Crayford, J.V., Hutson, D.H., 1980. Comperative metabolism of phenobarbital in the rat (cfe) and mouse (cf1). Food Cosmet. Toxicol. 18, 503–509. Cui, Y., Konig, J., Keppler, D., 2001. Vectorial transport by double-transfected cells expressing the human uptake transporter slc21a8 and the apical export pump abcc2. Mol. Pharmacol. 60, 934–943. Cummings, J., Zelcer, N., Allen, J.D., Yao, D., Boyd, G., Maliepaard, M., Friedberg, T.H., Smyth, J.F., Jodrell, D.I., 2004. Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins. Biochem. Pharmacol. 67, 31–39. de Vries, M.H., Redegeld, F.A., Koster, A.S., Noordhoek, J., de Haan, J.G., Oude Elferink, R.P., Jansen, P.L., 1989. Hepatic, intestinal and renal transport of 1-naphthol-beta-d-glucuronide in mutant rats with hereditary-conjugated hyperbilirubinemia. Naunyn. Schmiedebergs Arch. Pharmacol. 340, 588–592. Denk, G.U., Soroka, C.J., Takeyama, Y., Chen, W.S., Schuetz, J.D., Boyer, J.L., 2004. Multidrug resistance-associated protein 4 is up-regulated in liver but down-regulated in kidney in obstructive cholestasis in the rat. J. Hepatol. 40, 585–591. DePierre, J.W., Seidegard, J., Morgenstern, R., Balk, L., Meijer, J., Astrom, A., Norelius, I., Ernster, L., 1984. Induction of cytosolic glutathione transferase and microsomal epoxide hydrolase activities in extrahepatic organs of the rat by phenobarbital, 3-methylcholanthrene and trans-stilbene oxide. Xenobiotica 14, 295–301. Desmond, P.V., Smyth, F.E., Mashford, M.L., 1994. Release of latent glucuronosyltransferase activity contributes to the sparing of glucuronidation in experimental liver injuries. J. Gastroenterol. Hepatol. 9, 350–354. Dietrich, C.G., Ottenhoff, R., de Waart, D.R., Oude Elferink, R.P., 2001a. Role of mrp2 and gsh in intrahepatic cycling of toxins. Toxicology 167, 73–81. Dietrich, C.G., de Waart, D.R., Ottenhoff, R., Bootsma, A.H., van Gennip, A.H., Elferink, R.P., 2001b. Mrp2-deficiency in the rat impairs biliary and intestinal excretion and influences metabolism and disposition of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo. Carcinogenesis 22, 805–811. Doerge, D.R., Chang, H.C., Churchwell, M.I., Holder, C.L., 2000. Analysis of soy isoflavone conjugation in vitro and in human blood using liquid chromatography-mass spectrometry. Drug Metab. Dispos. 28, 298–307. Donner, M.G., Keppler, D., 2001. Up-regulation of basolateral multidrug resistance protein 3 (mrp3) in cholestatic rat liver. Hepatology 34, 351–359.
27
( 2 0 0 6 ) 447–486
Donner, M.G., Warskulat, U., Saha, N., Haussinger, D., 2004. Enhanced expression of basolateral multidrug resistance protein isoforms mrp3 and mrp5 in rat liver by lps. Biol. Chem. 385, 331–339. Duanmu, Z., Kocarek, T.A., Runge-Morris, M., 2001. Transcriptional regulation of rat hepatic aryl sulfotransferase (sult1a1) gene expression by glucocorticoids. Drug Metab. Dispos. 29, 1130–1135. Duanmu, Z., Dunbar, J., Falany, C.N., Runge-Morris, M., 2000. Induction of rat hepatic aryl sulfotransferase (sult1a1) gene expression by triamcinolone acetonide: impact on minoxidil-mediated hypotension. Toxicol. Appl. Pharmacol. 164, 312–320. Duanmu, Z., Locke, D., Smigelski, J., Wu, W., Dahn, M.S., Falany, C.N., Kocarek, T.A., Runge-Morris, M., 2002. Effects of dexamethasone on aryl (sult1a1)- and hydroxysteroid (sult2a1)-sulfotransferase gene expression in primary cultured human hepatocytes. Drug Metab. Dispos. 30, 997–1004. Dutton, G.J., 1980. Glucuronidation of Drugs and other Compounds. CRC Press, Boca Raton. Ebert, B., Seidel, A., Lampen, A., 2005. Identification of bcrp as transporter of benzo[a]pyrene conjugates metabolically formed in caco-2 cells and its induction by ah-receptor agonists. Carcinogenesis 26, 1754–1763. Ejendal, K.F., Hrycyna, C.A., 2002. Multidrug resistance and cancer: the role of the human abc transporter abcg2. Curr. Protein Pept. Sci. 3, 503–511. Elferink, R.P., Tytgat, G.N., Groen, A.K., 1997. Hepatic canalicular membrane. 1. The role of mdr2 P-glycoprotein in hepatobiliary lipid transport. FASEB J. 11, 19–28. Elferink, R.P., Ottenhoff, R., Liefting, W., de Haan, J., Jansen, P.L., 1989. Hepatobiliary transport of glutathione and glutathione conjugate in rats with hereditary hyperbilirubinemia. J. Clin. Invest. 84, 476–483. Eriksson, G., Strath, D., 1981. Decreased UDP-glucuronic acid in rat liver after ether narcosis: an isotachophoretic study. FEBS Lett. 124, 39–42. Ethell, B.T., Anderson, G.D., Burchell, B., 2003. The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases. Biochem. Pharmacol. 65, 1441–1449. Evans, W.E., Johnson, J.A., 2001. Pharmacogenomics: the inherited basis for interindividual differences in drug response. Annu. Rev. Genomics Hum. Genet. 2, 9–39. Falany, C.N., Comer, K.A., Dooley, T.P., Glatt, H., 1995. Human dehydroepiandrosterone sulfotransferase. Purification, molecular cloning, and characterization. Ann. N.Y. Acad. Sci. 774, 59–72. Falany, C.N., Xie, X., Wang, J., Ferrer, J., Falany, J.L., 2000. Molecular cloning and expression of novel sulphotransferase-like cdnas from human and rat brain. Biochem. J. 346 (Pt 3), 857–864. Fattinger, K., Funk, C., Pantze, M., Weber, C., Reichen, J., Stieger, B., Meier, P.J., 2001. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin. Pharmacol. Ther. 69, 223–231. Fernandez-Checa, J.C., Takikawa, H., Horie, T., Ookhtens, M., Kaplowitz, N., 1992. Canalicular transport of reduced glutathione in normal and mutant eisai hyperbilirubinemic rats. J. Biol. Chem. 267, 1667–1673. Fisher, M.B., Paine, M.F., Strelevitz, T.J., Wrighton, S.A., 2001. The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism. Drug Metab. Rev. 33, 273–297. Fouassier, L., Kinnman, N., Lefevre, G., Lasnier, E., Rey, C., Poupon, R., Elferink, R.P., Housset, C., 2002. Contribution of
european journal of pharmaceutical sciences
mrp2 in alterations of canalicular bile formation by the endothelin antagonist bosentan. J. Hepatol. 37, 184– 191. Funk, C., Ponelle, C., Scheuermann, G., Pantze, M., 2001. Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (bsep) in the rat. Mol. Pharmacol. 59, 627–635. Galinsky, R.E., Levy, G., 1981. Dose- and time-dependent elimination of acetaminophen in rats: pharmacokinetic implications of cosubstrate depletion. J. Pharmacol. Exp. Ther. 219, 14–20. Geng, W., Schwab, A.J., Horie, T., Goresky, C.A., Pang, K.S., 1998. Hepatic uptake of bromosulfophthalein–glutathione in perfused eisai hyperbilirubinemic mutant rat liver: a multiple-indicator dilution study. J. Pharmacol. Exp. Ther. 284, 480–492. Gerk, P.M., Li, W., Vore, M., 2004. Estradiol 3-glucuronide is transported by the multidrug resistance-associated protein 2 but does not activate the allosteric site bound by estradiol 17-glucuronide. Drug Metab. Dispos. 32, 1139– 1145. Glatt, H., Davis, W., Meinl, W., Hermersdorfer, H., Venitt, S., Phillips, D.H., 1998. Rat, but not human, sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture. Carcinogenesis 19, 1709–1713. Golden, P.L., Pollack, G.M., 2003. Blood–brain barrier efflux transport. J. Pharm. Sci. 92, 1739–1753. Gotoh, Y., Suzuki, H., Kinoshita, S., Hirohashi, T., Kato, Y., Sugiyama, Y., 2000. Involvement of an organic anion transporter (canalicular multispecific organic anion transporter/multidrug resistance-associated protein 2) in gastrointestinal secretion of glutathione conjugates in rats. J. Pharmacol. Exp. Ther. 292, 433–439. Gram, T.E., Gillette, J.R., 1971. Biotransformation of drugs. In: Bacq, Z.M. (Ed.), Fundamentals of Biochemical Pharmacology. Pergamon Press Ltd., New York, pp. 571–609. Gregus, Z., Madhu, C., Klaassen, C.D., 1990. Effect of microsomal enzyme inducers on biliary and urinary excretion of acetaminophen metabolites in rats. Decreased hepatobiliary and increased hepatovascular transport of acetaminophen-glucuronide after microsomal enzyme induction. Drug Metab. Dispos. 18, 10–19. Gregus, Z., Oguro, T., Klaassen, C.D., 1994a. Nutritionally and chemically induced impairment of sulfate activation and sulfation of xenobiotics in vivo. Chem. Biol. Interact. 92, 169–177. Gregus, Z., Watkins, J.B., Thompson, T.N., Klaassen, C.D., 1983. Depletion of hepatic uridine diphosphoglucuronic acid decreases the biliary excretion of drugs. J. Pharmacol. Exp. Ther. 225, 256–262. Gregus, Z., Kim, H.J., Madhu, C., Liu, Y., Rozman, P., Klaassen, C.D., 1994b. Sulfation of acetaminophen and acetaminophen-induced alterations in sulfate and 3 -phosphoadenosine 5 -phosphosulfate homeostasis in rats with deficient dietary intake of sulfur. Drug Metab. Dispos. 22, 725–730. Guarino, A.M., Conway, W.D., Fales, H.M., 1969. Mass spectral identification of probenecid metabolites in rat bile. Eur. J. Pharmacol. 8, 244–252. Guillemette, C., 2003. Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenom. J. 3, 136–158. Haimeur, A., Conseil, G., Deeley, R.G., Cole, S.P., 2004. The mrp-related and bcrp/abcg2 multidrug resistance proteins: biology, substrate specificity and regulation. Curr. Drug Metab. 5, 21–53.
27
( 2 0 0 6 ) 447–486
479
Hamaguchi, H., Yamaguchi, Y., Goto, M., Misumi, M., Hisama, N., Miyanari, N., Mori, K., Ogawa, M., 1994. Hepatic biliary transport after hepatocyte transplantation in eizai hyperbilirubinemic rats. Hepatology 20, 220–224. Hashimoto, K., Uchiumi, T., Konno, T., Ebihara, T., Nakamura, T., Wada, M., Sakisaka, S., Maniwa, F., Amachi, T., Ueda, K., Kuwano, M., 2002. Trafficking and functional defects by mutations of the ATP-binding domains in mrp2 in patients with Dubin–Johnson syndrome. Hepatology 36, 1236–1245. Hauser, S.C., Ziurys, J.C., Gollan, J.L., 1988. A membrane transporter mediates access of uridine 5 -diphosphoglucuronic acid from the cytosol into the endoplasmic reticulum of rat hepatocytes: implications for glucuronidation reactions. Biochim. Biophys. Acta 967, 149–157. Heijn, M., Oude Elferink, R.P., Jansen, P.L., 1992. ATP-dependent multispecific organic anion transport system in rat erythrocyte membrane vesicles. Am. J. Physiol. 262, C104–C110. Her, C., Wood, T.C., Eichler, E.E., Mohrenweiser, H.W., Ramagli, L.S., Siciliano, M.J., Weinshilboum, R.M., 1998. Human hydroxysteroid sulfotransferase sult2b1: two enzymes encoded by a single chromosome 19 gene. Genomics 53, 284–295. Hirano, M., Maeda, K., Shitara, Y., Sugiyama, Y., 2004. Contribution of oatp2 (oatp1b1) and oatp8 (oatp1b3) to the hepatic uptake of pitavastatin in humans. J. Pharmacol. Exp. Ther. 311, 139–146. Hirohashi, T., Suzuki, H., Sugiyama, Y., 1999. Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (mrp3). J. Biol. Chem. 274, 15181–15185. Hirohashi, T., Suzuki, H., Takikawa, H., Sugiyama, Y., 2000a. ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 (mrp3). J. Biol. Chem. 275, 2905–2910. Hirohashi, T., Suzuki, H., Chu, X.Y., Tamai, I., Tsuji, A., Sugiyama, Y., 2000b. Function and expression of multidrug resistance-associated protein family in human colon adenocarcinoma cells (caco-2). J. Pharmacol. Exp. Ther. 292, 265–270. Hirouchi, M., Suzuki, H., Sugiyama, Y., 2005. Treatment of hyperbilirubinemia in eisai hyperbilirubinemic rat by transfecting human mrp2/abcc2 gene. Pharm. Res. 22, 661–666. Hjelle, J.J., Hazelton, G.A., Klaassen, C.D., 1985. Acetaminophen decreases adenosine 3 -phosphate 5 -phosphosulfate and uridine diphosphoglucuronic acid in rat liver. Drug Metab. Dispos. 13, 35–41. Hoffmaster, K.A., Zamek-Gliszczynski, M.J., Pollack, G.M., Brouwer, K.L., 2004. Hepatobiliary disposition of the metabolically stable opioid peptide [d-penicillamine2,5]enkephalin (dpdpe): pharmacokinetic consequences of the interplay between multiple transport systems. J. Pharmacol. Exp. Ther. 311, 1203–1210. Homolya, L., Varadi, A., Sarkadi, B., 2003. Multidrug resistance-associated proteins: export pumps for conjugates with glutathione, glucuronate or sulfate. Biofactors 17, 103–114. Horikawa, M., Kato, Y., Sugiyama, Y., 2002a. Reduced gastrointestinal toxicity following inhibition of the biliary excretion of irinotecan and its metabolites by probenecid in rats. Pharm. Res. 19, 1345–1353. Horikawa, M., Kato, Y., Tyson, C.A., Sugiyama, Y., 2002b. The potential for an interaction between mrp2 (abcc2) and various therapeutic agents: probenecid as a candidate inhibitor of the biliary excretion of irinotecan metabolites. Drug Metab. Pharmacokinet. 17, 23–33.
480
european journal of pharmaceutical sciences
Huang, L., Vore, M., 2001. Multidrug resistance P-glycoprotein 2 is essential for the biliary excretion of indocyanine green. Drug Metab. Dispos. 29, 634–637. Huang, L., Hoffman, T., Vore, M., 1998. Adenosine triphosphate-dependent transport of estradiol-17beta(beta-d-glucuronide) in membrane vesicles by mdr1 expressed in insect cells. Hepatology 28, 1371–1377. Huang, L., Smit, J.W., Meijer, D.K., Vore, M., 2000. Mrp2 is essential for estradiol-17beta(beta-d-glucuronide)-induced cholestasis in rats. Hepatology 32, 66–72. Iida, S., Mizuma, T., Sakuma, N., Hayashi, M., Awazu, S., 1989. Transport of acetaminophen conjugates in isolated rat hepatocytes. Drug Metab. Dispos. 17, 341–344. Ikeda, H., Nishi, S., Sakai, M., 2004. Transcription factor nrf2/mafk regulates rat placental glutathione S-transferase gene during hepatocarcinogenesis. Biochem. J. 380, 515–521. Ilias, A., Urban, Z., Seidl, T.L., Le Saux, O., Sinko, E., Boyd, C.D., Sarkadi, B., Varadi, A., 2002. Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human abcc6 (mrp6). J. Biol. Chem. 277, 16860–16867. Imai, Y., Asada, S., Tsukahara, S., Ishikawa, E., Tsuruo, T., Sugimoto, Y., 2003. Breast cancer resistance protein exports sulfated estrogens but not free estrogens. Mol. Pharmacol. 64, 610–618. Inoue, H., Tsuruta, A., Kudo, S., Ishii, T., Fukushima, Y., Iwano, H., Yokota, H., Kato, S., 2005. Bisphenol a glucuronidation and excretion in liver of pregnant and non-pregnant female rats. Drug Metab. Dispos. 33, 55–59. Ishizuka, H., Konno, K., Naganuma, H., Sasahara, K., Kawahara, Y., Niinuma, K., Suzuki, H., Sugiyama, Y., 1997. Temocaprilat, a novel angiotensin-converting enzyme inhibitor, is excreted in bile via an ATP-dependent active transporter (cmoat) that is deficient in eisai hyperbilirubinemic mutant rats (ehbr). J. Pharmacol. Exp. Ther. 280, 1304–1311. Ishizuka, H., Konno, K., Shiina, T., Naganuma, H., Nishimura, K., Ito, K., Suzuki, H., Sugiyama, Y., 1999. Species differences in the transport activity for organic anions across the bile canalicular membrane. J. Pharmacol. Exp. Ther. 290, 1324–1330. Ito, K., Suzuki, H., Sugiyama, Y., 2001a. Single amino acid substitution of rat mrp2 results in acquired transport activity for taurocholate. Am. J. Physiol. Gastrointest. Liver Physiol. 281, G1034–G1040. Ito, K., Suzuki, H., Sugiyama, Y., 2001b. Charged amino acids in the transmembrane domains are involved in the determination of the substrate specificity of rat mrp2. Mol. Pharmacol. 59, 1077–1085. Ito, K., Wakabayashi, T., Horie, T., 2005. Mrp2/abcc2 transport activity is stimulated by protein kinase calpha in a baculo virus co-expression system. Life Sci. 77, 539–550. Ito, K., Koresawa, T., Nakano, K., Horie, T., 2004. Mrp2 is involved in benzylpenicillin-induced choleresis. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G42–G49. Ito, K., Oleschuk, C.J., Westlake, C., Vasa, M.Z., Deeley, R.G., Cole, S.P., 2001c. Mutation of trp1254 in the multispecific organic anion transporter, multidrug resistance protein 2 (mrp2) (abcc2), alters substrate specificity and results in loss of methotrexate transport activity. J. Biol. Chem. 276, 38108–38114. Jansen, P.L., van Klinken, J.W., van Gelder, M., Ottenhoff, R., Elferink, R.P., 1993. Preserved organic anion transport in mutant TR− rats with a hepatobiliary secretion defect. Am. J. Physiol. 265, G445–G450. Jedlitschky, G., Cassidy, A.J., Sales, M., Pratt, N., Burchell, B., 1999. Cloning and characterization of a novel human olfactory UDP-glucuronosyltransferase. Biochem. J. 340 (Pt 3), 837–843.
27
( 2 0 0 6 ) 447–486
Jedlitschky, G., Leier, I., Buchholz, U., Hummel-Eisenbeiss, J., Burchell, B., Keppler, D., 1997. ATP-dependent transport of bilirubin glucuronides by the multidrug resistance protein mrp1 and its hepatocyte canalicular isoform mrp2. Biochem. J. 327 (Pt 1), 305–310. Ji, B., Ito, K., Suzuki, H., Sugiyama, Y., Horie, T., 2002. Multidrug resistance-associated protein2 (mrp2) plays an important role in the biliary excretion of glutathione conjugates of 4-hydroxynonenal. Free Radic. Biol. Med. 33, 370–378. Ji, B., Ito, K., Sekine, S., Tajima, A., Horie, T., 2004. Ethacrynic-acid-induced glutathione depletion and oxidative stress in normal and mrp2-deficient rat liver. Free Radic. Biol. Med. 37, 1718–1729. Johnson, D.R., Habeebu, S.S., Klaassen, C.D., 2002. Increase in bile flow and biliary excretion of glutathione-derived sulfhydryls in rats by drug-metabolizing enzyme inducers is mediated by multidrug resistance protein 2. Toxicol. Sci. 66, 16–26. Kamali, F., 1993. The effect of probenecid on paracetamol metabolism and pharmacokinetics. Eur. J. Clin. Pharmacol. 45, 551–553. Kartenbeck, J., Leuschner, U., Mayer, R., Keppler, D., 1996. Absence of the canalicular isoform of the mrp gene-encoded conjugate export pump from the hepatocytes in Dubin–Johnson syndrome. Hepatology 23, 1061–1066. Kato, Y., Suzuki, H., Sugiyama, Y., 2002. Toxicological implications of hepatobiliary transporters. Toxicology 181–182, 287–290. Kawai, K., Kawasaki-Tokui, Y., Odaka, T., Tsuruta, F., Kazui, M., Iwabuchi, H., Nakamura, T., Kinoshita, T., Ikeda, T., Yoshioka, T., Komai, T., Nakamura, K., 1997. Disposition and metabolism of the new oral antidiabetic drug troglitazone in rats, mice and dogs. Arzneimittelforschung 47, 356–368. Keppler, D., Konig, J., 1997. Hepatic canalicular membrane 5: expression and localization of the conjugate export pump encoded by the mrp2 (cmrp/cmoat) gene in liver. FASEB J. 11, 509–516. Keppler, D., Konig, J., Buchler, M., 1997. The canalicular multidrug resistance protein, cmrp/mrp2, a novel conjugate export pump expressed in the apical membrane of hepatocytes. Adv. Enz. Regul. 37, 321–333. Kim, H.J., Rozman, P., Madhu, C., Klaassen, C.D., 1992. Homeostasis of sulfate and 3 -phosphoadenosine 5 -phosphosulfate in rats after acetaminophen administration. J. Pharmacol. Exp. Ther. 261, 1015–1021. Kitaura, K., Takikawa, H., Yamanaka, M., 1997. Effects of organic anions and bile acid conjugates on biliary excretion of ltc4 in the rat. Prostaglandins 54, 745–755. Klokouzas, A., Wu, C.P., van Veen, H.W., Barrand, M.A., Hladky, S.B., 2003. Cgmp and glutathione-conjugate transport in human erythrocytes. Eur. J. Biochem. 270, 3696–3708. Koeppel, T.A., Trauner, M., Mennone, A., Arrese, M., Rios-Velez, L., Boyer, J.L., 1998. Role of glutathione in hepatic bile formation during reperfusion after cold ischemia of the rat liver. J. Hepatol. 28, 812–819. Konig, J., Rost, D., Cui, Y., Keppler, D., 1999. Characterization of the human multidrug resistance protein isoform mrp3 localized to the basolateral hepatocyte membrane. Hepatology 29, 1156–1163. Kool, M., van der Linden, M., de Haas, M., Scheffer, G.L., de Vree, J.M., Smith, A.J., Jansen, G., Peters, G.J., Ponne, N., Scheper, R.J., Elferink, R.P., Baas, F., Borst, P., 1999. Mrp3, an organic anion transporter able to transport anti-cancer drugs. Proc. Natl. Acad. Sci. U.S.A. 96, 6914–6919. Kopplow, K., Letschert, K., Konig, J., Walter, B., Keppler, D., 2005. Human hepatobiliary transport of organic anions analyzed by quadruple-transfected cells. Mol. Pharmacol. 68, 1031–1038.
european journal of pharmaceutical sciences
Koster, H., Scholtens, E., Mulder, G.J., 1979. Inhibition of sulfation of phenols in vivo by 2,6-dichloro-4-nitrophenol: selectivity of its action in relation to other conjugations in the rat in vivo. Med. Biol. 57, 340–344. Koster, H., Halsema, I., Scholtens, E., Meerman, J.H., Pang, K.S., Mulder, G.J., 1982. Selective inhibition of sulfate conjugation in the rat: pharmacokinetics and characterization of the inhibitory effect of 2,6-dichloro-4-nitrophenol. Biochem. Pharmacol. 31, 1919–1924. Kostrubsky, V.E., Vore, M., Kindt, E., Burliegh, J., Rogers, K., Peter, G., Altrogge, D., Sinz, M.W., 2001. The effect of troglitazone biliary excretion on metabolite distribution and cholestasis in transporter-deficient rats. Drug Metab. Dispos. 29, 1561–1566. Kouzuki, H., Suzuki, H., Sugiyama, Y., 2000. Pharmacokinetic study of the hepatobiliary transport of indomethacin. Pharm. Res. 17, 432–438. Krajka-Kuzniak, V., Szaefer, H., Baer-Dubowska, W., 2004. Modulation of 3-methylcholanthrene-induced rat hepatic and renal cytochrome p450 and phase ii enzymes by plant phenols: protocatechuic and tannic acids. Toxicol. Lett. 152, 117–126. Krishnamurthy, P., Ross, D.D., Nakanishi, T., Bailey-Dell, K., Zhou, S., Mercer, K.E., Sarkadi, B., Sorrentino, B.P., Schuetz, J.D., 2004. The stem cell marker bcrp/abcg2 enhances hypoxic cell survival through interactions with heme. J. Biol. Chem. 279, 24218–24225. Kullak-Ublick, G.A., Stieger, B., Hagenbuch, B., Meier, P.J., 2000. Hepatic transport of bile salts. Semin. Liver Dis. 20, 273–292. Kuroda, M., Kobayashi, Y., Tanaka, Y., Itani, T., Mifuji, R., Araki, J., Kaito, M., Adachi, Y., 2004. Increased hepatic and renal expressions of multidrug resistance-associated protein 3 in eisai hyperbilirubinuria rats. J. Gastroenterol. Hepatol. 19, 146–153. Kusuhara, H., Suzuki, H., Sugiyama, Y., 1998a. The role of P-glycoprotein and canalicular multispecific organic anion transporter in the hepatobiliary excretion of drugs. J. Pharm. Sci. 87, 1025–1040. Kusuhara, H., Han, Y.H., Shimoda, M., Kokue, E., Suzuki, H., Sugiyama, Y., 1998b. Reduced folate derivatives are endogenous substrates for cmoat in rats. Am. J. Physiol. 275, G789–G790. Le, H.T., Franklin, M.R., 1997. Selective induction of phase ii drug metabolizing enzyme activities by quinolines and isoquinolines. Chem. Biol. Interact. 103, 167–178. LeCluyse, E.L., Bullock, P.L., Parkinson, A., Hochman, J.H., 1996. Cultured rat hepatocytes. Pharm. Biotechnol. 8, 121–159. Lee, Y.J., Kusuhara, H., Sugiyama, Y., 2004a. Do multidrug resistance-associated protein-1 and -2 play any role in the elimination of estradiol-17 beta-glucuronide and 2,4-dinitrophenyl-S-glutathione across the blood–cerebrospinal fluid barrier? J. Pharm. Sci. 93, 99–107. Lee, Y.M., Cui, Y., Konig, J., Risch, A., Jager, B., Drings, P., Bartsch, H., Keppler, D., Nies, A.T., 2004b. Identification and functional characterization of the natural variant mrp3-arg1297his of human multidrug resistance protein 3 (mrp3/abcc3). Pharmacogenetics 14, 213–223. Leslie, E.M., Ito, K., Upadhyaya, P., Hecht, S.S., Deeley, R.G., Cole, S.P., 2001. Transport of the beta-o-glucuronide conjugate of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (nnal) by the multidrug resistance protein 1 (mrp1). Requirement for glutathione or a non-sulfur-containing analog. J. Biol. Chem. 276, 27846–27854. Letourneau, I.J., Bowers, R.J., Deeley, R.G., Cole, S.P., 2005. Limited modulation of the transport activity of the human multidrug resistance proteins mrp1, mrp2 and mrp3 by nicotine glucuronide metabolites. Toxicol. Lett. 157, 9–19.
27
( 2 0 0 6 ) 447–486
481
Liu, G., Sanchez-Fernandez, R., Li, Z.S., Rea, P.A., 2001a. Enhanced multispecificity of arabidopsis vacuolar multidrug resistance-associated protein-type ATP-binding cassette transporter, atmrp2. J. Biol. Chem. 276, 8648–8656. Liu, J., Chen, H., Miller, D.S., Saavedra, J.E., Keefer, L.K., Johnson, D.R., Klaassen, C.D., Waalkes, M.P., 2001b. Overexpression of glutathione S-transferase ii and multidrug resistance transport proteins is associated with acquired tolerance to inorganic arsenic. Mol. Pharmacol. 60, 302–309. Liu, J.H., Smith, P.C., 2006. Predicting the pharmacokinetics of acyl glucuronides and their parent compounds in disease states. Curr. Drug Metab. 7. Liu, L., Klaassen, C.D., 1996. Regulation of hepatic sulfotransferases by steroidal chemicals in rats. Drug Metab. Dispos. 24, 854–858. Liu, X., Chism, J.P., LeCluyse, E.L., Brouwer, K.R., Brouwer, K.L., 1999a. Correlation of biliary excretion in sandwich-cultured rat hepatocytes and in vivo in rats. Drug Metab. Dispos. 27, 637–644. Liu, X., LeCluyse, E.L., Brouwer, K.R., Lightfoot, R.M., Lee, J.I., Brouwer, K.L., 1999b. Use of ca2+ modulation to evaluate biliary excretion in sandwich-cultured rat hepatocytes. J. Pharmacol. Exp. Ther. 289, 1592–1599. Liu, X., LeCluyse, E.L., Brouwer, K.R., Gan, L.S., Lemasters, J.J., Stieger, B., Meier, P.J., Brouwer, K.L., 1999c. Biliary excretion in primary rat hepatocytes cultured in a collagen-sandwich configuration. Am. J. Physiol. 277, G12–G21. Loeser, W., Siegers, C.P., 1985. Effects of phenobarbital, phorone and carbon tetrachloride pretreatment on the biliary excretion of acetaminophen in rats. Arch. Int. Pharmacodyn. Ther. 275, 180–188. Low, L.K., 1998. Metabolic changes of drugs and related organic compounds. In: Delgado, J.N., Remers, W.A. (Eds.), Wilson and gisvold’s textbook of organic medicinal and pharmaceutical chemistry. Lippincott-Raven, Philadelphia, pp. 43–122. Lu, S.C., Cai, J., Kuhlenkamp, J., Sun, W.M., Takikawa, H., Takenaka, O., Horie, T., Yi, J., Kaplowitz, N., 1996. Alterations in glutathione homeostasis in mutant eisai hyperbilirubinemic rats. Hepatology 24, 253–258. Madon, J., Eckhardt, U., Gerloff, T., Stieger, B., Meier, P.J., 1997. Functional expression of the rat liver canalicular isoform of the multidrug resistance-associated protein. FEBS Lett. 406, 75–78. Madon, J., Hagenbuch, B., Landmann, L., Meier, P.J., Stieger, B., 2000. Transport function and hepatocellular localization of mrp6 in rat liver. Mol. Pharmacol. 57, 634–641. Manautou, J.E., de Waart, D.R., Kunne, C., Zelcer, N., Goedken, M., Borst, P., Elferink, R.O., 2005. Altered disposition of acetaminophen in mice with a disruption of the mrp3 gene. Hepatology 42, 1091–1098. Markovich, D., 2001. Physiological roles and regulation of mammalian sulfate transporters. Physiol. Rev. 81, 1499–1533. Mason, J., Cardin, C.J., 1977. The competition of molybdate and sulphate ions for a transport system in the ovine small intestine. Res. Vet. Sci. 22, 313–315. Matsushima, S., Maeda, K., Kondo, C., Hirano, M., Sasaki, M., Suzuki, H., Sugiyama, Y., 2005. Identification of the hepatic efflux transporters of organic anions using double-transfected madin-darby canine kidney ii cells expressing human organic anion-transporting polypeptide 1b1 (oatp1b1)/multidrug resistance-associated protein 2, oatp1b1/multidrug resistance 1, and oatp1b1/breast cancer resistance protein. J. Pharmacol. Exp. Ther. 314, 1059–1067. Meerman, J.H., Sterenborg, H.M., Mulder, G.J., 1983. Use of pentachlorophenol as long-term inhibitor of sulfation of phenols and hydroxamic acids in the rat in vivo. Biochem. Pharmacol. 32, 1587–1593.
482
european journal of pharmaceutical sciences
Meier, P.J., 1995. Molecular mechanisms of hepatic bile salt transport from sinusoidal blood into bile. Am. J. Physiol. 269, G801–G812. Meijer, D.K.F., Smit, J.W., Muller, M., 1997. Hepatobiliary elimination of cationic drugs: the role of P-glycoprotein and other ATP-dependent transporters. Adv. Drug Del. Rev. 25, 159–200. Meisheri, K.D., Johnson, G.A., Puddington, L., 1993. Enzymatic and non-enzymatic sulfation mechanisms in the biological actions of minoxidil. Biochem. Pharmacol. 45, 271–279. Miyauchi, S., Sugiyama, Y., Iga, T., Hanano, M., 1988. Membrane-limited hepatic transport of the conjugative metabolites of 4-methylumbelliferone in rats. J. Pharm. Sci. 77, 688–692. Miyazaki, K., Takemoto, C., Satoh, T., Ueno, K., Igarashi, T., Kitagawa, H., 1983. Toxicity and biotransformation of acetaminophen in rat hepatocytes. (i). Uptake and release. Res. Commun. Chem. Pathol. Pharmacol. 39, 77–86. Mizuno, N., Suzuki, M., Kusuhara, H., Suzuki, H., Takeuchi, K., Niwa, T., Jonker, J.W., Sugiyama, Y., 2004. Impaired renal excretion of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (e3040) sulfate in breast cancer resistance protein (bcrp1/abcg2) knockout mice. Drug Metab. Dispos. 32, 898–901. Monaghan, G., Clarke, D.J., Povey, S., See, C.G., Boxer, M., Burchell, B., 1994. Isolation of a human yac contig encompassing a cluster of ugt2 genes and its regional localization to chromosome 4q13. Genomics 23, 496–499. Moran, T.D., Smith, P.A., 2002. Morphine-3beta-d-glucuronide suppresses inhibitory synaptic transmission in rat substantia gelatinosa. J. Pharmacol. Exp. Ther. 302, 568–576. Morgenstern, R., Lundqvist, G., Andersson, G., Balk, L., DePierre, J.W., 1984. The distribution of microsomal glutathione transferase among different organelles, different organs, and different organisms. Biochem. Pharmacol. 33, 3609–3614. Morikawa, A., Goto, Y., Suzuki, H., Hirohashi, T., Sugiyama, Y., 2000. Biliary excretion of 17beta-estradiol 17beta-d-glucuronide is predominantly mediated by cmoat/mrp2. Pharm. Res. 17, 546–552. Morris, M.E., Yuen, V., Tang, B.K., Pang, K.S., 1988. Competing pathways in drug metabolism. I. Effect of input concentration on the conjugation of gentisamide in the once-through in situ perfused rat liver preparation. J. Pharmacol. Exp. Ther. 245, 614–624. Mulder, G.J., Scholtens, E., 1978. The availability of inorganic sulphate in blood for sulphate conjugation of drugs in rat liver in vivo. (35s)sulphate incorporation into harmol sulphate. Biochem. J. 172, 247–251. Mulder, G.J., Hinson, J.A., Gillette, J.R., 1977. Generation of reactive metabolites of n-hydroxy-phenacetin by glucoronidation and sulfation. Biochem. Pharmacol. 26, 189–196. Murata, M., Tamai, I., Sai, Y., Nagata, O., Kato, H., Sugiyama, Y., Tsuji, A., 1998. Hepatobiliary transport kinetics of hsr-903, a new quinolone antibacterial agent. Drug Metab. Dispos. 26, 1113–1119. Naderer, O.J., Dupuis, R.E., Heinzen, E.L., Wiwattanawongsa, K., Johnson, M.W., Smith, P.C., 2005. The influence of norfloxacin and metronidazole on the disposition of mycophenolate mofetil. J. Clin. Pharmacol. 45, 219–226. Nagata, K., Ozawa, S., Miyata, M., Shimada, M., Gong, D.W., Yamazoe, Y., Kato, R., 1993. Isolation and expression of a cdna encoding a male-specific rat sulfotransferase that catalyzes activation of n-hydroxy-2-acetylaminofluorene. J. Biol. Chem. 268, 24720–24725. Nakatomi, K., Yoshikawa, M., Oka, M., Ikegami, Y., Hayasaka, S., Sano, K., Shiozawa, K., Kawabata, S., Soda, H., Ishikawa, T.,
27
( 2 0 0 6 ) 447–486
Tanabe, S., Kohno, S., 2001. Transport of 7-ethyl-10-hydroxycamptothecin (sn-38) by breast cancer resistance protein abcg2 in human lung cancer cells. Biochem. Biophys. Res. Commun. 288, 827–832. Niinuma, K., Takenaka, O., Horie, T., Kobayashi, K., Kato, Y., Suzuki, H., Sugiyama, Y., 1997. Kinetic analysis of the primary active transport of conjugated metabolites across the bile canalicular membrane: comparative study of S-(2,4-dinitrophenyl)-glutathione and 6-hydroxy-5,7dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole glucuronide. J. Pharmacol. Exp. Ther. 282, 866–872. Ninomiya, M., Ito, K., Horie, T., 2005. Functional analysis of dog multidrug resistance-associated protein 2 (mrp2) in comparison with rat mrp2. Drug Metab. Dispos. 33, 225–232. Nishida, T., Hardenbrook, C., Gatmaitan, Z., Arias, I.M., 1992a. ATP-dependent organic anion transport system in normal and TR− rat liver canalicular membranes. Am. J. Physiol. 262, G629–G635. Nishida, T., Gatmaitan, Z., Roy-Chowdhry, J., Arias, I.M., 1992b. Two distinct mechanisms for bilirubin glucuronide transport by rat bile canalicular membrane vesicles. Demonstration of defective ATP-dependent transport in rats (tr−) with inherited conjugated hyperbilirubinemia. J. Clin. Invest. 90, 2130–2135. Nishino, A., Kato, Y., Igarashi, T., Sugiyama, Y., 2000. Both cmoat/mrp2 and another unknown transporter(s) are responsible for the biliary excretion of glucuronide conjugate of the non-peptide angiotensin ii antagonist, telmisaltan. Drug Metab. Dispos. 28, 1146–1148. Ogasawara, T., Takikawa, H., 2001. Biliary excretion of phenolphthalein glucuronide in the rat. Hepatol. Res. 20, 221–231. Ogawa, K., Suzuki, H., Hirohashi, T., Ishikawa, T., Meier, P.J., Hirose, K., Akizawa, T., Yoshioka, M., Sugiyama, Y., 2000. Characterization of inducible nature of mrp3 in rat liver. Am. J. Physiol. Gastrointest. Liver Physiol. 278, G438–G440. Oguro, T., Gregus, Z., Madhu, C., Liu, L., Klaassen, C.D., 1994. Molybdate depletes hepatic 3-phosphoadenosine 5-phosphosulfate and impairs the sulfation of acetaminophen in rats. J. Pharmacol. Exp. Ther. 270, 1145–1151. Otterness, D.M., Wieben, E.D., Wood, T.C., Watson, W.G., Madden, B.J., McCormick, D.J., Weinshilboum, R.M., 1992. Human liver dehydroepiandrosterone sulfotransferase: molecular cloning and expression of cdna. Mol. Pharmacol. 41, 865–872. Oude Elferink, R.P., Jansen, P.L., 1994. The role of the canalicular multispecific organic anion transporter in the disposal of endo- and xenobiotics. Pharmacol. Ther. 64, 77–97. Oude Elferink, R.P., de Haan, J., Lambert, K.J., Hagey, L.R., Hofmann, A.F., Jansen, P.L., 1989. Selective hepatobiliary transport of nordeoxycholate side chain conjugates in mutant rats with a canalicular transport defect. Hepatology 9, 861–865. Oude Elferink, R.P., Ottenhoff, R., Liefting, W.G., Schoemaker, B., Groen, A.K., Jansen, P.L., 1990. ATP-dependent efflux of gssg and gs-conjugate from isolated rat hepatocytes. Am. J. Physiol. 258, G699–G706. Pang, K.S., Terrell, J.A., 1981. Retrograde perfusion to probe the heterogeneous distribution of hepatic drug metabolizing enzymes in rats. J. Pharmacol. Exp. Ther. 216, 339–346. Pang, K.S., Schwab, A.J., Goresky, C.A., Chiba, M., 1994. Transport, binding, and metabolism of sulfate conjugates in the liver. Chem. Biol. Interact. 92, 179–207. Pang, K.S., Koster, H., Halsema, I.C., Scholtens, E., Mulder, G.J., 1981. Aberrant pharmacokinetics of harmol in the perfused rat liver preparation: sulfate and glucuronide conjugations. J. Pharmacol. Exp. Ther. 219, 134–140.
european journal of pharmaceutical sciences
Pang, K.S., Koster, H., Halsema, I.C., Scholtens, E., Mulder, G.J., Stillwell, R.N., 1983. Normal and retrograde perfusion to probe the zonal distribution of sulfation and glucuronidation activities of harmol in the perfused rat liver preparation. J. Pharmacol. Exp. Ther. 224, 647–653. Parkinson, A., 2001. Biotransformation of xenobiotics. In: Klaassen, C.D., Thomas, M.J., Hazucha, M.J. (Eds.), Casarett and Doull’s Toxicology: The Basic Science of Poisons. McGraw-Hill Medical Publishing Division, New York, pp. 113–186. Patel, N.J., Zamek-Gliszczynski, M.J., Zhang, P., Han, Y.H., Jansen, P.L., Meier, P.J., Stieger, B., Brouwer, K.L., 2003. Phenobarbital alters hepatic mrp2 function by direct and indirect interactions. Mol. Pharmacol. 64, 154–159. Patten, E.J., DeLong, M.J., 1999. Effects of sulindac, sulindac metabolites, and aspirin on the activity of detoxification enzymes in ht-29 human colon adenocarcinoma cells. Cancer Lett. 147, 95–100. Paulusma, C.C., van Geer, M.A., Evers, R., Heijn, M., Ottenhoff, R., Borst, P., Oude Elferink, R.P., 1999. Canalicular multispecific organic anion transporter/multidrug resistance protein 2 mediates low-affinity transport of reduced glutathione. Biochem. J. 338 (Pt 2), 393–401. Paulusma, C.C., Kool, M., Bosma, P.J., Scheffer, G.L., ter Borg, F., Scheper, R.J., Tytgat, G.N., Borst, P., Baas, F., Oude Elferink, R.P., 1997. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin–Johnson syndrome. Hepatology 25, 1539–1542. Paumi, C.M., Wright, M., Townsend, A.J., Morrow, C.S., 2003. Multidrug resistance protein (mrp) 1 and mrp3 attenuate cytotoxic and transactivating effects of the cyclopentenone prostaglandin, 15-deoxy-delta(12,14)prostaglandin j2 in mcf7 breast cancer cells. Biochemistry 42, 5429–5437. Prochaska, H.J., Talalay, P., 1988. Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver. Cancer Res. 48, 4776–4782. Radominska, A., Comer, K.A., Zimniak, P., Falany, J., Iscan, M., Falany, C.N., 1990. Human liver steroid sulphotransferase sulphates bile acids. Biochem. J. 272, 597–604. Radominska-Pandya, A., Czernik, P.J., Little, J.M., Battaglia, E., Mackenzie, P.I., 1999. Structural and functional studies of UDP-glucuronosyltransferases. Drug Metab. Rev. 31, 817–899. Rae, J.M., Johnson, M.D., Lippman, M.E., Flockhart, D.A., 2001. Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cdna and oligonucleotide expression arrays. J. Pharmacol. Exp. Ther. 299, 849–857. Ratna, S., Chiba, M., Bandyopadhyay, L., Pang, K.S., 1993. Futile cycling between 4-methylumbelliferone and its conjugates in perfused rat liver. Hepatology 17, 838–853. Raub, T.J., Irizarry, A., Gao, H., Ryan, T.P., 2005. In: Brouwer, K.L.R., Zamek-Gliszczynski, M.J., Nezasa, K., Tian, X. (Eds.), Pathology of Acetaminophen-treated Wild-type and abcc2−/− mice. Indianapolis, IN. Rendic, S., Di Carlo, F.J., 1997. Human cytochrome p450 enzymes: a status report summmarizing their reactions, substrates, inducers, and inhibitors. Drug Metab. Rev. 29, 413–580. Reuter, S., Mayer, D., 1995. Transport of dehydroepiandrosterone and dehydroepiandrosterone sulphate into rat hepatocytes. J. Steroid Biochem. Mol. Biol. 54, 227–235. Ritter, J.K., Chen, F., Sheen, Y.Y., Tran, H.M., Kimura, S., Yeatman, M.T., Owens, I.S., 1992. A novel complex locus ugt1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini. J. Biol. Chem. 267, 3257–3261. Rius, M., Nies, A.T., Hummel-Eisenbeiss, J., Jedlitschky, G., Keppler, D., 2003. Cotransport of reduced glutathione with
27
( 2 0 0 6 ) 447–486
483
bile salts by mrp4 (abcc4) localized to the basolateral hepatocyte membrane. Hepatology 38, 374–384. Roberts, M.S., Magnusson, B.M., Burczynski, F.J., Weiss, M., 2002. Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin. Pharmacokinet. 41, 751–790. Romberg, R., Olofsen, E., Sarton, E., den Hartigh, J., Taschner, P.E., Dahan, A., 2004. Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences. Anesthesiology 100, 120–133. Runge-Morris, M., Rose, K., Kocarek, T.A., 1996. Regulation of rat hepatic sulfotransferase gene expression by glucocorticoid hormones. Drug Metab. Dispos. 24, 1095– 1101. Runge-Morris, M., Wu, W., Kocarek, T.A., 1999. Regulation of rat hepatic hydroxysteroid sulfotransferase (sult2-40/41) gene expression by glucocorticoids: evidence for a dual mechanism of transcriptional control. Mol. Pharmacol. 56, 1198–1206. Runge-Morris, M., Rose, K., Falany, C.N., Kocarek, T.A., 1998. Differential regulation of individual sulfotransferase isoforms by phenobarbital in male rat liver. Drug Metab. Dispos. 26, 795–801. Rushmore, T.H., Pickett, C.B., 1990. Transcriptional regulation of the rat glutathione S-transferase ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. J. Biol. Chem. 265, 14648–14653. Said, M., Noort, D., Magdalou, J., Ziegler, J.C., van der Marel, G.A., van Boom, J.H., Mulder, G.J., Siest, G., 1992. Selective and potent inhibition of different hepatic UDP-glucuronosyltransferase activities by omega, omega, omega-triphenylalcohols and UDP derivatives. Biochem. Biophys. Res. Commun. 187, 140–145. Sampath, J., Adachi, M., Hatse, S., Naesens, L., Balzarini, J., Flatley, R.M., Matherly, L.H., Schuetz, J.D., 2002. Role of mrp4 and mrp5 in biology and chemotherapy. AAPS Pharm. Sci. 4, E14. Sano, N., Takikawa, H., Yamanaka, M., 1993. Estradiol-17 beta-glucuronide-induced cholestasis. Effects of ursodeoxycholate-3-o-glucuronide and 3,7-disulfate. J. Hepatol. 17, 241–246. Sasabe, H., Tsuji, A., Sugiyama, Y., 1998. Carrier-mediated mechanism for the biliary excretion of the quinolone antibiotic grepafloxacin and its glucuronide in rats. J. Pharmacol. Exp. Ther. 284, 1033–1039. Sasaki, M., Suzuki, H., Ito, K., Abe, T., Sugiyama, Y., 2002. Transcellular transport of organic anions across a double-transfected madin-darby canine kidney ii cell monolayer expressing both human organic anion-transporting polypeptide (oatp2/slc21a6) and multidrug resistance-associated protein 2 (mrp2/abcc2). J. Biol. Chem. 277, 6497–6503. Sasaki, M., Suzuki, H., Aoki, J., Ito, K., Meier, P.J., Sugiyama, Y., 2004. Prediction of in vivo biliary clearance from the in vitro transcellular transport of organic anions across a double-transfected madin-darby canine kidney ii monolayer expressing both rat organic anion transporting polypeptide 4 and multidrug resistance associated protein 2. Mol. Pharmacol. 66, 450–459. Savina, P.M., Brouwer, K.L., 1992. Probenecid-impaired biliary excretion of acetaminophen glucuronide and sulfate in the rat. Drug Metab. Dispos. 20, 496–501. Scheffer, G.L., Hu, X., Pijnenborg, A.C., Wijnholds, J., Bergen, A.A., Scheper, R.J., 2002. Mrp6 (abcc6) detection in normal human tissues and tumors. Lab Invest. 82, 515–518. Schneider, E.G., Durham, J.C., Sacktor, B., 1984. Sodium-dependent transport of inorganic sulfate by rabbit
484
european journal of pharmaceutical sciences
renal brush-border membrane vesicles. Effects of other ions. J. Biol. Chem. 259, 14591–14599. Schuetz, E.G., Strom, S., Yasuda, K., Lecureur, V., Assem, M., Brimer, C., Lamba, J., Kim, R.B., Ramachandran, V., Komoroski, B.J., Venkataramanan, R., Cai, H., Sinal, C.J., Gonzalez, F.J., Schuetz, J.D., 2001. Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome p450. J. Biol. Chem. 276, 39411–39418. Seah, V.M., Wong, K.P., 1994. 2,6-dichloro-4-nitrophenol (dcnp), an alternate-substrate inhibitor of phenolsulfotransferase. Biochem. Pharmacol. 47, 1743–1749. Seitz, S., Kretz-Rommel, A., Oude Elferink, R.P., Boelsterli, U.A., 1998. Selective protein adduct formation of diclofenac glucuronide is critically dependent on the rat canalicular conjugate export pump (mrp2). Chem. Res. Toxicol. 11, 513–519. Shibayama, Y., Ikeda, R., Motoya, T., Yamada, K., 2004. St. John’s wort (hypericum perforatum) induces overexpression of multidrug resistance protein 2 (mrp2) in rats: a 30-day ingestion study. Food Chem. Toxicol. 42, 995–1002. Shimamura, H., Suzuki, H., Tagaya, O., Horie, T., Sugiyama, Y., 1996. Biliary excretion of glycyrrhizin in rats: kinetic basis for multiplicity in bile canalicular transport of organic anions. Pharm. Res. 13, 1833–1837. Silverman, J.A., Schrenk, D., 1997. Hepatic canalicular membrane. 4. Expression of the multidrug resistance genes in the liver. FASEB J. 11, 308–313. Singer, S.S., Ansel, A.Z., Van Brunt, N., Torres, J., Galaska, E.G., 1984. Enzymatic sulfation of steroids–xx. Effects of ten drugs on the hepatic glucocorticoid sulfotransferase activity of rats in vitro and in vivo. Biochem. Pharmacol. 33, 3485–3490. Slattery, J.T., Levy, G., 1979. Acetaminophen kinetics in acutely poisoned patients. Clin. Pharmacol. Ther. 25, 184–195. Slitt, A.L., Cherrington, N.J., Maher, J.M., Klaassen, C.D., 2003. Induction of multidrug resistance protein 3 in rat liver is associated with altered vectorial excretion of acetaminophen metabolites. Drug Metab. Dispos. 31, 1176–1186. Smith, A.J., van Helvoort, A., van Meer, G., Szabo, K., Welker, E., Szakacs, G., Varadi, A., Sarkadi, B., Borst, P., 2000. Mdr3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J. Biol. Chem. 275, 23530–23539. Smith, M.T., 2003. Mechanisms of troglitazone hepatotoxicity. Chem. Res. Toxicol. 16, 679–687. Smith, P.C., Benet, L.Z., McDonagh, A.F., 1990a. Covalent binding of zomepirac glucuronide to proteins: evidence for a schiff base mechanism. Drug Metab. Dispos. 18, 639–644. Smith, P.C., McDonagh, A.F., Benet, L.Z., 1990b. Effect of esterase inhibition on the disposition of zomepirac glucuronide and its covalent binding to plasma proteins in the guinea pig. J. Pharmacol. Exp. Ther. 252, 218–224. Smith, P.C., Langendijk, P.N., Bosso, J.A., Benet, L.Z., 1985. Effect of probenecid on the formation and elimination of acyl glucuronides: studies with zomepirac. Clin. Pharmacol. Ther. 38, 121–127. Soars, M.G., Ring, B.J., Wrighton, S.A., 2003. The effect of incubation conditions on the enzyme kinetics of UDP-glucuronosyltransferases. Drug Metab. Dispos. 31, 762–767. Sonoda, J., Xie, W., Rosenfeld, J.M., Barwick, J.L., Guzelian, P.S., Evans, R.M., 2002. Regulation of a xenobiotic sulfonation cascade by nuclear pregnane x receptor (pxr). Proc. Natl. Acad. Sci. U.S.A. 99, 13801–13806. Soroka, C.J., Lee, J.M., Azzaroli, F., Boyer, J.L., 2001. Cellular localization and up-regulation of multidrug
27
( 2 0 0 6 ) 447–486
resistance-associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver. Hepatology 33, 783–791. Spahn-Langguth, H., Benet, L.Z., 1992. Acyl glucuronides revisited: is the glucuronidation process a toxification as well as a detoxification mechanism? Drug Metab. Rev. 24, 5–47. Spears, K.J., Ross, J., Stenhouse, A., Ward, C.J., Goh, L.B., Wolf, C.R., Morgan, P., Ayrton, A., Friedberg, T.H., 2005. Directional trans-epithelial transport of organic anions in porcine llc-pk1 cells that co-express human oatp1b1 (oatp-c) and mrp2. Biochem. Pharmacol. 69, 415–423. Stieger, B., Fattinger, K., Madon, J., Kullak-Ublick, G.A., Meier, P.J., 2000. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (bsep) of rat liver. Gastroenterology 118, 422–430. Strautnieks, S.S., Bull, L.N., Knisely, A.S., Kocoshis, S.A., Dahl, N., Arnell, H., Sokal, E., Dahan, K., Childs, S., Ling, V., Tanner, M.S., Kagalwalla, A.F., Nemeth, A., Pawlowska, J., Baker, A., Mieli-Vergani, G., Freimer, N.B., Gardiner, R.M., Thompson, R.J., 1998. A gene encoding a liver-specific abc transporter is mutated in progressive familial intrahepatic cholestasis. Nat. Genet. 20, 233–238. Strott, C.A., 2002. Sulfonation and molecular action. Endocr Rev. 23, 703–732. Sugatani, J., Nishitani, S., Yamakawa, K., Yoshinari, K., Sueyoshi, T., Negishi, M., Miwa, M., 2005. Transcriptional regulation of human ugt1a1 gene expression: activated glucocorticoid receptor enhances constitutive androstane receptor/pregnane × receptor-mediated UDP-glucuronosyltransferase 1a1 regulation with glucocorticoid receptor-interacting protein 1. Mol. Pharmacol. 67, 845–855. Sugatani, J., Kojima, H., Ueda, A., Kakizaki, S., Yoshinari, K., Gong, Q.H., Owens, I.S., Negishi, M., Sueyoshi, T., 2001. The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase ugt1a1 gene and regulation by the nuclear receptor car. Hepatology 33, 1232–1238. Sugawara, N., Lai, Y., Yuasa, M., Dhar, S.K., Arizono, K., 1996. Biliary excretion of copper, manganese, and horseradish peroxidase in eisai hyperbilirubinemic mutant rats (ehbrs) with defective biliary excretion of glutathione. Biol. Trace Elem. Res. 55, 181–189. Sugiyama, D., Kusuhara, H., Shitara, Y., Abe, T., Meier, P.J., Sekine, T., Endou, H., Suzuki, H., Sugiyama, Y., 2001. Characterization of the efflux transport of 17beta-estradiol-d-17beta-glucuronide from the brain across the blood–brain barrier. J. Pharmacol. Exp. Ther. 298, 316–322. Suzuki, M., Suzuki, H., Sugimoto, Y., Sugiyama, Y., 2003. Abcg2 transports sulfated conjugates of steroids and xenobiotics. J. Biol. Chem. 278, 22644–22649. Sweeny, D.J., Reinke, L.A., 1988. Sulfation of acetaminophen in isolated rat hepatocytes. Relationship to sulfate ion concentrations and intracellular levels of 3 -phosphoadenosine-5 -phosphosulfate. Drug Metab. Dispos. 16, 712–715. Takada, T., Weiss, H.M., Kretz, O., Gross, G., Sugiyama, Y., 2004. Hepatic transport of pki166, an epidermal growth factor receptor kinase inhibitor of the pyrrolo-pyrimidine class, and its main metabolite, acu154. Drug Metab. Dispos. 32, 1272–1278. Takenaka, O., Horie, T., Suzuki, H., Sugiyama, Y., 1995a. Different biliary excretion systems for glucuronide and sulfate of a model compound; study using eisai hyperbilirubinemic rats. J. Pharmacol. Exp. Ther. 274, 1362–1369.
european journal of pharmaceutical sciences
Takenaka, O., Horie, T., Kobayashi, K., Suzuki, H., Sugiyama, Y., 1995b. Kinetic analysis of hepatobiliary transport for conjugated metabolites in the perfused liver of mutant rats (ehbr) with hereditary conjugated hyperbilirubinemia. Pharm. Res. 12, 1746–1755. Takikawa, H., Sano, N., Minagawa, K., Yamanaka, M., 1992. Effects of ursodeoxycholate, its glucuronide and disulfate and beta-muricholate on biliary bicarbonate concentration and biliary lipid excretion. J. Hepatol. 15, 77–84. Takikawa, H., Minagawa, K., Sano, N., Yamanaka, M., 1993. Lithocholate-3-o-glucuronide-induced cholestasis. A study with congenital hyperbilirubinemic rats and effects of ursodeoxycholate conjugates. Dig. Dis. Sci. 38, 1543–1548. Takikawa, H., Yamazaki, R., Sano, N., Yamanaka, M., 1996. Biliary excretion of estradiol-17 beta-glucuronide in the rat. Hepatology 23, 607–613. Takikawa, H., Sano, N., Ogasawara, T., Yamanaka, M., 1998. Enhanced biliary excretion of lithocholate-3-sulfate by ursodeoxycholate-3,7-disulfate infusion in eisai hyperbilirubinemic rat (ehbr). Dig. Dis. Sci. 43, 188–192. Takikawa, H., Nishikawa, K., Sano, N., Yamanaka, M., Horie, T., 1995. Mechanisms of biliary excretion of lithocholate-3-sulfate in eisai hyperbilirubinemic rats (ehbr). Dig. Dis. Sci. 40, 1792–1797. Takikawa, H., Sano, N., Narita, T., Uchida, Y., Yamanaka, M., Horie, T., Mikami, T., Tagaya, O., 1991. Biliary excretion of bile acid conjugates in a hyperbilirubinemic mutant Sprague-Dawley rat. Hepatology 14, 352–360. Tan, E., Pang, K.S., 2001. Sulfation is rate limiting in the futile cycling between estrone and estrone sulfate in enriched periportal and perivenous rat hepatocytes. Drug Metab. Dispos. 29, 335–346. Tanaka, H., Sano, N., Takikawa, H., 2003. Biliary excretion of phenolphthalein sulfate in rats. Pharmacology 68, 177–182. Tanaka, Y., Kobayashi, Y., Gabazza, E.C., Higuchi, K., Kamisako, T., Kuroda, M., Takeuchi, K., Iwasa, M., Kaito, M., Adachi, Y., 2002. Increased renal expression of bilirubin glucuronide transporters in a rat model of obstructive jaundice. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G656–G660. Thompson, R., Strautnieks, S., 2000. Inherited disorders of transport in the liver. Curr. Opin. Genet. Dev. 10, 310–313. Tosh, D., Borthwick, E.B., Sharp, S., Burchell, A., Burchell, B., Coughtrie, M.W., 1996. Heterogeneous expression of sulphotransferases in periportal and perivenous hepatocytes prepared from male and female rat liver. Biochem. Pharmacol. 51, 369–374. Tukey, R.H., Strassburg, C.P., 2000. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu. Rev. Pharmacol. Toxicol. 40, 581–616. Tukey, R.H., Strassburg, C.P., 2001. Genetic multiplicity of the human UDP-glucuronosyltransferases and regulation in the gastrointestinal tract. Mol. Pharmacol. 59, 405–414. Turner, K.C., Brouwer, K.L., 1997. In vitro mechanisms of probenecid-associated alterations in acetaminophen glucuronide hepatic disposition. Drug Metab. Dispos. 25, 1017–1021. van Aubel, R.A., Koenderink, J.B., Peters, J.G., Van Os, C.H., Russel, F.G., 1999. Mechanisms and interaction of vinblastine and reduced glutathione transport in membrane vesicles by the rabbit multidrug resistance protein mrp2 expressed in insect cells. Mol. Pharmacol. 56, 714–719. van Aubel, R.A., Smeets, P.H., Peters, J.G., Bindels, R.J., Russel, F.G., 2002. The mrp4/abcc4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary camp and cgmp. J. Am. Soc. Nephrol. 13, 595–603. van Aubel, R.A., van Kuijck, M.A., Koenderink, J.B., Deen, P.M., van Os, C.H., Russel, F.G., 1998. Adenosine
27
( 2 0 0 6 ) 447–486
485
triphosphate-dependent transport of anionic conjugates by the rabbit multidrug resistance-associated protein mrp2 expressed in insect cells. Mol. Pharmacol. 53, 1062–1067. Wacher, V.J., Salphati, L., Benet, L.Z., 2001. Active secretion and enterocytic drug metabolism barriers to drug absorption. Adv. Drug Deliv. Rev. 46, 89–102. Watkins, J.B., Klaassen, C.D., 1982. Effect of inducers and inhibitors of glucuronidation on the biliary excretion and choleretic action of valproic acid in the rat. J. Pharmacol. Exp. Ther. 220, 305–310. Wei, P., Zhang, J., Egan-Hafley, M., Liang, S., Moore, D.D., 2000. The nuclear receptor car mediates specific xenobiotic induction of drug metabolism. Nature 407, 920–923. Weinshilboum, R.M., Otterness, D.M., Aksoy, I.A., Wood, T.C., Her, C., Raftogianis, R.B., 1997. Sulfation and sulfotransferases. 1. Sulfotransferase molecular biology: Cdnas and genes. FASEB J. 11, 3–14. Wielinga, P.R., van der Heijden, I., Reid, G., Beijnen, J.H., Wijnholds, J., Borst, P., 2003. Characterization of the mrp4and mrp5-mediated transport of cyclic nucleotides from intact cells. J. Biol. Chem. 278, 17664–17671. Wijnholds, J., Mol, C.A., van Deemter, L., de Haas, M., Scheffer, G.L., Baas, F., Beijnen, J.H., Scheper, R.J., Hatse, S., De Clercq, E., Balzarini, J., Borst, P., 2000. Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc. Natl. Acad. Sci. U.S.A. 97, 7476–7481. Williams, J.A., Stone, E.M., Fakis, G., Johnson, N., Cordell, J.A., Meinl, W., Glatt, H., Sim, E., Phillips, D.H., 2001. N-acetyltransferases, sulfotransferases and heterocyclic amine activation in the breast. Pharmacogenetics 11, 373–388. Williams, J.A., Hyland, R., Jones, B.C., Smith, D.A., Hurst, S., Goosen, T.C., Peterkin, V., Koup, J.R., Ball, S.E., 2004. Drug–drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (auci/auc) ratios. Drug Metab. Dispos. 32, 1201–1208. Wittenburg, H., Carey, M.C., 2002. Biliary cholesterol secretion by the twinned sterol half-transporters abcg5 and abcg8. J. Clin. Invest. 110, 605–609. Wood, T.C., Aksoy, I.A., Aksoy, S., Weinshilboum, R.M., 1994. Human liver thermolabile phenol sulfotransferase: Cdna cloning, expression and characterization. Biochem. Biophys. Res. Commun. 198, 1119–1127. Wortelboer, H.M., Usta, M., van der Velde, A.E., Boersma, M.G., Spenkelink, B., van Zanden, J.J., Rietjens, I.M., van Bladeren, P.J., Cnubben, N.H., 2003. Interplay between mrp inhibition and metabolism of mrp inhibitors: the case of curcumin. Chem. Res. Toxicol. 16, 1642–1651. Wright, A.W., Dickinson, R.G., 2004. Abolition of valproate-derived choleresis in the mrp2 transporter-deficient rat. J. Pharmacol. Exp. Ther. 310, 584–588. Xia, C.Q., Liu, N., Yang, D., Miwa, G., Gan, L.S., 2005. Expression, localization, and functional characteristics of breast cancer resistance protein in caco-2 cells. Drug Metab. Dispos. 33, 637–643. Xie, W., Yeuh, M.F., Radominska-Pandya, A., Saini, S.P., Negishi, Y., Bottroff, B.S., Cabrera, G.Y., Tukey, R.H., Evans, R.M., 2003. Control of steroid, heme, and carcinogen metabolism by nuclear pregnane x receptor and constitutive androstane receptor. Proc. Natl. Acad. Sci. U.S.A. 100, 4150– 4155. Xiong, H., Yoshinari, K., Brouwer, K.L., Negishi, M., 2002a. Role of constitutive androstane receptor in the in vivo induction of mrp3 and cyp2b1/2 by phenobarbital. Drug Metab. Dispos. 30, 918–923.
486
european journal of pharmaceutical sciences
Xiong, H., Turner, K.C., Ward, E.S., Jansen, P.L., Brouwer, K.L., 2000. Altered hepatobiliary disposition of acetaminophen glucuronide in isolated perfused livers from multidrug resistance-associated protein 2-deficient tr(−) rats. J. Pharmacol. Exp. Ther. 295, 512–518. Xiong, H., Suzuki, H., Sugiyama, Y., Meier, P.J., Pollack, G.M., Brouwer, K.L., 2002b. Mechanisms of impaired biliary excretion of acetaminophen glucuronide after acute phenobarbital treatment or phenobarbital pretreatment. Drug Metab. Dispos. 30, 962–969. Xu, C., Li, C.Y., Kong, A.N., 2005. Induction of phase i, ii and iii drug metabolism/transport by xenobiotics. Arch. Pharm. Res. 28, 249–268. Yagi, Y., Shibutani, S., Hodoshima, N., Ishiwata, K., Okudaira, N., Li, Q., Sai, Y., Kato, Y., Tsuji, A., 2003. Involvement of multiple transport systems in the disposition of an active metabolite of a prodrug-type new quinolone antibiotic, prulifloxacin. Drug Metab. Pharmacokinet. 18, 381–389. Yamaguchi, Y., Hamaguchi, H., Yamada, S., Fujiwara, K., Higashio, K., Miyanari, N., Ichiguchi, O., Goto, M., Mori, K., Ogawa, M., 1997. Recombinant human hepatocyte growth factor facilitates biliary transport after hepatocyte transplantation in eisai hyperbilirubinemic rats. Dig. Dis. Sci. 42, 522–528. Yamashita, G., Tazuma, S., Horikawa, K., Aihara, N., Ochi, H., Teramen, K., Yamashita, Y., Sasaki, M., Ohya, T., Kajiyama, G., 1993. Partial characterization of mechanism(s) by which sulphobromophthalein reduces biliary lipid secretion. Biochem. J. 291 (Pt 1), 173–177. Yamazoe, Y., Manabe, S., Murayama, N., Kato, R., 1987. Regulation of hepatic sulfotransferase catalyzing the activation of n-hydroxyarylamide and n-hydroxyarylamine by growth hormone. Mol. Pharmacol. 32, 536–541. Yamazoe, Y., Nagata, K., Ozawa, S., Kato, R., 1994. Structural similarity and diversity of sulfotransferases. Chem. Biol. Interact. 92, 107–117. Yamazoe, Y., Gong, D., Murayama, N., Abu-Zeid, M., Kato, R., 1989. Regulation of hepatic cortisol sulfotransferase in rats by pituitary growth hormone. Mol. Pharmacol. 35, 707–712. Yanase, K., Tsukahara, S., Asada, S., Ishikawa, E., Imai, Y., Sugimoto, Y., 2004. Gefitinib reverses breast cancer resistance protein-mediated drug resistance. Mol. Cancer Ther. 3, 1119–1125. Yeh, S.Y., 1975. Urinary excretion of morphine and its metabolites in morphine-dependent subjects. J. Pharmacol. Exp. Ther. 192, 201–210. Yoshikawa, M., Ikegami, Y., Hayasaka, S., Ishii, K., Ito, A., Sano, K., Suzuki, T., Togawa, T., Yoshida, H., Soda, H., Oka, M., Kohno, S., Sawada, S., Ishikawa, T., Tanabe, S., 2004. Novel camptothecin analogues that circumvent abcg2-associated drug resistance in human tumor cells. Int. J. Cancer 110, 921–927. Zamek-Gliszczynski, M.J., Brouwer, K.L.R., 2004. In vitro models for estimating hepatobiliary clearance. In: Borchardt, R.T., Kerns, E.H., Lipinski, C.A., Thakker, D.R., Wang, B. (Eds.), Pharmaceutical Profiling in Drug Discovery for Lead Selection. AAPS Press, Arlington, VA, pp. 259–292. Zamek-Gliszczynski, M.J., Xiong, H., Patel, N.J., Turncliff, R.Z., Pollack, G.M., Brouwer, K.L.R., 2003. Pharmacokinetics of 5 (and 6)-carboxy-2 ,7 -dichlorofluorescein and its diacetate promoiety in the liver. J. Pharmacol. Exp. Ther. 304, 801– 809. Zamek-Gliszczynski, M.J., Hoffmaster, K.A., Nezasa, K., Tian, X., Brouwer, K.L.R., 2006a. Species differences in mechanisms of biliary excretion of harmol sulfate and glucuronide in rats and mice. Biochem. Pharmacol., submitted for publication.
27
( 2 0 0 6 ) 447–486
Zamek-Gliszczynski, M.J., Hoffmaster, K.A., Humphreys, J.E., Brouwer, K.L.R., 2006b. Differential involvement of mrp2 (abcc2) and bcrp1 (abcg2) in biliary excretion of 4-methylumbelliferyl glucuronide and sulfate in the rat. J. Pharmacol. Exp. Ther. 317, submitted for publication. Zamek-Gliszczynski, M.J., Nezasa, K., Tian, X., Kalvass, J.C., Patel, N.J., Raub, T.J., Brouwer, K.L.R., 2006c. Biliary excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in abcc2(−/−), abcg2(−/−), and mdr1a(−/−)/mdr1b(−/−) mice. Mol. Pharmacol. submitted for publication. Zamek-Gliszczynski, M.J., Nezasa, K., Tian, X., Bridges, A.S., Belinsky, M.G., Kruh, G.D., Brouwer, K.L.R., 2006d. Elucidation of the role of mrp3 and mrp4 in hepatic basolateral excretion of sulfate and glucuronide conjugates of acetaminophen, 4-methylumbelliferone, and harmol using abcc3(−/−) and abcc4(−/−) mice. Mol. Pharmacol, submitted for publication. Zamek-Gliszczynski, M.J., Hoffmaster, K.A., Tian, X., Zhao, R., Polli, J.W., Humphreys, J.E., Webster, L.O., Bridges, A.S., Kalvass, J.C., Brouwer, K.L., 2005. Multiple mechanisms are involved in the biliary excretion of acetaminophen sulfate in the rat: role of mrp2 and bcrp1. Drug Metab. Dispos. 33, 1158–1165. Zelcer, N., Saeki, T., Reid, G., Beijnen, J.H., Borst, P., 2001. Characterization of drug transport by the human multidrug resistance protein 3 (abcc3). J. Biol. Chem. 276, 46400–46407. Zelcer, N., Saeki, T., Bot, I., Kuil, A., Borst, P., 2003a. Transport of bile acids in multidrug-resistance-protein 3-overexpressing cells co-transfected with the ileal na+-dependent bile-acid transporter. Biochem. J. 369, 23–30. Zelcer, N., Reid, G., Wielinga, P., Kuil, A., van der Heijden, I., Schuetz, J.D., Borst, P., 2003b. Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (mrp) 4 (ATP-binding cassette c4). Biochem. J. 371, 361–367. Zelcer, N., Huisman, M.T., Reid, G., Wielinga, P., Breedveld, P., Kuil, A., Knipscheer, P., Schellens, J.H., Schinkel, A.H., Borst, P., 2003c. Evidence for two interacting ligand binding sites in human multidrug resistance protein 2 (ATP-binding cassette c2). J. Biol. Chem. 278, 23538–23544. Zelcer, N., van de Wetering, K., Hillebrand, M., Sarton, E., Kuil, A., Wielinga, P.R., Tephly, T., Dahan, A., Beijnen, J.H., Borst, P., 2005. Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Proc. Natl. Acad. Sci. U.S.A. 102, 7274–7279. Zeng, H., Liu, G., Rea, P.A., Kruh, G.D., 2000. Transport of amphipathic anions by human multidrug resistance protein 3. Cancer Res. 60, 4779–4784. Zhang, J., Ye, Z., Lou, Y., 2004. Metabolism of chlorambucil by rat liver microsomal glutathione S-transferase. Chem. Biol. Interact. 149, 61–67. Zhang, J., Ye, Z., Lou, Y., 2005. Metabolism of melphalan by rat liver microsomal glutathione S-transferase. Chem. Biol. Interact. 152, 101–106. Zhu, X., Veronese, M.E., Sansom, L.N., McManus, M.E., 1993a. Molecular characterisation of a human aryl sulfotransferase cdna. Biochem. Biophys. Res. Commun. 192, 671–676. Zhu, X., Veronese, M.E., Iocco, P., McManus, M.E., 1996. Cdna cloning and expression of a new form of human aryl sulfotransferase. Int. J. Biochem. Cell. Biol. 28, 565–571. Zhu, X., Veronese, M.E., Bernard, C.C., Sansom, L.N., McManus, M.E., 1993b. Identification of two human brain aryl sulfotransferase cdnas. Biochem. Biophys. Res. Commun. 195, 120–127.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/ejps
Review
Integration of hepatic drug transporters and phase II metabolizing enzymes: Mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites Maciej J. Zamek-Gliszczynski, Keith A. Hoffmaster, Ken-ichi Nezasa, Melanie N. Tallman, Kim L.R. Brouwer ∗ University of North Carolina at Chapel Hill, School of Pharmacy, Chapel Hill, NC 27599, USA
a r t i c l e
i n f o
a b s t r a c t
Article history:
The liver is the primary site of drug metabolism in the body. Typically, metabolic conversion
Received 4 November 2005
of a drug results in inactivation, detoxification, and enhanced likelihood for excretion in
Accepted 6 December 2005
urine or feces. Sulfation, glucuronidation, and glutathione conjugation represent the three most prevalent classes of phase II metabolism, which may occur directly on the parent compounds that contain appropriate structural motifs, or, as is usually the case, on func-
Keywords:
tional groups added or exposed by phase I oxidation. These three conjugation reactions
Phase II metabolism
increase the molecular weight and water solubility of the compound, in addition to adding
Transport
a negative charge to the molecule. As a result of these changes in the physicochemical
Sulfation
properties, phase II conjugates tend to have very poor membrane permeability, and neces-
Glucuronidation
sitate carrier-mediated transport for biliary or hepatic basolateral excretion into sinusoidal
Glutathione conjugation
blood for eventual excretion into urine. This review summarizes sulfation, glucuronida-
Multidrug resistance-associated
tion, and glutathione conjugation reactions, as well as recent progress in elucidating the
protein
hepatic transport mechanisms responsible for the excretion of these conjugates from the
Breast cancer resistance protein
liver. The discussion focuses on alterations of metabolism and transport by chemical mod-
Liver
ulators, and disease states, as well as pharmacodynamic and toxicological implications of hepatic metabolism and/or transport modulation for certain active phase II conjugates. A
Abbreviations:
brief discussion of issues that must be considered in the design and interpretation of phase
SULT, sulfotransferase; PST, phenol
II metabolite transport studies follows.
sulfotransferase; PAPS, phosphoadenosine phosphosulfate; UGT, uridine diphosphate-glucuronosyl transferase; UDP-GA, uridine diphosphate-glucuronic acid; GST, glutathione-S-transferase; Oat, organic anion transporter; Oatp, organic anion transporting polypeptide; Mrp, Abcc, multidrug
∗
Corresponding author. Tel.: +1 919 962 7030. E-mail address: [email protected] (K.L.R. Brouwer).
0928-0987/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2005.12.007
© 2006 Elsevier B.V. All rights reserved.
448
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
resistance-associated protein; Bcrp, Abcg2, breast cancer resistance protein; Mdr1, P-glycoprotein, P-gp, Abcb1, multidrug resistance protein 1; Bsep; Abcb11, bile salt export pump; Mdr2, Abcb4, MDR3 in humans, multidrug resistance protein 2; CAR, constitutive androstane receptor; CMVs, canalicular membrane vesicles
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.
Overview of phase II metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
449
2.1.
Sulfation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
449
2.2.
Glucuronidation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
450
2.3.
Glutathione conjugation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
451
Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
452
3.
4.
1.
448
3.1.
Basolateral (sinusoidal) excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
452
3.2.
Biliary excretion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
455
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
459
4.1.
Co-modulation examples. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
459
4.2.
Cholestasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
459
4.3.
Pharmacodynamic consequences. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
460
4.4.
Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
461
4.5.
Species differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
461
4.6.
Transporter multiplicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
464
4.7.
Model systems for studying hepatic excretion of sulfate, glucuronide, and glutathione conjugates . . . . . . . . . . . . . . . . . . . . . .
474
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
476
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
476
Introduction
The liver has long been recognized as the primary site of drug metabolism in the body. Drug metabolism is classified into phase I and phase II reactions. Phase I metabolism usually does not result in a large change in molecular weight or water solubility of the substrate, but is of great importance because oxidative reactions add or expose sites where phase II metabolism can subsequently occur. In contrast, phase II conjugation typically results in an appreciable increase in molecular weight and water solubility. Phase I reactions are mediated primarily by the cytochrome P450 family of microsomal enzymes, but others (e.g. flavin monooxygenases, peroxidases, amine oxidases, dehydrogenases, xanthine oxidases, etc.) also catalyze oxidation of certain functional groups (Low, 1998). Inhibition, induction, and polymorphisms of cytochrome P450 enzymes are an intense area of research, because this class of metabolic enzymes is responsible for the biotransformation of the majority of drugs, thus their modulation has important therapeutic and toxic implications (Evans and Johnson, 2001; Rendic and Di Carlo, 1997). Most compounds undergo phase I oxidation prior to phase II conjugation [e.g. phenobarbital (Crayford and Hutson, 1980)], but molecules with sites amenable to conjugation may undergo phase II reactions directly [e.g. acetaminophen (Gram and Gillette, 1971)]. Molecules that undergo direct phase II conjugation may also undergo competing (e.g. acetaminophen) or additional [e.g. troglitazone (Kawai et al., 1997)] phase I oxidation.
Unbound compounds in sinusoidal blood are taken up into hepatocytes typically by a transporter-mediated mechanism or by diffusion across the basolateral membrane, depending on molecular lipophilicity, charge, size, and three-dimensional structure. Substrates of phase II metabolism are typically lipophilic (e.g. acetaminophen, 4-methylumbelliferone, dehydroepiandrosterone) and access the intracellular space by diffusion (Iida et al., 1989; Miyauchi et al., 1988; Miyazaki et al., 1983; Reuter and Mayer, 1995). In contrast, phase II conjugates formed inside the hepatocyte are typically too hydrophilic to passively diffuse across the canalicular membrane into bile or across the hepatic basolateral membrane into sinusoidal blood, and necessitate carrier-mediated transport to cross this diffusional barrier. Distinct transport proteins are present in the apical (canalicular) and basolateral (sinusoidal) domains of the hepatocyte’s plasma membrane, where they efficiently pump substrates out of the cell. This review provides a summary of the three most relevant phase II drug conjugation reactions, sulfation, glucuronidation, and glutathione conjugation, as well as documented interactions between these metabolites and hepatic efflux transporters (both canalicular and basolateral). Discussion of key issues in the study of hepatic transport of conjugates follows, with special emphasis on examples of comodulation of phase II metabolism and transport, multiplicity of hepatic transport mechanisms, and choice of appropriate model systems for investigating the hepatic transport of conjugates.
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
2.
Overview of phase II metabolism
2.1.
Sulfation
Hepatic sulfation of xenobiotics is a common phase II metabolic mechanism for increasing molecular hydrophilicity in preparation for biliary excretion or efflux across the hepatic basolateral membrane for subsequent renal clearance. Xenobiotic detoxification may occur by direct sulfation of the parent compound [e.g. acetaminophen (Gram and Gillette, 1971)] or may follow phase I oxidation [e.g. hydroxyphenobarbital (Crayford and Hutson, 1980)]. However, hepatic xenobiotic sulfation also can lead to activation of hepatotoxins [e.g. phenacetin: covalent microsomal protein binding (Mulder et al., 1977); troglitazone: potent bile salt export pump inhibition leading to cholestasis (Funk et al., 2001)]; DNA-binding carcinogens [e.g. safrole (Boberg et al., 1983), tamoxifen (Glatt et al., 1998)], and prodrugs [e.g. minoxidil (Buhl et al., 1990)]. Sulfation is a high affinity and low capacity phase II reaction, which works in concert with glucuronidation on overlapping substrates; sulfation predominates at low substrate concentrations and glucuronidation at high substrate concentrations, when sulfation has been saturated (Pang et al., 1994). Since sulfation activity is higher in the periportal region of the liver, and glucuronidation in the perivenous region, saturation of sulfation results in a concave-up parabolic increase in glucuronidation rate, so that the combined rate of these two reactions is linear and hepatic extraction ratio constant, until glucuronidation is saturated at very high substrate concentrations (Morris et al., 1988; Pang and Terrell, 1981; Pang et al., 1981, 1983, 1994; Ratna et al., 1993). Conjugation of hydroxyl, but also amino, N-oxide, and sulfhydryl groups on xenobiotics and small endobiotics with sulfate occurs in the cytosol, while sulfation of carbohydrates attached to peptides or lipids, as well as proteins occurs in the Golgi network (Strott, 2002). Intracellular inorganic sulfate originates from hydrolysis of sulfoconjugates, oxidation of reduced organic sulfur, or uptake of sulfate from blood across the basolateral membrane (Markovich, 2001). In the cytosol, inorganic sulfate is conjugated with adenosine monophosphate by ATP sulfurylase to form adenosine 5 -phosphosulfate (APS), which is subsequently phosphorylated by APS kinase to form 3 -phosphoadenosine-5 -phosphosulfate (PAPS), the donor of sulfonate groups (SO3 − ) in all sulfate, or more correctly sulfonate, conjugation reactions (Low, 1998). Synthesis of PAPS is fast, but is limited by hepatic sulfate concentrations, which are largely dependent on equilibration with circulating inorganic sulfate (Hjelle et al., 1985; Kim et al., 1992; Mulder and Scholtens, 1978). In addition to the strong correlation between circulating inorganic sulfate and hepatic PAPS, changes in systemic sulfate concentrations result in similar changes in hepatic sulfate and PAPS levels, suggesting that uptake from blood and not hepatic biosynthesis is the major source of inorganic sulfate in the liver (Gregus et al., 1994a,b). Hepatic PAPS concentrations [∼80 (rat) and ∼23 (human) nmol/g liver, as compared with ∼400 (rat) and ∼300 (human) nmol/g liver uridine diphosphate-glucuronic acid (Cappiello et al., 1989, 1991; Hjelle et al., 1985)] are low enough to be depleted rapidly, and at substrate concentrations lower than those necessary to
449
achieve sulfotransferase maximal velocity (Hjelle et al., 1985; Kim et al., 1992). Hence, sulfation in many cases is a cofactorand not enzyme-limited reaction. However, many in vitro systems (e.g. single-pass isolated perfused liver and hepatocytes) inherently maintain a constant extrahepatic inorganic sulfate concentration, so that hepatic PAPS is not depleted and saturation of sulfation is caused by attainment of sulfotransferase maximal velocity (Pang et al., 1981; Sweeny and Reinke, 1988). The class of cytosolic sulfotransferase (SULT) enzymes is subdivided into three families: SULT1 [phenol sulfotransferase (PST) family], SULT2 [hydroxysteroid sulfotransferase (HST) family], and brain-specific SULT4 (Falany et al., 2000; Weinshilboum et al., 1997). The SULT1 family is further subdivided into four subfamilies: SULT1A (phenolic-type xenobiotics), SULT1B (dopa/tyrosine and thyroid hormones), SULT1C (hydroxyarylamines), and SULT1E (estrogens); while the SULT2 family is subdivided into two subfamilies: SULT2A (neutral steroids/bile acids) and SULT2B (sterols) (Her et al., 1998; Otterness et al., 1992; Strott, 2002; Yamazoe et al., 1994). Sulfation of xenobiotics is primarily mediated by the SULT1A subfamily, which catalyzes sulfation of hydroxyl groups and monoamine groups on phenolic-type molecules (Williams et al., 2001; Yamazoe et al., 1994); however, SULT1C also plays a role in xenobiotic sulfation by sulfating hydroxyarylamines, which can be activated into carcinogens by sulfation [e.g. Nhydroxy-2-acetylaminofluorene (Nagata et al., 1993)]. Humans express three isoforms of SULT1A: thermostable SULT1A1 and SULT1A2, which catalyze sulfation of hydroxyl groups on phenolic-type molecules (sometimes referred to as PPST1 and P-PST2), and thermolabile SULT1A3, which catalyzes sulfation of monoamine groups on aromatic molecules (MPST) (Wood et al., 1994; Zhu et al., 1993a,b, 1996). SULT2A is primarily responsible for conjugation of bile acids with sulfate (Falany et al., 1995; Radominska et al., 1990). It is important to note that while individual SULT isoenzymes have substrate preference, there is evidence of substrate overlap at the level of subfamilies and even families [e.g. SULT1A1 sulfates N-hydroxy-2-acetylaminofluorene, albeit at a lower rate than SULT1C1 (Nagata et al., 1993); the major soy isoflavone, genistein, is sulfated by SULT1A1, SULT1E, and SULT2A1, although the sulfation rate by SULT2 is three- to five-fold slower than that observed for SULT1 (Doerge et al., 2000)]. Although numerous functional studies in isolated perfused livers have proven conclusively and repeatedly that xenobiotic sulfation occurs primarily in the periportal region of the liver, Western blots from periportal and perivenous hepatocytes, as well as immunohistochemical analysis of liver sections, indicate that SULT1A is distributed fairly evenly throughout the liver (Tan and Pang, 2001; Tosh et al., 1996). These data suggest that zone-dependent xenobiotic sulfation cannot be explained by higher periportal SULT1A expression, but rather must be caused by more complex physiological phenomena. Despite SULTs being only weakly inducible, significant effort has been made in identifying the receptors and prototypical agents responsible for induction. Steroids, and especially glucocorticoids, induce SULTs in rats and humans (Duanmu et al., 2000; Liu and Klaassen, 1996; RungeMorris et al., 1996). In contrast, phenobarbital and 3-
450
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
methylcholanthrene alter mRNA levels of certain SULTs, but ultimately have no effect on SULT protein levels (Runge-Morris et al., 1998). Induction of SULT1A in rat occurs by glucocorticoid receptor activation, while SULT2A transcription appears to be controlled by both the glucocorticoid receptor and transcriptional factor(s) (Duanmu et al., 2001; Runge-Morris et al., 1999). Rat SULT1C and SULT2A function is increased by growth hormone, presumably due to upregulation of enzyme expression (Yamazoe et al., 1987; Yamazoe et al., 1989). Rat SULT2A transcription is effectively repressed by androgens through a mechanism involving the androgen receptor (Runge-Morris et al., 1999); however, effects of this repression on protein and functional activity remain to be demonstrated. Human SULT2A also is inducible by dexamethasone, but in contrast to rat, human SULT1A is unaffected by dexamethasone treatment (Duanmu et al., 2002). Activation of the pregnane X receptor is, at least in part, responsible for induction of SULT2A in rat, mouse, and human hepatocytes (Duanmu et al., 2002; Sonoda et al., 2002). The farnesoid X receptor also has been shown to control SULT2A transcription in rats (Sonoda et al., 2002), which may be of great physiological importance considering that this transcription factor is activated by bile acids (Duanmu et al., 2002), and SULT2A is responsible for bile acid sulfation (Radominska et al., 1990). However, effects of this transcription factor on protein and functional activity remain to be investigated. Lack of changes in protein levels following phenobarbital and 3-methylcholanthrene treatments suggest that constitutive androstane receptor and aryl hydrocarbon receptor are ultimately of little consequence to SULT protein levels and function (Radominska et al., 1990; Wei et al., 2000). Relative to cytochrome P450 enzymes, little is known about the transcriptional control of SULTs, especially the PSTs, which are most relevant to drug metabolism. This limited knowledge may be due to the cofactor-limited maximal velocity of sulfation and relatively moderate extent of SULT induction, usually two- to three-fold. SULTs are generally cofactor-limited in rats and humans, thus induction of SULTs is not expected to profoundly change the maximal velocity of sulfation (Galinsky and Levy, 1981; Kim et al., 1992; Slattery and Levy, 1979). However, under linear conditions, SULT induction causes increased sulfation rates in the cytosol (Liu and Klaassen, 1996; Sonoda et al., 2002), which has been demonstrated to result in significant pharmacodynamic changes in vivo (Duanmu et al., 2000). Inhibition of sulfation may be achieved by either inhibition of SULTs or depletion of PAPS. The commonly used SULT1 inhibitors, 2,6-dichloro-4-dinitrophenol and pentachlorophenol (both are mechanism-based inhibitors), do not significantly inhibit glucuronidation, glutathione conjugation, acetylation, or biliary excretion at low concentrations used for inhibition of sulfation. These inhibitors are eliminated slowly, and effectively inhibit sulfation, thus shifting the reaction from a cofactor- to an enzyme-limited process (Koster et al., 1979, 1982; Meerman et al., 1983; Seah and Wong, 1994; Singer et al., 1984). Molybdate (MoO4 2− ) competes with inorganic sulfate for transport into tissues and tubular reabsorption, as well as for ATP-sulfurylase, resulting in decreased sulfate and PAPS levels which leads to impaired sulfation (Bandurski et al., 1956; Mason and Cardin, 1977; Oguro et al., 1994; Schneider et al., 1984). It is important to note that sulfate
conjugation is reversible; sulfate conjugates may be desulfated in the liver by sulfatases, subsequently re-conjugated, deconjugated, etc., giving rise to the phenomenon of ‘futile cycling’ between the parent compound and sulfate metabolite (Pang et al., 1994).
2.2.
Glucuronidation
In many ways, glucuronidation complements sulfation, in that conjugation with glucuronic acid occurs on many of the same molecular moieties as sulfation, but is most prevalent at higher substrate concentrations, when sulfation has become saturated either due to co-substrate depletion or enzymesaturation. Like sulfate metabolites, glucuronides usually are inactivated detoxification products ready for biliary or urinary excretion, but there are a few notable exceptions. Morphine-6glucuronide is as, if not more, potent an analgesic as the parent compound (Romberg et al., 2004). Furthermore, numerous molecules with a carboxylic acid group may form an acyl glucuronide that undergoes molecular rearrangements, known as acyl migration, resulting in an isomeric sugar whose free aldehyde can react with nitrogen-containing amino acid side chains to form a Schiff base covalent adduct between protein and the glucuronide conjugate (Smith et al., 1990a). Alternatively, the acyl carbon on the glucuronide conjugate may undergo direct nucleophilic attack by an oxygen, nitrogen, or sulfur atom on an amino acid side chain making a covalent adduct between a protein and the aglycone drug (SpahnLangguth and Benet, 1992). Therefore, like sulfate conjugates, glucuronides cannot be viewed as simply pharmacologically and toxicologically inactive species. Unlike sulfation, xenobiotic glucuronidation occurs exclusively inside microsomal membranes. Uridine diphosphateglucuronosyl transferases (UGTs) are anchored via the Cterminus to the endoplasmic reticulum membrane, with the enzyme facing the inside of the lumen. Substrates for the UGTs include compounds containing nucleophilic functional groups, such as carboxyl, hydroxyl, thiol, amino, or activated carbon centers. The co-factor in glucuronidation reactions, uridine diphosphate-glucuronic acid (UDP-GA), is synthesized by a two-step reaction in the cytosol. Glucose-1-phosphate is conjugated with uridine diphosphate (UDP) by UDP-glucose pyrophosphorylase to UDP-glucose, which is subsequently oxidized to UDP-GA by UDP-glucose dehydrogenase (Clarke and Burchell, 1994; Dutton, 1980). Although the mechanism by which hydrophilic UDP-GA gains access to the endoplasmic reticulum lumen is not well understood, it has been speculated that a carrier-mediated process is involved. Highly watersoluble glucuronide conjugates are thought to leave the microsomal lumen via a carrier-mediated process, perhaps via a bi-directional mechanism shared with UDP-GA (RadominskaPandya et al., 1999). This transport process is disrupted in vitro in isolated microsomal incubations; thus, low detergent or pore-forming peptide (alamethacin) concentrations are necessary to allow UDP-GA to enter and glucuronide conjugates to exit the microsomal lumen in order to approach glucuronidation rates comparable to intact hepatocytes (Dutton, 1980; Fisher et al., 2001; Soars et al., 2003). Intracellular UDP-GA concentrations are higher than PAPS, ∼300–400 nmol/g liver, but may be depleted by high concentrations of substrates under-
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
going glucuronidation (e.g. acetaminophen) (Cappiello et al., 1991; Hjelle et al., 1985). UGT enzymes are subdivided into two families: UGT1 and UGT2. Isoenzymes in the UGT1A subfamily all contain a conserved C-terminal region that is responsible for UDPGA binding and attachment to the endoplasmic reticulum membrane, and that is encoded by the same four exons. What differentiates the various members of UGT1A subfamily is the N-terminal region, which is encoded by different exon 1 sequences and is thought to be responsible for binding of the aglycone substrate (Ritter et al., 1992). Nine functional isoforms comprise the UGT1A subfamily (Guillemette, 2003; Ritter et al., 1992; Tukey and Strassburg, 2000). UGT1A1 is of particular interest because it is responsible for glucuronidation, and thus the detoxification, of the hepatic heme breakdown product, bilirubin (Bosma et al., 1994). Deficiency of UGT1A1 causes unconjugated hyperbilirubinemia, as observed in the Gunn rat and patients with Crigler-Najar or Gilbert’s syndrome (Bosma et al., 1995). UGT1A6 traditionally has been recognized as the isoform responsible for the glucuronidation of phenols (e.g. acetaminophen), but more recent work indicates that there is considerable substrate overlap between the isoenzymes of the UGT1A subfamily (Court et al., 2001; Williams et al., 2004). In contrast, UGT2 family enzymes are all products of distinct genes (Monaghan et al., 1994). The UGT2A subfamily contains only one isoenzyme, UGT2A1, which has garnered fairly little attention in systemic drug disposition due to its primary localization in olefactory tissues (Jedlitschky et al., 1999; Tukey and Strassburg, 2001). The UGT2B subfamily is comprised of seven isoenzymes. The UGT2B family plays an important role in the glucuronidation of many endobiotics (Ethell et al., 2003). UGT2B7 is recognized for its role in glucuronidation of morphine, one of only a few pharmacologically active glucuronide conjugates (Coffman et al., 1997). UGT modulation is an area of active research. In general, the induction of UGTs results in only a two- to threefold increase in protein, which is in sharp contrast to the cytochrome P450 family. Prototypical inducers of the UGT1A subfamily include aromatic hydrocarbons, such as 3-methylcholanthrene, and the phase II specific monofunctional inducers, such as oltipraz (Prochaska and Talalay, 1988; Rushmore and Pickett, 1990). Recent data have suggested that certain UGTs also are responsive to pregnane X receptor, constitutive androstane receptor, glucocorticoid receptor, and peroxisome proliferator-activated receptor ligands (Barbier et al., 2003; Sugatani et al., 2001, 2005; Xie et al., 2003). Specific UGT probes have been employed as competitive inhibitors of particular UGT isoforms (Cummings et al., 2004). Probenecid inhibits glucuronidation both as a competitive inhibitor and an inhibitor of UDP-GA import into the endoplasmic reticulum lumen (Abernethy et al., 1985; Hauser et al., 1988; Smith et al., 1985). 7,7,7-Triphenylheptyl-UDP has been utilized as a mechanism-based UGT inhibitor (Said et al., 1992). Alternately, UDP-GA may be depleted (e.g. diethyl ether) and glucuronidation impaired due to limited availability of the cofactor (Eriksson and Strath, 1981; Gregus et al., 1983). Like sulfation, glucuronide conjugation is reversible. Some glucuronide conjugates can be deconjugated in an acidic environment, but in vivo, this is usually accomplished enzymat-
451
ically via -glucuronidases. Low -glucuronidase activity is present in the liver, and -glucuronidase has maximal activity at pH 5. Thus, hepatic futile cycling observed for many sulfate metabolites typically is not appreciable for glucuronide conjugates, but is considerable for acyl glucuronides because as esters they are cleaved by esterases in the liver (Liu and Smith, 2006; Smith et al., 1990b). However, high -glucuronidase activity in the gut microflora may result in enterohepatic recycling of parent drug after cleavage of glucuronide metabolites (Naderer et al., 2005). Many glucuronide conjugates excreted in bile into the duodenum subsequently are deconjugated to the aglycone, which may be reabsorbed resulting in enterohepatic cycling of that compound, a form of reversible metabolism (Roberts et al., 2002). Glucuronidation activity in the liver is not uniformly distributed, but rather increases from the periportal region to the perivenous region, where it is highest. Thus, hepatic glucuronidation activity is distributed in a manner opposite to sulfation (Pang and Terrell, 1981; Pang et al., 1983). From a physiological perspective, the distribution of glucuronidation activity is logical since it is a microsomal reaction that often occurs on molecular handles created by phase I oxidation, which also is localized to the lumen of the endoplasmic reticulum and is highest in perivenous hepatocytes.
2.3.
Glutathione conjugation
Glutathione conjugation is of particular importance because substrates of this reaction are often potent electrophiles. Conjugation with intracellular glutathione results in the detoxification of these species, which could otherwise covalently bind intracellular macromolecules. A broad spectrum of diverse electrophiles can undergo glutathione conjugation. Molecular moieties amenable to glutathione conjugation include electrophilic carbon atoms as well as electrophilic nitrogen, oxygen, and sulfur atoms (Parkinson, 2001). Substrates of glutathione conjugation can be parent compound electrophiles, as well as electrophilic phase I metabolites, and even certain phase II conjugates. Given the high intracellular concentrations (∼10 mM) of glutathione in the liver, glutathione conjugation may occur spontaneously, but is much more efficient when catalyzed by GSTs (Parkinson, 2001). GSTmediated metabolism predominantly occurs in the cytosol, but some GST activity also resides in the endoplasmic reticulum (Morgenstern et al., 1984). Since, hepatic concentrations of glutathione are by far the highest of the co-factors utilized in the three discussed reactions, intracellular glutathione is difficult to deplete. When intracellular glutathione is depleted, severe hepatotoxity may follow. The unique role of glutathione conjugation in detoxification is perhaps best illustrated by glutathione itself not being a high-energy unstable cofactor, like PAPS or UDP-GA, but rather a stable tripeptide that reacts with high-energy unstable substrates. For this very reason, many pharmaceutical companies have begun screening drug candidates for glutathione adducts primarily as predictors of the formation of unstable metabolites that may form toxic covalent adducts with intracellular molecules. Glutathione is synthesized by the formation of a peptide bond between glutamic acid and cysteine catalyzed by ␥-glutamylcysteine synthetase and subsequent addition of
452
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
glycine by glutathione synthetase. Although intracellular glutathione is difficult to deplete in the liver due to its very high concentrations, it can be accomplished at extremely high doses of substrate. Furthermore, glutathione levels may be decreased by administration of buthionine-S-sulfoximine, via inhibition of ␥-glutamylcysteine (Parkinson, 2001). In addition to its myriad physiological roles, glutathione represents an important co-factor for conjugation and detoxification of electrophilic xenobiotics or metabolites. The high intracellular concentration gradient of glutathione is thought to provide the driving force for non-ATP-mediated transport processes (e.g. organic anion transporting polypeptides), as well as to stimulate the function of ATP-driven transport processes (e.g. multidrug resistance-associated protein 2) (Haimeur et al., 2004). Glutathione conjugation is catalyzed by a family of detoxification enzymes known as glutathione-S-transferases (GSTs). GSTs are present in both membrane and cytosolic fractions, and are classified by their cellular localization. Cytosolic or soluble GSTs are responsible predominantly for conjugation of xenobiotics with glutathione. Approximately 20 cytosolic GSTs have been identified in vertebrates, and have been categorized into seven distinct classes: alpha, pi, mu, theta, omega, zeta, and sigma. The membrane bound isoforms include the mitochondrial and the microsomal GSTs; some membranebound GST isoforms have been implicated in the metabolism and biotransformation of drugs in mammals (Zhang et al., 2004, 2005). Cytosolic GSTs have very little structural similarity to their membrane-bound counterparts, and exist as hetero(only alpha and mu) or homo-dimers in the cytoplasm. Dimerization is necessary for GSTs to carry out their function in catalyzing glutathione conjugation as well as some reduction reactions (Parkinson, 2001). Although some GSTs have been shown to be upregulated in tumorigenesis, the specific pathways involved in maintaining basal regulation of these proteins is not understood completely. Regulation of GSTs has been hypothesized to occur through an Nrf-2 mediated pathway, impacted in part by the disposition of endogenous electrophiles (Ikeda et al., 2004). Induction of GST expression by xenobiotics commonly occurs after ingestion of many naturally derived products such as plant phenols, extracts of natural products (e.g. St. John’s Wort, Ginkgo biloba), and even common herbs, such as garlic (Ameen et al., 2003; Krajka-Kuzniak et al., 2004; Shibayama et al., 2004). Common therapeutic agents also can impact the expression of the GST enzymes. Several examples include rifampin-mediated induction of GSTP1 (as well as UGT1A), induction of GSTs by some NSAIDS, and increases in GST activity by some quinolones (Le and Franklin, 1997; Patten and DeLong, 1999; Rae et al., 2001). Furthermore, induction studies suggest that expression of some GSTs is controlled by the constitutive androstane receptor, pregnane X receptor, and arylhydrocarbon receptor (DePierre et al., 1984; Rae et al., 2001; Shibayama et al., 2004). An important feature of glutathione conjugates is that they typically are not deconjugated in the same manner as sulfate or glucuronide metabolites. However, the peptide bonds in the glutathione molecule of the metabolite may be hydrolyzed sequentially to form a cysteinylglycine metabolite, which can be hydrolyzed to a cysteine metabolite, followed by
N-acetylation to form a mercapturate metabolite (Parkinson, 2001). Other phase II reactions (e.g. amino acid conjugation, acetylation, and methylation) are less common metabolic pathways for xenobiotics. Amino acid conjugation occurs predominantly on very small molecules, which are rare in current drug development. Acetylation and methylation result in decreased water solubility. Therefore, these phase II metabolites are not discussed further in this review.
3.
Transport
Generally, sulfate, glucuronide, and glutathione metabolites are too hydrophilic to diffuse passively out of hepatocytes into either bile or sinusoidal blood following intrahepatic formation. Therefore, carrier-mediated processes are required to transport phase II conjugates across either the canalicular or basolateral membrane. Although the field of hepatic transport is a relatively new discipline, it is now widely recognized as a critical process in hepatobiliary drug disposition. While numerous transport proteins are present on the hepatic sinusoidal and canalicular membrane, thus far it appears that only apical multidrug resistance-associated protein 2 (Mrp2, Abcc2) and breast cancer resistance protein (Bcrp, Abcg2), as well as basolateral Mrp3 (Abcc3) and Mrp4 (Abcc4) play a major role in the hepatic biliary and basolateral excretion of sulfate, glucuronide, and glutathione metabolites. Therefore, this review focuses on reported interactions between these four transport proteins and phase II metabolites. Other transport proteins, which play a minor role in hepatic excretion of phase II metabolites are mentioned only briefly.
3.1.
Basolateral (sinusoidal) excretion
Excretion of drugs and/or metabolites from the hepatocyte across the basolateral membrane into sinusoidal blood theoretically may be mediated by one of the bidirectional transporters [organic anion transporting polypeptides (Oatps) or organic anion transporters (Oats)]. However, since Oatps and Oats are hypothesized to be driven by ion exchange (glutathione and ␣-ketoglutarate, respectively), they most likely function as uptake transporters under physiologicallyrelevant conditions. While members of the Oatp and Oat family can transport some phase II conjugates and exhibit bidirectional transport behavior in expression systems in vitro, their driving force strongly favors inwardly-directed transport in the liver in vivo. Given the focus of this review on hepatic excretory mechanisms, these proteins are not discussed further. Members of the ATP-driven Mrp family are primarily responsible for basolateral excretion of xenobiotics and endobiotics from hepatocytes. In the liver, Mrp3, Mrp4, Mrp5, and Mrp6 reside on the basolateral membrane and pump organic anions and bile acids from the hepatocyte into sinusoidal blood (Homolya et al., 2003). Of the hepatic basolateral efflux transporters, Mrp3 has been the most extensively studied, due to its important physiological function as the compensatory efflux mechanism when Mrp2 is absent or impaired (Konig et al., 1999). Interactions between Mrp3 and phase II conju-
453
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 1A – Summary of reported interactions between sulfate conjugates and Mrp3 X-sulfate
Experimental system
Species of Mrp3 origin
Interaction with Mrp3
Affinity
Reference
Lithocholate-S
Sf9 vesicle Sf9 vesicle
Human Human
Not determined IC50 ∼ 7.3 M
Akita et al. (2002) Zelcer et al. (2003a)
Sf9 vesicle LLC-PK1 vesicle
Rat Rat
Direct transport Etoposide-G uptake inhibition Direct transport Direct transport
Not determined Not determined
Akita et al. (2002) Hirohashi et al. (1999)
Glycolithocholate-S
Sf9 vesicle
Human
IC50 ∼ 10.6 M
Zelcer et al. (2003a)
Taurolithocholate-S
Sf9 vesicle Sf9 vesicle
Human Human
Not determined IC50 ∼ 9.1 M
Akita et al. (2002) Zelcer et al. (2003a)
Sf9 vesicle Sf9 vesicle LLC-PK1 vesicle LLC-PK1 vesicle LLC-PK1 vesicle
Human Rat Rat Rat Rat
Etoposide-G uptake inhibition Direct transport Etoposide-G uptake inhibition E2 17G uptake inhibition Direct transport Direct transport E2 17G uptake inhibition Taurocholate uptake inhibition Direct transport E2 17G uptake inhibition Taurocholate uptake inhibition Direct transport Direct transport Etoposide-G uptake modulation E2 17G uptake inhibition
Competitive KI ∼ 11 M Not determined KM 3.1 ± 0.6 M IC50 ∼ 0.81 M IC50 ∼ 1.3 M
Zelcer et al. (2003a) Akita et al. (2002) Hirohashi et al. (2000a) Hirohashi et al. (2000a) Hirohashi et al. (2000a)
Not determined IC50 ∼ 10.7 M IC50 ∼ 12.4 M
Hirohashi et al. (2000a) Hirohashi et al. (2000a) Hirohashi et al. (2000a)
KM 46.3 ± 7.3 M Not Observed Not observed (0–50 M)
Lee et al. (2004a,b) Zelcer et al. (2003b) Zelcer et al. (2003b)
IC50 ∼ 276 M
Hirohashi et al. (1999)
Not observed 2–20 M: stimulated (<4×), 100 M: inhibited (>30%) 2–100 M: stimulated (<5×), 20 M: decreased EEG KM ∼ 18× 0–100 M: stimulates (<70%) 500 M: inhibits (∼75%) Conc. dependent (∼2.5× at 166 M) Not observed
Chu et al. (2004) Chu et al. (2004)
Not observed
Zelcer et al. (2003a)
Conc. dependent (∼6× at 500 M) ∼35%
Hirohashi et al. (1999)
∼35%
Zamek-Gliszczynski et al. (2006d, in press) Manautou et al. (2005)
Taurochenodeoxycholate-S LLC-PK1 vesicle LLC-PK1 vesicle LLC-PK1 vesicle
Rat Rat Rat
Dehydroepiandrosterone-S
MDCKII vesicle Sf9 vesicle Sf9 vesicle
Human Human Human
Estrone-3-S
LLC-PK1 vesicle
Rat
Ethinylestradiol-S
Sf9 vesicle Sf9 vesicle
Human Human
Direct transport E2 17G uptake modulation
Sf9 vesicle
Human
Ethinylestradiol-G(EEG) uptake stimulation
E3040-S
LLC-PK1 vesicle
Rat
E2 17G uptake modulation
4-Methylumbelliferone-S
Sf9 vesicle
Human
Sf9 vesicle
Human
Sf9 vesicle
Human
LLC-PK1 vesicle
Rat
E2 17G uptake stimulation Etoposide-G uptake stimulation Leukotriene C4 (LTCH) uptake stimulation E2 17G uptake stimultion
Abcc3−/− mouse liver perfusion
Mouse
Impaired basolateral excretion
Abcc3−/− mouse liver perfusion Abcc3−/− mouse liver perfusion Abcc3−/− mouse
Mouse
Abcc3−/− mouse liver perfusion
Mouse
Impaired basolateral excretion Impaired basolateral excretion Lower plasma concentrations Impaired basolateral excretion
Acetaminophen-S
Harmol-S
Mouse Mouse
gates are summarized in Tables 1A–1C. Mrp3 is responsible for basolateral excretion of bile acids and other organic anions, and is especially important in the excretion of glucuronide metabolites into sinusoidal blood. While Mrp3 can efficiently transport sulfated bile acids, which are also good competitive inhibitors of this transporter, interactions of sulfated xenobi-
Not observed Slight decrease, not significant ∼30%
Chu et al. (2004)
Hirohashi et al. (1999)
Zelcer et al. (2003a) Zelcer et al. (2003a)
Zamek-Gliszczynski al. (2006d, in press)
et
Manautou et al. (2005) Zamek-Gliszczynski al. (2006d, in press)
et
otics and steroids with Mrp3 are very weak. Sulfate conjugates of xenobiotics stimulate Mrp3 function in a concentrationdependent manner at M concentrations and require nearly mM concentrations to exert notable inhibitory effects. Furthermore, in rats, basolateral clearance of glucuronide conjugates is generally in good agreement with Mrp3 expression
454
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 1B – Summary of reported interactions between glucuronide conjugates and Mrp3 X-glucuronide
Experimental system
Species of Mrp3 origin
Interaction with Mrp3
Affinity
Reference
Estradiol-17-(DG)
Sf9 vesicles Sf9 vesicles Sf9 vesicles HEK293 vesicles HEK293T vesicles
Human Human Human Human Human
Direct transport Direct transport Direct transport Direct transport Direct transport
Akita et al. (2002) Zelcer et al. (2001) Bodo et al. (2003) Zeng et al. (2000) Letourneau et al. (2005)
MDCKII vesicles Sf9 vesicles
Human Human
HEK293 Vesicles Sf9 vesicles Sf9 vesicles LLC-PK1 vesicles Sf9 vesicles
Human Rat Rat Rat Rat
LLC-PK1 vesicles
Rat
Sf9 vesicles Sf9 vesicles
Human Human
Sf9 vesicles
Human
Sf9 vesicles LLC-PK1 vesicles Sf9 vesicles
Rat Rat Rat
Sf9 vesicles
Rat
LLC-PK1 vesicles
Rat
HeLa vesicles
Rat
Sf9 vesicles
Human
Sf9 vesicles
Human
Sf9 vesicles
Rat
LLC-PK1 vesicles
Rat
Abcc3−/− mouse liver perfusion
Mouse
Direct transport Methotrexate uptake inhibition Direct transport Direct transport Direct transport Direct transport Methotrexate uptake inhibition Taurocholate uptake inhibition Direct transport Methotrexate uptake inhibition E2 17G uptake inhibition Direct transport Direct transport Methotrexate uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition Impaired basolateral excretion
KM 42.9 ± 4.3 M KM 17.7 ± 2.6 M KM ∼ 25–30 M KM 25.6 ± 5.4 M Not determined, GSH independent KM 24.2 ± 5.8 M Conc. dependent, ∼70% at 100 M Not determined KM 33.4 ± 2.2 M Not determined KM ∼ 110 M Conc. dependent, ∼90% at 100 M ∼20% at 75 M
Harmol-G
Abcc3−/− mouse liver perfusion
Mouse
Naphthol-G
LLC-PK1 vesicles
Rat
E3040-G
4-Methylumbelliferone-G
Not determined Conc. dependent, ∼70% at 50 M KI 5.6 ± 1.0 M
Lee et al. (2004b) Akita et al. (2002) Liu et al. (2003) Akita et al. (2002) Ito et al. (2001a) Hirohashi et al. (1999) Akita et al. (2002) Hirohashi et al. (2000a) Akita et al. (2002) Akita et al. (2002) Akita et al. (2002)
Not determined Not determined Conc. dependent, ∼90% at 50 M KI 2.6 ± 0.2 M
Akita et al. (2002) Hirohashi et al. (1999) Akita et al. (2002)
IC50 ∼ 2.3 M
Hirohashi et al. (1999)
IC50 ∼ 3.7 M
Hirohashi et al. (1999)
KI 105 ± 21 M
Akita et al. (2002)
∼30% at 50 M
Zelcer et al. (2003a)
KI 77 ± 11 M
Akita et al. (2002)
IC50 ∼ 39 M
Hirohashi et al. (1999)
∼85%
Zamek-Gliszczynski al. (2006d, in press)
et
Impaired basolateral excretion
∼65%
Zamek-Gliszczynski al. (2006d, in press)
et
E2 17G uptake inhibition Direct transport
IC50 ∼ 39 M
Hirohashi et al. (1999)
KM 11.4 ± 2.6 M
Zelcer et al. (2001)
KM 9.2 ± 2.3 M KI 5.0 ± 0.6 M
Chu et al. (2004) Chu et al. (2004)
No effect (0–100 M)
Chu et al. (2004)
IC50 <1 M
Cummings et al. (2004)
Not determined
Lee et al. (2004b)
Akita et al. (2002)
Etoposide-G
Sf9 vesicles
Human
Ethinylestradiol-G
Sf9 vesicles Sf9 vesicles
Human Human
Sf9 vesicles
Human
NU/ICRF505-G
Sf9 vesicles
Human
Bilirubin-mono-G
MDCKII vesicles
Human
Direct transport E2 17G uptake inhibition EthinylestradiolS(EES) uptake modulation E2 17G uptake inhibition Direct transport
Bilirubin-bis-G
MDCKII vesicles
Human
Direct transport
Not determined
Lee et al. (2004b)
Acetaminophen-G
Sf9 vesicles
Human
IC50 ∼ 2 mM
Zelcer et al. (2003c)
Sf9 vesicles
Rat
E2 17G uptake inhibition Direct transport
KM 910 ± 10 M
Xiong et al. (2002)
455
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 1B (Continued ) Experimental system
Species of Mrp3 origin
Interaction with Mrp3
Affinity
Reference
Abcc3−/− mouse liver perfusion Abcc3−/− mouse liver perfusion Abcc3−/− mouse
Mouse
∼96% ∼65%
Zamek-Gliszczynski et al. (2006d, in press) Manautou et al. (2005)
Mouse
∼90%
Manautou et al. (2005)
Hydroxyphenobarbital-G
Sf9 vesicles
Rat
IC50 , 0.46 ± 0.03 mM
Xiong et al. (2002)
Morphine-3-G
Sf9 vesicles HEK293 cells Sf9 vesicles
Human Human Human
KM ∼ 0.5–1 mM Not determined KI ∼ 290 M
Zelcer et al. (2005) Zelcer et al. (2005) Zelcer et al. (2005)
Abcc3−/− mouse
Mouse
∼98%
Zelcer et al. (2005)
Morphine-6-G
HEK293 cells Abcc3−/− Mouse
Human Mouse
Not determined ∼50%
Zelcer et al. (2005) Zelcer et al. (2005)
Nicotine-N-G
HEK293T vesicles
Human Human
HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
Not observed at 100 M Not observed at 100 M Not observed at 100 M Not observed at 100 M IC50 ∼ 100 M, GSH independent IC50 ∼ 100 M, GSH independent
Letourneau et al. (2005)
HEK293T vesicles
Impaired basolateral excretion Impaired basolateral excretion Lower plasma concentrations Acetaminophen-G uptake inhibition Direct transport Direct transport E2 17G uptake inhibition Lower plasma concentrations Direct transport Lower plasma concentrations E2 17G uptake inhibition Methotrexate uptake inhibition E2 17G uptake inhibition Methotrexate uptake inhibition Methotrexate uptake inhibition Methotrexate uptake inhibition
X-glucuronide
Cotinine-N-G
Hydroxycotinine-O-G
Mouse
levels, unlike sulfate conjugates, which do not seem to be affected by Mrp3 induction (Slitt et al., 2003; Takenaka et al., 1995a; Xiong et al., 2000). Glutathione itself does not appear to be an Mrp3 substrate, and does not stimulate Mrp3 function, but prototypical glutathione-containing endobiotics have some affinity for Mrp3 in expression systems in vitro. As is evident in Table 1C, there are conflicting reports regarding the ability of the prototypical glutathione-conjugated xenobiotic, dinitrophenyl-S-glutathione, to inhibit Mrp3 function at a moderate potency, as well as the ability of this glutathione conjugate to be transported by Mrp3 with an appreciable efficiency. Furthermore, biliary excretion of acetaminophen glutathione, as well as plasma and hepatic concentrations of this conjugate were not altered in Mrp3 gene knockout mice (Manautou et al., 2005). Ultimately, the importance of Mrp3 in the basolateral excretion of glutathione conjugates remains to be established, but current available data suggest that this is not the major hepatic basolateral efflux transport system for this class of phase II conjugates. Mrp4 and Mrp5 were identified initially as basolateral excretion mechanisms for cyclic nucleotides and nucleoside analogs (Haimeur et al., 2004; Rius et al., 2003; Sampath et al., 2002). Interactions between phase II conjugates and Mrp4 are summarized in Tables 2A and 2B. Sulfate conjugates of bile acids and steroids appear to exhibit high affinity for Mrp4. Although current data indicate that glucuronide metabolites also interact with Mrp4, they appear to have a lower affinity for this transporter than sulfate conjugates. While glu-
Letourneau et al. (2005) Letourneau et al. (2005) Letourneau et al. (2005) Letourneau et al. (2005) Letourneau et al. (2005)
tathione itself is a very low affinity Mrp4 substrate and does not appear to stimulate its activity, limited data suggest that Mrp4 can transport and be inhibited by glutathione conjugates, and thus might play some role in hepatic basolateral efflux of glutathione conjugates (Rius et al., 2003). Mrp5 is expressed at relatively low levels in healthy liver, but Mrp5 mRNA is up-regulated under cholestatic conditions, suggesting that Mrp5 protein levels may be increased as part of hepatic response to cholestatic conditions (Donner et al., 2004). Mrp5 can transport a spectrum of substrates similar to (although narrower than) Mrp4, including glutathione conjugates and cyclic nucleotides (Wijnholds et al., 2000), and could play a role in hepatic basolateral excretion of anionic conjugates. Mrp6 has been shown to localize to the basolateral/lateral surface of hepatocytes (Madon et al., 2000; Scheffer et al., 2002); Mrp6 transports glutathione conjugates and BQ123, a cyclicpentapeptide endothelin receptor antagonist (Belinsky et al., 2002; Ilias et al., 2002). Relatively little is known about the contribution of Mrp5 and Mrp6 to hepatic basolateral excretion of conjugated organic anions, and further studies are needed to evaluate their potential contribution.
3.2.
Biliary excretion
Biliary excretion of drugs and metabolites, as well as endogenous substances such as bile acids, phospholipids, and cholesterol, is a carrier-mediated, energy-dependent process. The bile salt export pump (Bsep; Abcb11) is responsible for the
456
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 1C – Summary of reported interactions between glutathione conjugates and Mrp3 X-glutathione
Experimental system
Species of Mrp3 origin
Interaction with Mrp3
Affinity
Reference
GSH
Sf9 vesicle MDCKII cells Ovarian carcinoma 2008 cells HEK293T vesicles
Human Human Human
Direct transport Direct transport Direct transport
Not observed Not observed Not observed
Zelcer et al. (2001) Kool et al. (1999) Kool et al. (1999)
Human Human Human Human Human
Not observed at 3 mM Not determined Not determined KM 5.3 ± 2.6 M KI > 10 M
Letourneau et al. (2005)
Sf9 vesicle MDCKII vesicle HEK293 vesicle Sf9 vesicle
Akita et al. (2002) Lee et al. (2004b) Zeng et al. (2000) Akita et al. (2002)
Sf9 vesicle Sf9 vesicle
Rat Rat
Not determined KI ∼ 2.5 M
Akita et al. (2002) Akita et al. (2002)
LLC-PK1 vesicle
Rat
IC50 ∼ 3.3 M
Hirohashi et al. (1999)
HeLa vesicle
Rat
IC50 >1 M
Hirohashi et al. (1999)
Deoxyprostaglandin J2 -SG
MCF7 vesicle
Human
Modulation of E217G uptake Direct transport Direct transport Direct transport E2 17G uptake inhibition Direct transport E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition Direct transport
KM ∼ 2.9 M
Paumi et al. (2003)
Dinitrophenol-SG
Sf9 vesicle
Human
Direct transport
Zelcer et al. (2001)
HEK293 vesicle MDCKII cells Sf9 vesicle Sf9 vesicle
Human Human Human Human
Zeng et al. (2000) Kool et al. (1999) Akita et al. (2002) Akita et al. (2002)
Sf9 vesicle LLC-PK1 vesicle Sf9 vesicle
Rat Rat Rat
Not determined Not determined KI 83.8 ± 2.7 M
Akita et al. (2002) Hirohashi et al. (1999) Akita et al. (2002)
LLC-PK1 vesicle
Rat
IC50 ∼ 83 M
Hirohashi et al. (1999)
HeLa vesicle
Rat
IC50 ∼ 57 M
Hirohashi et al. (1999)
HEK293 Vesicles
Human
Direct transport Direct transport Direct transport E2 17G uptake inhibition Direct transport Direct transport E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition E2 17G uptake inhibition
Very poor, uptake ∼3× background KM 5.7 ± 1.7 M Not determined Not determined KI 337 ± 41 M
Not observed 6 M
Liu et al. (2001a)
LLC-PK1 vesicle
Rat
Hirohashi et al. (1999)
Abcc3−/− mouse liver perfusion
Mouse
No effect (0–500 M) Not observed
Manautou et al. (2005)
Abcc3−/− mouse
Mouse
∼60%
Manautou et al. (2005)
Abcc3−/− mouse liver perfusion
Mouse
Not observed
Manautou et al. (2005)
Abcc3−/− mouse
Mouse
Slight decrease, not significant
Manautou et al. (2005)
Leukotriene C4
Dinitrophenolmercapturate Acetaminophen-SG
Acetaminophencysteinylglycine/cysteine
biliary excretion of unconjugated and glycine- and taurineconjugated bile acids (Kullak-Ublick et al., 2000; Meier, 1995). While Bsep is not thought to transport phase II metabolites of drugs, numerous xenobiotics, including cyclosporin A, rifampicin, troglitazone, bosentan, and glibenclamide recently have been reported to inhibit Bsep function (Byrne et al., 2002; Fattinger et al., 2001), leading to drug-induced cholestasis and hepatotoxicity (Bohan and Boyer, 2002). Multidrug resistance protein (Mdr)2 (Abcb4, MDR3 in humans) acts as a flippase for phosphatidylcholine, which is an important component
E2 17G uptake inhibition Impaired basolateral excretion Lower plasma concentrations Impaired basolateral excretion Lower plasma concentrations
of micelles that solubilize bile acids in the lumen of the bile canaliculus (Carrella and Roda, 1999; Elferink et al., 1997). The high percent homology of MDR2 with P-glycoprotein allows Mdr2 to transport some organic cations (e.g. digoxin, paclitaxel, and vinblastine), albeit at a much lower rate than P-glycoprotein (Smith et al., 2000). Other than transporting an essential constituent of bile into the canalicular lumen, Mdr2 is not thought to be responsible for direct transport of phase II conjugates. In fact biliary excretion of estradiol17-(-d-glucuronide) is enhanced ∼30% in Mdr2 knockout
457
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 2A – Summary of reported interactions between sulfate conjugates and Mrp4 X-sulfate
Experimental system
Species of Mrp4 origin
Interaction with Mrp4
Affinity
Reference
Dehydroepiandrosterone-S
Sf9 vesicles HEK-293 vesicles V79 vesicles
Human Human Human
KM 1.9 ± 0.2 M IC50 ∼ 3 M ∼65% at 5 M
Zelcer et al. (2003b) Zelcer et al. (2003b) Rius, 2003
Lithocholate-S
HEK-293 vesicles
Human
Direct transport E2 17G uptake inhibition Cholyltaurine uptake inhibition E2 17G uptake inhibition
IC50 ∼ 10 M
Zelcer et al. (2003b)
Taurolithocholate-S
HEK-293 vesicles
Human
E2 17G uptake inhibition
Zelcer et al. (2003b)
Glycolithocholate-S
HEK-293 vesicles
Human
E2 17G uptake inhibition
IC50 ∼ 10 M competitive IC50 ∼ 10 M
Estrone-3-S
HEK-293 vesicles HEK-293 vesicles
Human Human
IC50 ∼ 45 M IC50 ∼ 95 M
Zelcer et al. (2003b) Zelcer et al. (2003b)
Estradiol-3-S
HEK-293 vesicles HEK-293 vesicles
Human Human
IC50 ∼ 50 M IC50 ∼ 70 M
Zelcer et al. (2003b) Zelcer et al. (2003b)
Estradiol-3,17-diS
HEK-293 vesicles
Human
E2 17G uptake inhibition DHEAS uptake inhibition E2 17G uptake inhibition DHEAS uptake inhibition E2 17G uptake inhibition
Zelcer et al. (2003b)
HEK-293 vesicles
Human
IC50 ∼ 2 M competitive IC50 ∼ 0.2 M
Acetaminophen-S
Abcc4−/− mouse liver perfusion
Mouse
∼35%
Zamek-Gliszczynski al. (2006d, in press)
et
4-Methylumbelliferone-S
Abcc4−/− mouse liver perfusion
Mouse
Impaired basolateral excretion
∼35%
Zamek-Gliszczynski al. (2006d, in press)
et
Harmol-S
Abcc4−/− mouse liver perfusion
Mouse
Impaired basolateral excretion
∼45%
Zamek-Gliszczynski al. (2006d, in press)
et
mice (Huang and Vore, 2001). In addition, the ATP-dependent half-transporters Abcg5 and Abcg8, form a heterodimer, that functions to excrete cholesterol from hepatocytes into bile (Wittenburg and Carey, 2002). At present the ability of the Abcg5/Abcg8 heterodimer to transport anything other than cholesterol has not been reported. Xenobiotics may inhibit biliary excretion of phospholipids and cholesterol [e.g. bosentan (Fouassier et al., 2002)], but the possibility that certain phase II conjugates may inhibit these transporters remains to be investigated. The ATP-dependent multidrug resistance protein 1 (Mdr1; P-glycoprotein; P-gp; Abcb1) arguably is the most studied ATP-binding cassette transporter due to its notorious role in limiting oral bioavailability and CNS penetration of substrates: bulky, lipophilic and amphiphilic organic cations (Golden and Pollack, 2003; Wacher et al., 2001). In the liver, P-gp is localized to the canalicular membrane, where it functions as the major mechanism for translocation of organic cations from hepatocytes into bile (Kusuhara et al., 1998a; Meijer et al., 1997; Silverman and Schrenk, 1997). Under normal conditions, P-gp does not appear to be involved in the biliary excretion of phase II conjugates; the hydrophilic anionic nature of these metabolites makes them unlikely P-gp substrates. One of the few exceptions is estradiol-17-(-d-glucuronide) (E2 17G), which has affinity for recombinant P-gp. However, in P-gp knockout mice biliary excretion was not altered (Huang et al., 1998; Huang et al., 2000). Recent work by Zamek-Gliszczynski et al. (2006c) utilizing Mdr1a/Mdr1b double gene knockout mice failed to demonstrate any impairment in the biliary excretion of the sulfate and glucuronide conjugates of acetaminophen, 4-methylumbelliferone, or harmol relative to wild-type control mice.
DHEAS uptake inhibition Impaired basolateral excretion
Zelcer et al. (2003b)
Zelcer et al. (2003b)
Animals with hereditary conjugated hyperbilirubinemia (TR− and EHBR rats, Corriedale sheep) and patients with Dubin–Johnson syndrome exhibit normal bile acid output, but impaired biliary excretion of most organic anions (Keppler and Konig, 1997; Thompson and Strautnieks, 2000). The multidrug resistance-associated protein 2 (Mrp2; Abcc2) is an ATPdependent canalicular transporter responsible for the biliary excretion of many drugs (e.g., ceftriazone, ampicillin, dibromosulfophthalein), as well as their glucuronide, sulfate, and glutathione conjugates (Homolya et al., 2003; Keppler and Konig, 1997; Oude Elferink and Jansen, 1994). In addition, Mrp2 also transports sulfated and glucuronidated bile acids (Meier, 1995). Aside from in vitro characterization of recombinant Mrp2, the majority of studies examining the hepatic relevance of Mrp2 have utilized Mrp2-deficient rats. Livers of Mrp2-deficient rats exhibit negligible biliary excretion of most glucuronide and glutathione conjugates, whereas the biliary excretion of sulfate metabolites is impaired only partially. However, recent investigations indicated that rat livers contain much more Mrp2 protein than dog livers, and may therefore overestimate the importance and kinetic efficiency (i.e. the intrinsic clearance) of this transporter in biliary excretion (Ninomiya et al., 2005). Furthermore, studies with Abcc2 gene knockout mice indicated that Mrp2 plays a less important role in the biliary exceretion of phase II conjugates in mice than in rats (Zamek-Gliszczynski et al., 2005, 2006b,c). The breast cancer resistance protein (Bcrp; Abcg2) is the most recently identified hepatic canalicular drug transport protein. The importance of Bcrp in the biliary excretion of phase II conjugates is just emerging. Bcrp is an ATP-dependent half-transporter, which presumably forms a dimer or an even
458
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 2B – Summary of reported interactions between glucuronide and glutathione conjugates and Mrp4 Conjugate
Experimental system
Species of Mrp4 origin
Interaction with Mrp4
Affinity
Reference
Sf9 vesicles Sf9 vesicles Erythrocyte vesicles HEK-293 vesicles Sf9 vesicles
Human Human Human
Direct transport Direct transport cGMP uptake modulation
KM 30.3 ± 6.2 M Not determined ∼90% at 65 M
Chen et al. (2001) van Aubel et al. (2002) Klokouzas et al. (2003)
Human Human
IC50 ∼ 30 M ∼60% at 30 M
Zelcer et al. (2003b) Chen et al. (2002)
Sf9 vesicles
Human
∼25% at 100 M
van Aubel et al. (2002)
Dehydroepiandrosterone-G
HEK-293 vesicles HEK-293 vesicles
Human Human
DHEAS uptake inhibition Methotrexate uptake inhibition Methotrexate uptake inhibition E2 17G uptake inhibition DHEAS uptake inhibition
IC50 ∼ 80 M IC50 ∼ 80 M
Zelcer et al. (2003b) Zelcer et al. (2003b)
Estradiol-3-G
HEK-293 vesicles HEK-293 vesicles
Human Human
E2 17G uptake inhibition DHEAS uptake inhibition
IC50 ∼ 120 M IC50 ∼ 80 M
Zelcer et al. (2003b) Zelcer et al. (2003b)
Napththol-G
Sf9 vesicles
Human
IC50 ∼ 17 M
van Aubel et al. (2002)
Nitrophenol-G
Sf9 vesicles
Human
IC50 ∼ 341 M
van Aubel et al. (2002)
Acetaminophen-G
Abcc4−/− mouse liver perfusion
Mouse
Methotrexate uptake inhibition Methotrexate uptake inhibition Impaired basolateral excretion
Not observed
Zamek-Gliszczynski al. (2006d, in press)
et
4-Methylumbelliferone-G
Abcc4−/− mouse liver perfusion
Mouse
Impaired basolateral excretion
Not observed
Zamek-Gliszczynski al. (2006d, in press)
et
Harmol-G
Abcc4−/− mouse liver perfusion
Mouse
Impaired basolateral excretion
∼20%
Zamek-Gliszczynski al. (2006d, in press)
et
V79 vesicles Erythrocyte vesicles V79 vesicles
Human Human
Direct transport cGMP uptake modulation
Rius et al. (2003) Klokouzas et al. (2003)
Human
HEK293 cells HEK293 cells
Human Human
Cholyltaurine uptake stimulation cAMP efflux modulation cGMP efflux modulation
KM 2.7 ± 0.2 mM Not observed (0.5–4 mM) ∼60× at 5 mM Not observed Not observed
Wielinga et al. (2003) Wielinga et al. (2003)
GSSG
V79 vesicles
Human
∼50% at 5 mM
Rius et al. (2003)
Methyl-SG
V79 vesicles V79 vesicles
Human Human
KM 1.2 ± 0.2 mM ∼22× at 5 mM
Rius et al. (2003) Rius et al. (2003)
Decyl-SG
V79 vesicles
Human
∼50% at 5 mM
Rius et al. (2003)
Leukotriene C4
Sf9 vesicles
Human
van Aubel et al. (2002)
Bimane-SG
HepG2 cells
Human
Not observed (1 M) Not determined
Dinitrophenol-SG
HepG2 cells
Human
Conc. dependent
Bai et al. (2004)
Sf9 vesicles
Human
IC50 ∼ 13 M
van Aubel et al. (2002)
Sf9 vesicles
Human
IC50 ∼ 5 M
van Aubel et al. (2002)
X-glucuronide Estradiol-17-(DG)
X-Glutathione GSH
Dinitrophenol-mercapturate
larger homo-complex to become functional. BCRP excrete an anthracyclines, the active metabolite of CPT-11 (SN-38), as well as many sulfate and glucuronide conjugates into bile (Bates et al., 2001; Ejendal and Hrycyna, 2002; Suzuki et al., 2003). Reported interactions between phase II conjugates and Bcrp are summarized in Tables 4A and 4B. Bcrp appears to be responsible for the non-Mrp2-mediated component of biliary excretion of sulfate metabolites. The role of Bcrp in the biliary excretion of sulfate conjugates has been demonstrated
Cholyltaurine uptake inhibition Direct transport Cholyltaurine uptake modulation Cholyltaurine uptake inhibition Methotrexate uptake modulation Direct transport Bimane-SG efflux inhibition Methotrexate uptake inhibition Methotrexate uptake inhibition
Rius et al. (2003)
Bai et al. (2004)
in vitro, as well as in the whole organ by using GF120918 (an inhibitor of both P-gp and Bcrp); GF120918 partially impairs the biliary excretion of sulfate conjugates in the wild-type rat liver, and nearly completely abolishes sulfate metabolite excretion in the bile of livers from Mrp2-deficient rats (Suzuki et al., 2003; Zamek-Gliszczynski et al., 2005, 2006b). Subsequent liver perfusion studies with Abcg2 gene knockout mice provided the definitive proof for the involvement of Bcrp in the biliary excretion of sulfate metabolites (Zamek-Gliszczynski et
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
al., 2006c). Although Suzuki et al. (2003) reported that recombinant human BCRP interacted with glucuronide conjugates, data generated in Mrp2-deficient rats indicated that the biliary excretion of some glucuronide conjugates was negligible in the absence of Mrp2 (Patel et al., 2003; Takenaka et al., 1995b; Xiong et al., 2000). Subsequent work utilizing Abcg2 gene knockout mice demonstrated clearly that Bcrp mediated the biliary excretion of several model glucuronide conjugates (ZamekGliszczynski et al., 2006c). As previously mentioned, rat livers contain high levels of Mrp2 protein and may exaggerate the importance of Mrp2 in biliary excretion (Ninomiya et al., 2005). The role of Bcrp in biliary excretion of glutathione conjugates remains to be elucidated. In vitro recombinant Bcrp appears to have some transport activity for dinitrophenyl-S-glutathione. However, Bcrp function is not impaired by leukotriene C4 and is very poorly impaired by dinitrophenyl-S-glutathione, suggesting that the affinity of glutathione conjugates for Bcrp is weak (Suzuki et al., 2003). Furthermore, in Mrp2-deficient rat livers, biliary excretion of glutathione conjugates is negligible, despite the presence of functional Bcrp (Chen et al., 2003a; Zamek-Gliszczynski et al., 2005). Therefore, it is unlikely that Bcrp plays a major role in the biliary excretion of glutathione conjugates.
4.
Discussion
4.1.
Co-modulation examples
Modulators of transport and/or metabolism may alter both processes. This statement is especially true for inducers, which typically exert their action by binding to receptors controlling gene transcription. Thus, activation of a nuclear receptor, such as the pregnane X receptor, results in activation of numerous genes, some of which encode phase II metabolic enzymes and drug transporters. Unlike inducers, prototypical “selective” inhibitors usually have adequate separation in potencies to avoid non-specific interactions with other processes. However, as “selective” inhibitors become better characterized, it often becomes apparent that they inhibit more than one process, sometimes interacting with both metabolism and transport. Two examples of metabolic and transport co-modulators are discussed below. Phenobarbital is a prototypical activator of the constitutive androstane receptor (CAR), and the effects of phenobarbital on both metabolism and transport have been recognized (Xu et al., 2005). In addition to inducing certain phase I oxidative enzymes, phenobarbital is an inducer of Mrp3 and UGTs (Sugatani et al., 2001; Xiong et al., 2002a). Immediately following chronic exposure to phenobarbital, Mrp2 expression may be induced (less than two-fold), but Mrp2 protein levels decrease below baseline levels 48 h after cessation of phenobarbital exposure (Patel et al., 2003; Slitt et al., 2003). Phenobarbital glucuronide is excreted into bile by Mrp2 and has been shown in vitro to inhibit Mrp2 function, so phenobarbital glucuronide may act as a competitive Mrp2 inhibitor (Patel et al., 2003; Xiong et al., 2002b). Thus, phenobarbital exposure enhances the clearance by glucuronidation and redirects the route of excretion of the glucuronide conjugates by enhancing Mrp3-mediated basolateral excretion and impair-
459
ing biliary excretion via Mrp2. Following phenobarbital exposure, glucuronidated substrates are eliminated more rapidly, and recovery of glucuronide conjugates in urine is enhanced, whereas biliary excretion of glucuronide conjugates may be diminished, resulting in an enhanced urine/bile glucuronide recovery (Brouwer and Jones, 1990; Gregus et al., 1990; Loeser and Siegers, 1985; Watkins and Klaassen, 1982; Xiong et al., 2002b). Probenecid is a prototypical non-specific competitive inhibitor of organic anion transport, which may impair the transport of substrates for organic anion transporters (Oats), organic anion transporting polypeptides (Oatps), and multidrug resistance-associated proteins (Mrps) (Beyer et al., 1951; Sugiyama et al., 2001; Zamek-Gliszczynski et al., 2003). Due to its low affinity as a competitive inhibitor, probenecid is administered at high concentrations to impair organic anion transport; because probenecid is glucuronidated, it also behaves as a competitive inhibitor of glucuronidation (Abernethy et al., 1985; Guarino et al., 1969; Kamali, 1993; Smith et al., 1985). In addition to competitively inhibiting glucuronidation, probenecid also impairs the transport of UDP-GA into the lumen of the endoplasmic reticulum, inhibiting glucuronide conjugation directly and by limiting the co-factor available to the enzyme (Hauser et al., 1988). As exemplified by acetaminophen glucuronide, probenecid co-administration impairs glucuronidation, and also retards subsequent hepatic excretion (Savina and Brouwer, 1992; Turner and Brouwer, 1997).
4.2.
Cholestasis
The interplay between phase II metabolism and transport is perhaps most evident under cholestatic conditions. When hepatocytes are exposed to potentially toxic levels of bile salts that are forced to adapt their metabolism and transport to deal with the impaired biliary excretion of unconjugated and/or conjugated bile acids. Cholestasis can be induced by certain xenobiotics, disease states, as well as physical ligation of the bile duct, representing obstructive cholestasis, or can result from a variety of gene deficiencies. Mrp2 deficiency, which results in conjugated hyperbilirubinemia, is perhaps the most relevant to the focus of this review due to the major role that this transporter plays in the biliary excretion of phase II metabolites. Changes in hepatic transport that occur during cholestasis have been studied extensively in bile-duct-ligated rodents. In models of obstructive jaundice, hepatic Mrp2 expression is decreased ∼3–14-fold and ∼5-fold at the protein and mRNA levels, respectively, depending on the time elapsed since ligation. More pronounced downregulation occurs at later times since organic anions excreted into the bile canaliculi cannot proceed to the duodenum and remain trapped in the bile ducts (Donner and Keppler, 2001; Tanaka et al., 2002). To compensate for the inability to excrete bile acids and other organic anions into bile, basolateral Mrp3 is markedly induced, ∼6–50-fold and ∼6–30-fold at the protein and mRNA levels, respectively, depending on the time elapsed since ligation. Upregulation of Mrp3 increases with time, presumably to enhance excretion of potentially toxic anions into sinusoidal blood for clearance by the kidneys thus avoiding hepatic accumulation (Ogawa et
460
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
al., 2000; Soroka et al., 2001; Tanaka et al., 2002). To accommodate the increased hepatic basolateral excretion of organic anions into blood, Mrp2 expression is upregulated in kidneys resulting in increased renal clearance of organic anions following bile duct ligation (Tanaka et al., 2002). In addition to alterations in transport, glucuronidation of phenolic-type molecules appears to be modestly decreased, presumably to accommodate the liver’s inability to secrete metabolites into bile (Desmond et al., 1994). Mrp2-deficient rats (GY/TR− and EHBR) are the most extensively studied animal model of hereditary conjugated hyperbilirubinemia. Livers from these mutant rats exhibit altered phase II metabolism and hepatic transport; these changes protect the liver from toxic injury that might otherwise be caused by the absence of functional Mrp2. Hepatic glucuronidation and sulfation appear to be functionally upregulated in Mrp2deficient rats, which can result in more efficient clearance of compounds that undergo direct phase II conjugation, such as acetaminophen (Nishino et al., 2000; Seitz et al., 1998; Xiong et al., 2000; Zamek-Gliszczynski et al., 2005). Since glutathione biliary excretion is mediated primarily by Mrp2, Mrp2-deficient rats have negligible biliary glutathione output, resulting in increased hepatic glutathione concentrations (∼50–150% in reduced glutathione and ∼3-fold in oxidized glutathione) which protects hepatocytes from toxicity of potent electrophiles, such as the oxidative metabolite of acetaminophen, N-acetyl-p-quinoneimine (Elferink et al., 1989; Ji et al., 2004; Johnson et al., 2002). Interestingly, Abcc2 gene knockout mice are protected from acetaminopheninduced hepatotoxicity at doses that are toxic in wild-type mice (Raub et al., 2005), presumably due to elevated hepatic glutathione concentrations resulting from impaired biliary excretion of glutathione. Glutathione synthetase activity is not increased in the livers of Mrp2-deficient rats and ␥glutamylcysteine synthetase activity has been reported to be unchanged or slightly increased (Lu et al., 1996; Sugawara et al., 1996). Basolateral Mrp3 expression in livers of Mrp2deficient rats is an order of magnitude greater than in wildtype rats, allowing for efficient basolateral excretion of phase II conjugates and other organic anions whose biliary excretion is fully or partially impaired. Taken together, upregulated phase II metabolism and basolateral Mrp3 allow Mrp2-deficient livers to quickly inactivate and detoxify certain xenobiotics, and subsequently efficiently excrete their metabolites into sinusoidal blood for clearance by the kidneys. As in obstructive jaundice, upregulation of hepatic Mrp3 is complemented by upregulation of Mrp3 and to a lesser extent Mrp4 in the kidneys of Mrp2-deficient rats (Chen et al., 2005; Kuroda et al., 2004). Alterations in compensatory basolateral efflux mechanisms have focused traditionally on Mrp3 due to the highly inducible nature of this protein under cholestatic conditions. However, recently Mrp4 also has been implicated in the hepatic basolateral excretion of sulfated bile acids and also in hepatic response to cholestasis (Assem et al., 2004; Schuetz et al., 2001; Zelcer et al., 2003b). In bile duct ligated rats, Mrp4 protein is progressively upregulated after surgery to a maximum of ∼7-fold (Denk et al., 2004). In addition, expression of the bile salt export pump is downregulated in farnesoid X receptor gene knockout mice, resulting in elevated hepatic bile acid
concentrations and upregulation of Mrp4 (Schuetz et al., 2001). Furthermore, Mrp4 and Sult2a1, the bile acid sulfotransferase, are coordinately regulated by the constitutive androstrane receptor; thus, prototypical activators of this nuclear receptor induce both the enzyme and transporter (Assem et al., 2004). In Abcc4 gene knockout mice, Sult2a1 constitutive expression is downregulated, demonstrating the sulfotransferase-efflux transporter interplay (Assem et al., 2004). Mrp4 is upregulated and bile acid sulfation is increased secondary to Bsep downregulation, suggesting that sulfation and subsequent basolateral excretion act as an overflow detoxification pathway when biliary excretion of bile acids is impaired (Schuetz et al., 2001; Zelcer et al., 2003b).
4.3.
Pharmacodynamic consequences
Not all phase II conjugates lack pharmacological activity, and for those metabolites, alterations in hepatic metabolism and/or transport can have profound pharmacodynamic implications. A discussion of two examples of pharmacological consequences of modulation of hepatic metabolism and transport follows. The opioid analgesic, morphine, forms two glucuronide conjugates in humans: morphine-3- and morphine-6-glucuronide. Whereas morphine-3-glucuronide lacks pharmacological activity, morphine-6-glucuronide is equally or more potent than the parent compound (Moran and Smith, 2002; Romberg et al., 2004). Both glucuronide conjugates of morphine are formed primarily in the liver, and subsequently are excreted predominantly across the basolateral membrane into sinusoidal blood (Yeh, 1975). Following excretion into sinusoidal blood, morphine glucuronides may gain access to the CNS. Recombinant Mrp3 transports morphine glucuronides in vitro (Zelcer et al., 2005). In Abcc3 gene knockout mice, appearance of intrahepatically-formed morphine3-glucuronide in blood was decreased markedly (∼50-fold), with a resulting shift in elimination of this metabolite from urine to feces (Zelcer et al., 2005). Unlike humans, mice do not form the active morphine-6-glucuronide metabolite, so the pharmacokinetic/dynamic consequences of the absence of Mrp3 were evaluated after direct i.p. injection of this metabolite in mice. Plasma concentrations of morphine-6glucuronide were ∼50% lower at 60 min and the antinociceptive effect also was decreased in the absence of Mrp3. Zelcer et al. (2005) proposed that morphine-6-glucuronide undergoes carrier-mediated uptake by the liver, and that in the absence of Mrp3, hepatic basolateral excretion of this active metabolite is diminished, resulting in decreased systemic exposure and effect. Modulation of hepatic excretion of active phase II conjugates may have noticeable pharmacodynamic consequences, but meaningful changes also can be observed with direct modulation of phase II metabolism that results in a pharmacologically active metabolite. Minoxidil requires activation through sulfation to become active topically as a hair growth stimulant and systemically as a peripheral vasodilator (Buhl et al., 1990; Meisheri et al., 1993). Duanmu et al. (2000) demonstrated that both inhibition and induction of SULT1A1 resulted in meaningful changes in the effect of minoxidil as a peripheral vasodilator. Co-admininstration of the SULT1A1 inhibitor,
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
pentachlorophenol, obliterated minoxidil-induced decreases in mean arterial pressure. In contrast, ∼2.5-fold induction of SULT1A1 with the glucocorticoid, triamcinolone acetonide, enhanced minoxidil’s blood pressure lowering effect ∼2-fold. Although the pharmacodynamic consequences of hepatic efflux modulation of minoxidil sulfate have not been examined to date, it is likely that the hypotensive effect could be attenuated if hepatic efflux was impaired and the metabolite was trapped inside the liver.
4.4.
Toxicity
Although phase II conjugates are typically water-soluble detoxification and/or inactivation products ready for basolateral or canalicular excretion, some metabolites are toxic, and modulation of their hepatic formation and/or excretion may have important implications with respect to adverse effects. Two specific examples demonstrating the cumulative contributions of hepatic metabolism and transport to toxicity are troglitazone and SN-38-glucuronide. Troglitazone was a blockbuster thiazolidinedione for the treatment of diabetes until it was withdrawn from the market due to drug-induced liver injury. Several hypotheses explaining the idiosyncratic hepatotoxicity observed during troglitazone treatment have been suggested (Smith, 2003). Troglitazone and/or its metabolite(s) inhibit Bsep causing impaired biliary secretion of unconjugated bile acids, which subsequently accumulate inside the hepatocyte. Bile acids have detergent-like properties and can cause toxicity at higher concentrations. Unconjugated bile acids are usually more toxic than conjugated bile acids, as is demonstrated by progressive intrahepatic familial cholestasis (absence of functional Bsep), which is much more serious and lethal at an earlier age than Dubin–Johnson syndrome (Strautnieks et al., 1998). The sulfate conjugate of troglitazone is a much more potent Bsep inhibitor than the parent drug (Funk et al., 2001). Therefore, sulfation of troglitazone may represent a toxification mechanism for this xenobiotic; if hepatic export is impaired, troglitazone sulfate may accumulate in hepatocytes with increased toxicity to the liver. In fact, Kostrubsky et al. (2001) demonstrated that in the Mrp2-deficient TR− rat, biliary excretion of troglitazone sulfate exhibited an ∼2-h delay; blood concentrations and urinary excretion were markedly increased, with an ∼2-fold increase in serum bilirubin over baseline 2 and 36 h following troglitazone administration. In contrast, serum bilirubin was not altered in wild-type rats. Troglitazone exemplifies how a phase II metabolite can exert its toxic effect at the transport level, and how impaired hepatic excretion of the toxic metabolite can exacerbate the toxicity. Another example of a phase II conjugate whose hepatic metabolism and subsequent carrier-mediated export has generated considerable interest is SN-38-glucuronide, the conjugate of the active metabolite of irinotecan. Many cancer patients receiving irinotecan chemotherapy experience severe diarrhea. Several hypotheses have been proposed for the exact mechanism(s) of irinotecan GI toxicity. One explanation is that SN-38 and its glucuronide conjugate are excreted in bile primarily by Mrp2; in the intestine, SN-38 glucuronide is deconjugated to SN-38, which causes the GI toxicity (Chu et al., 1997a,b; Kato et al., 2002). Horikawa et al. (2002a) demon-
461
strated that by co-administering probenecid, an inhibitor of glucuronidation and organic anion transport, the normal irinotecan dose for rats could be decreased by 50%, diarrhea was ameliorated, and plasma concentrations of SN-38 were maintained at efficacious levels.
4.5.
Species differences
While much effort has been devoted to the study of species differences in drug metabolism and drug–drug interactions at the metabolic level in order to more accurately predict human metabolism from pre-clinical data, differences in hepatic transport are just beginning to be recognized as an important contributor to inter-species variability in drug disposition. Species differences in drug/metabolite transport may be an important point to consider in the design and interpretation of drug disposition studies. Rats traditionally have been the species of choice for hepatobiliary drug disposition studies due to their convenient size, ease with which the common bile duct can be cannulated, and the absence of a gallbladder, which may complicate the experimental design and/or confound data interpretation. Mice are a common pre-clinical species for drug disposition studies, and the increasing availability of transport protein, metabolic enzyme, nuclear receptor, or pharmacological target gene knockout mouse models makes this species particularly amenable to investigations of hepatic disposition. However, recent data suggest that species differences in key hepatic efflux transporters are sufficiently profound to warrant careful re-examination of conclusions based on existing data, and to design future studies with caution. Rats have long been recognized as unusually efficient in the biliary excretion of organic anions, but the molecular mechanism(s) underlying these observations are only now being elucidated. Generally, it was assumed that rat Mrp2 exhibited a higher affinity for substrates than Mrp2 of other species. However, recent data have revealed that rat livers contain much more (∼10-fold) Mrp2 protein resulting in a much higher capacity for the biliary excretion of organic anions in rats than humans or other pre-clinical species (Ishizuka et al., 1999; Ninomiya et al., 2005). Species differences in drug transport can have profound implications on both the kinetic and mechanistic interpretation of data obtained from rats, and especially on the contribution of Mrp2 to the biliary excretion of an organic anion. Ishizuka et al. (1999) demonstrated that uptake of the Mrp2 substrate, dinitrophenyl-Sglutathione, in rat liver canalicular plasma membrane vesicles yielded a maximal velocity approximately an order of magnitude greater than in other species, while affinities of this substrate for various Mrp2s were fairly comparable. Furthermore, the unbound biliary in vivo excretion clearance (calculated relative to hepatic unbound drug concentrations) of the Mrp2 substrate, temocaprilat, were ∼4–50-fold greater in rats than in other pre-clinical species (Ishizuka et al., 1997; Ishizuka et al., 1999). Liver perfusion studies by Zamek-Gliszczynski et al., 2005, 2006b,c, see Tables 3A–3C, 4A and 4B) indicated that the role of Mrp2 in the biliary excretion of sulfate and glucuronide metabolites may be overemphasized based on comparisons between Mrp2-deficient and wild-type rats. In subsequent mouse liver perfusion studies, Zamek-Gliszczynski
462
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3A – Summary of reported interactions between sulfate conjugates and Mrp2 X-sulfate
Experimental system
Acetaminophen-S
TR− rat
Rat
TR− rat liver perfusion TR− rat liver perfusion TR− rat liver perfusion Abcc2−/− mouse liver perfusion
Rat
S.D. Rat CMVs
Rat
EHBR rat perfused intestine TR− rat liver perfusion Abcc2−/− mouse liver perfusion
Rat
4-Methylumbelliferone-S
Species of Mrp2 origin
Rat Rat Mouse
Rat Mouse
TR− rat liver perfusion Abcc2−/− mouse liver perfusion
Rat
EHBR rat
Rat
EHBR liver perfusion EHBR liver perfusion EHBR CMVs EHBR rat perfused intestine S.D. rat CMVs
Rat
Phenolphthalein-diS
EHBR rat
Rat
Indocyanine green
EHBR rat
Rat
EHBR rat
Rat
EHBR rat
Rat
Benzo[a]pyrene-1-S
MDCKII cells
Human
Benzo[a]pyrene-3-S
MDCKII cells
Human
PhIP-S
TR− rat
Rat
Ethinylestradiol-S
Sf9 Vesicles Sf9 Vesicles
Human Human
Sf9 Vesicles
Human
Sf9 Vesicles
Human
TR− rat
Rat
Harmol-S
E3040-S
Troglitazone-S
Mouse
Rat Rat Rat
Rat
Interaction with Mrp2
Affinity
Reference
Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion
>30%
Chen et al. (2003b)
∼81%
Xiong et al. (2000)
∼70%
Xiong et al. (2000)
∼80%
Zamek-Gliszczynski (2005) Zamek-Gliszczynski et al. (2006a,b,c,d, in press)
Stimulated DNP-SG uptake Impaired luminal secretion
Conc. dependent ∼3× at 500 M Not observed
Niinuma et al. (1997)
Impaired biliary excretion Impaired biliary excretion
∼60%
Zamek-Gliszczynski et al. (2006c, in press) Zamek-Gliszczynski et al. (2006c, in press)
Impaired biliary excretion Impaired biliary excretion
∼65%
Impaired biliary excretion Enhanced biliary excretion Impaired biliary excretion Impaired uptake Impaired luminal secretion
∼30%
Takenaka et al. (1995)
∼1.5×
Takenaka et al. (1995)
Not observed
Takenaka et al. (1995)
∼25% Not observed
Takenaka et al. (1995) Adachi et al. (2005)
Stimulation of DNP-SG uptake Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Enhanced apical excretion Enhanced apical excretion Impaired biliary excretion Direct transport Modulation of ethacrynic acid-SG uptake Stimulation of E217BG uptake Stimulation of EEG uptake
100 M: ∼2× decreases DNP-SG KM ∼ 3× ∼85%
Niinuma et al. (1997) Tanaka et al. (2003)
∼95%
Yamaguchi et al. (1997)
∼95%
Hamaguchi et al. (1994)
∼70%
Takikawa et al. (1995)
Not observed
Buesen et al. (2002)
Not observed
Buesen et al. (2002)
Not observed
Dietrich et al. (2001b)
Not observed 1–20 M: >50% Stimulation; 20–100 M: >50% inhibition Conc. dependent ∼16× at 50–100 M Conc. dependent ∼25× at 100 M 20 M: decreased EEG KM ∼ 5× 0–2 h∼90% decreased; 2–36 h normal
Chu et al. (2004) Chu et al. (2004)
Delayed biliary excretion
Not observed
Not observed
Not observed
Adachi et al. (2005)
Zamek-Gliszczynski et al. (2006c, in press) Zamek-Gliszczynski et al. (2006c, in press)
Chu et al. (2004) Chu et al. (2004)
Kostrubsky et al. (2001)
463
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3A (Continued) X-sulfate
Experimental system
Hydroxyphenobarbital-S
TR− rat liver perfusion EHBR rat
Rat
MDCKII cells HEK293 vesicles Wistar rat CMVs
Human Human Rat
Wistar rat CMV TR− rat CMV S.D. rat CMVs
Rat Rat Rat
EHBR rat
Rat
EHBR rat
Rat
EHBR rat
Rat
EHBR rat
Rat
S.D. rat
Rat
S.D. rat
Rat
Dibromosulfophthalein
EHBR rat
Rat
Taurochenodeoxycholate-S
S.D. CMVs EHBR CMVs
Rat Rat
Tauroursodeoxycholate-S
Wistar rat erythrocyte vesicles MDCKII cells
Rat
Grepafloxacin-S Sulfobromophthalein
Estrone-S
Taurocholate-S
Dehydroepiandrosterone-S
Ursodeoxycholate-diS
Lithocholate-S
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Impaired biliary excretion Impaired biliary excretion Direct transport Direct transport Impaired bilirubin-diG uptake Uptake Impaired uptake Inhibition of DNP-SG uptake Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Inhibition of SN-38-G biliary excretion Inhibition of E217G biliary excretion Impaired biliary excretion Direct transport Direct transport
∼70%
Patel et al. (2003)
Not observed
Sasabe et al. (1998)
Not determined KM ∼ 12 M ∼35% at 50 M
Cui et al. (2001) Cui et al. (2001) Nishida et al. (1992b)
KM 31 ± 4 M Complete obliteration KI ∼ 2.18 M
Nishida et al. (1992a) Nishida et al. (1992a) Horikawa et al. (2002b)
∼95%
Yamaguchi et al. (1997)
∼85%
Takikawa et al. (1991)
∼95%
Hamaguchi et al. (1994)
>95%
Yamashita et al. (1993)
∼65%
Horikawa et al. (2002a)
∼75%
Takikawa et al. (1996)
∼80%
Takikawa et al. (1995)
KM 8.8 ± 1.3 M Not observed
Akita et al. (2001) Akita et al. (2001)
Impaired GSSG uptake
∼40% at 10 M
Heijn et al. (1992)
Human
Direct transport
Matsushima et al. (2005)
LLC-PK1 cells
Human
MDCKII cells
Human
Not observed
Sasaki et al. (2002)
Wistar rat erythrocyte vesicles MDCKII cells LLC-PK1 Cells
Rat
Enhanced apical efflux Enhanced apical efflux Impaired GSSG uptake
Cl = 0.268 ± 0.013 L/ min/mg protein ∼5×
Not observed 10 M
Heijn et al. (1992)
Human Human
Not determined ∼2×
Cui et al. (2001) Spears et al. (2005)
Sf9 vesicles
Human
Zelcer et al. (2003b)
MDCKII cells
Human
Not observed (ATP or GSH) Not observed
EHBR rat
Rat
∼70%
Takikawa et al. (1998)
Wistar rat
Rat
Not observed
Kitaura et al. (1997)
EHBR rat
Rat
∼35%
Takikawa et al. (1991)
EHBR rat
Rat
∼70%
Takikawa et al. (1995)
Wistar Rat Erythrocyte Vesicles
Rat
∼50% at 10 M
Heijn et al. (1992)
Rat
Direct transport Enhanced apical efflux Direct transport Enhanced apical efflux Impaired biliary excretion Impaired LTC4 biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired GSSG uptake
Spears et al. (2005)
Sasaki et al. (2002)
464
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3A (Continued) X-sulfate
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Glycolithocholate-S
Nordeoxycholate-3-S
Wistar Rat Erythrocyte Vesicles TR− rat
Rat
Impaired GSSG uptake
Competitive KI 2.9 ± 2.1 M
Heijn et al. (1992)
Rat
Impaired biliary excretion Impaired biliary excretion
∼85%
Oude Elferink et al. (1989) Oude Elferink et al. (1989)
Taurinenordeoxycholate-3-S
TR− rat
Rat
Taurolithocholate-S
HEK293 vesicles MDCKII cells
Human Human
Direct transport Enhanced apical efflux Direct transport Direct transport Direct transport Impaired biliary excretion Direct transport Impaired GSSG uptake
KM ∼ 12 M ∼4×
Cui et al. (2001) Sasaki et al. (2002)
S.D. CMVs EHBR CMVs Sf9 Vesicles EHBR Rat
Rat Rat Rat Rat
KM 1.5 ± 0.3 M Not observed KM 3.9 ± 0.4 M Not Observed
Akita et al. (2001) Akita et al. (2001) Akita et al. (2001) Takikawa et al. (1991)
Sf9 vesicles Wistar erythrocyte vesicles Sf9 vesicles
Rat Rat
Not determined ∼90% at 10 M
Stieger et al. (2000) Heijn et al. (1992)
Not determined
Ito et al. (2001b)
Rat
Direct transport
et al. (2006c) demonstrated that Abcg2 gene knockout mice exhibit a more profound alteration in the biliary excretion of intrahepatically formed sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol compared to Abcc2 gene knockout mice. These differences may be attributed in large part to the fact that rats have more Mrp2 protein than other species (Ninomiya et al., 2005), and this must be taken into consideration in study design and data interpretation, as well as in interspecies scaling. In mice, the constitutive expression level of Mrp3 is much higher than in other species (Belinsky et al., 2005; Donner and Keppler, 2001; Soroka et al., 2001). Furthermore, mouse Mrp3 is not as inducible as rat Mrp3 or human MRP3 under conditions that result in profound increases in hepatic Mrp3 expression such as bile duct ligation (Belinsky et al., 2005). Therefore, hepatic basolateral excretion of Mrp3 substrates in mice may be more representative of the induced Mrp3 state in other species, such as in cholestasis or following chronic exposure to phenobarbital. In scaling hepatic clearance of Mrp3 substrates, such as glucuronide conjugates, from mice to other species, care should be taken to account for interspecies variability in Mrp3 expression and inducibility. Mrp2 and Mrp3 have arguably been the most intensively studied hepatic efflux transporters for organic anions such as sulfate, glucuronide, and glutathione metabolites. Thus, much is known about species differences in these two proteins. However, it is possible that other transport proteins relevant to the hepatic excretion of phase II conjugates, such as Bcrp and Mrp4, exhibit some degree of species variation. The field of drug transport is still in its infancy, and current efforts have focused primarily on elucidation of the physiological role of transport proteins in the liver. More detailed information with respect to species differences in trans-
∼75%
porters such as Bcrp and Mrp4 undoubtedly will be forthcoming.
4.6.
Transporter multiplicity
Prior to the 21st century, transport proteins were thought to accept a specific set of substrates based primarily on particular physicochemical properties (typically size, charge, and lipohilicity), with little or no substrate overlap between transporters. However, more recent studies have indicated that considerable substrate overlap exists between transporters mediating translocation in the same direction and localized to the same plasma membrane domain. Mounting evidence for transporter multiplicity suggests that it is insufficient to demonstrate that a compound of interest can be transported by a single recombinant transport protein in vitro. In vivo or whole organ inhibition studies and/or investigations in transporter gene knockout animal models are necessary to accurately determine whether a single transport protein is involved in translocation of a compound across a specific membrane, or whether multiple transport processes are involved, and to precisely determine the relative contribution of each process (Hoffmaster et al., 2004; Zamek-Gliszczynski et al., 2005, 2006b). Development of more comprehensive in vitro recombinant models, where transport by all relevant proteins on a given plasma membrane domain is evaluated, and the relative contribution of each candidate transport protein to the overall vectorial flux is predicted, has been proposed (Hirano et al., 2004; Kopplow et al., 2005; Matsushima et al., 2005). Biliary excretion of sulfate conjugates in rats exemplifies substrate overlap between Mrp2 and Bcrp (ZamekGliszczynski et al., 2005, 2006b). In the Mrp2-deficient rat and in the wild-type rat in the presence of the Bcrp and P-glycoprotein inhibitor, GF120918, biliary excretion of sul-
465
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3B – Summary of reported interactions between glucuronide conjugates and Mrp2 X-glucuronide
Experimental system
E3040-G
EHBR rat perfused intestine Sf9 vesicles S.D. rat CMVs EHBR rat
Harmol-G
Bilirubin-monoG
Bilirubin-diG
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Rat
Impaired luminal secretion
∼50%
Adachi et al. (2005)
Rat Rat Rat
Direct transport Uptake Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired uptake Inhibition of DNP-SG uptake Impaired uptake
Not determined KM 5.7 ± 4.0 M ∼75%
Ito et al. (2001b) Niinuma et al. (1997) Takenaka et al. (1995)
∼95%
Takenaka et al. (1995)
∼97%
Takenaka et al. (1995)
∼60% Competitive KI 3.84 ± 0.34 M ∼95% KM ∼ 44.6 M
Takenaka et al. (1995) Niinuma et al. (1997)
Impaired biliary excretion Impaired biliary excretion
∼65%
EHBR rat liver perfusion EHBR rat liver perfusion EHBR CMVs S.D. rat CMVs
Rat
EHBR rat CMVs
Rat
−
TR rat liver perfusion Abcc2−/− mouse liver perfusion
Rat Rat Rat
Rat Mouse
TR− rat CMVs
Rat
Impaired uptake
Wistar rat CMVs
Rat
TR− rat CMVs
Rat
Inhibition of LTC4 uptake Impaired uptake
Wistar rat CMVs
Rat
Wistar rat CMVs TR− rat CMVs
Rat Rat
Inhibition of LTC4 uptake Uptake Impaired uptake
Wistar rat CMVs
Rat
Impaired BSP uptake
EHBR rat CMVs
Not observed
Niinuma et al. (1997) Zamek-Gliszczynski et al. (2006a, in press) Zamek-Gliszczynski et al. (2006a, in press)
Complete obliteration IC50 ∼ 0.12 M
Jedlitschky et al. (1997)
Complete obliteration IC50 ∼ 0.10 M
Jedlitschky et al. (1997)
KM 65 ± 15 M Complete obliteration KI ∼ 4.2 M competitive Not observed
Nishida et al. (1992b) Nishida et al. (1992b)
Oude Elferink et al. (1989) Oude Elferink et al. (1989)
Jedlitschky et al. (1997)
Jedlitschky et al. (1997)
Nishida et al. (1992b)
Rat
Impaired uptake
Nordeoxycholate-3-G
−
TR rat
Rat
∼99.5%
Nordeoxycholate-23-G
TR− rat
Rat
Impaired biliary excretion Enhanced biliary excretion
Acetaminophen-G
Sf9 Vesicles
Human
TR− rat
Rat Rat
Conc. dependent ∼4× at 10 mM Complete obliteration ∼99.7%
Chen et al. (2003b)
TR− rat liver perfusion TR− rat liver perfusion Sf9 vesicles
∼99.8%
Xiong et al. (2000)
KI ∼ 4–5 mM
Xiong et al. (2000)
TR− rat liver perfusion Abcc2−/− mouse liver perfusion
Rat
Stimulation of E217G uptake Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Inhibition of CDF uptake Impaired biliary excretion Impaired biliary excretion
∼99.8%
Zamek-Gliszczynski (2005) Zamek-Gliszczynski et al. (2006c, in press)
2 Binding sites IC50 70.1 ± 51.8 M IC50 1.54 ± 0.16 mM ∼99.5%
4-Methylumbelliferone-G
Rat Rat
Mouse
Sf9 vesicles
Dog
Inhibition of E217G transport
TR− rat liver perfusion Sf9 vesicles
Rat
Impaired biliary excretion Inhibition of E217G transport
Rat
∼3.5×
Not observed
IC50 452 ± 28 M
Adachi et al. (1993)
Zelcer et al. (2003c)
Xiong et al. (2000)
Ninomiya (2005)
Zamek-Gliszczynski et al. (2006b, in press) Ninomiya (2005)
466
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3B (Continued ) X-glucuronide
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Inhibited DNP-SG uptake Impaired luminal secretion
Conc. dependent ∼75% at 500 M Not observed
Niinuma et al. (1997)
Mouse
Impaired biliary excretion
∼40%
Zamek-Gliszczynski et al. (2006c, in press)
Impaired biliary excretion Impaired biliary excretion Impaired uptake Inhibition of DNP-SG uptake Impaired biliary excretion Impaired uptake Inhibition of DNP-SG uptake Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Direct transport Inhibition of ethacrynic acid-SG uptake EES uptake modulation Impaired biliary excretion Impaired biliary excretion Direct transport
∼99.5%
Shimamura et al. (1996)
∼90% 10 mg/kg ∼70% 40 mg/kg ∼80% KI 1.03 ± 0.05 M
Chu et al. (1997b)
S.D. rat CMVs
Rat
EHBR rat perfused intestine Abcc2−/− mouse liver perfusion
Rat
Glycyrrhizin
EHBR rat
Rat
SN-38-G (carboxylate)
EHBR rat
Rat
EHBR rat CMVs S.D. rat CMVs
Rat Rat
EHBR rat
Rat
EHBR rat CMVs S.D. rat CMVs
Rat Rat
hydroxyPhIP-G
TR− rat
Rat
N-hydroxyPhIP-N2-G
TR− rat
Rat
N-hydroxyPhIP-N3-G
TR− rat
Rat
Ethinylestradiol-G
Sf9 vesicles Sf9 vesicles
Human Human
Sf9 vesicle
Human
Bisphenol A-G
EHBR rat
Rat
Indomethacin-G
EHBR rat
Rat
4-
HEK293T vesicles
Human
(methylnitrosamino)1-(3-pyridyl)-1butanol-G Nicotine-N-G
HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
Troglitazone-G
TR− rat
Rat
HSR-903-G R-isomer
EHBR rat
Rat
HSR-903-G S-isomer
EHBR rat
Rat
Hydroxyphenobarbital-G
TR− rat liver perfusion Sf9 vesicles
Rat
SN-38-G (lactone)
Cotinine-N-G
Hydroxycotinine-O-G
Rat
E2 17G uptake inhibition Methotrexate uptake inhibition E2 17G uptake inhibition Methotraxate uptake inhibition Methotrexate uptake inhibition Methotrexate uptake inhibition Delayed biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Inhibition of CDF uptake
∼85% 10 mg/kg ∼60% 40 mg/kg ∼90% KI 1.62 ± 0.05 M
Adachi et al. (2005)
Chu et al. (1997a) Chu et al. (1997a) Chu et al. (1997b) Chu et al. (1997a) Chu et al. (1997a)
Complete obliteration Complete obliteration ∼90%
Dietrich et al. (2001b)
KM 35.1 ± 3.5 M KI 20 ± 1 M
Chu et al. (2004) Chu et al. (2004)
No effect (0–100 M)
Chu et al. (2004)
Complete obliteration ∼50%
Inoue et al. (2005) Kouzuki et al. (2000)
Not determined
Leslie et al. (2001)
Not observed at 100 M Not observed at 100 M Not observed at 100 M Not observed at 100 M Not observed at 100 M Not observed at 100 M Decreased 0–4 h >75%; 4–36 h normal ∼98%
Letourneau et al. (2005)
Murata et al. (1998)
∼99%
Murata et al. (1998)
Complete obliteration IC50 0.68 ± 0.02 mM
Patel et al. (2003)
Dietrich et al. (2001b) Dietrich et al. (2001b)
Letourneau et al. (2005) Letourneau et al. (2005) Letourneau et al. (2005) Letourneau et al. (2005) Letourneau et al. (2005) Kostrubsky et al. (2001)
Xiong et al. (2002)
467
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3B (Continued ) X-glucuronide
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Phenolphthalein-G
Sf9 vesicles
Rabbit
∼95% at 1 mM
van Aubel et al. (1998)
EHBR rat
Rat
Inhbition of E217G uptake Impaired biliary excretion
Complete obliteration
Ogasawara and Takikawa (2001)
Telmisaltan-G
EHBR rat
Rat
∼50%
Nishino et al. (2000)
Grepafloxacin-G
EHBR rat
Rat
∼99.4%
Sasabe et al. (1998)
S.D. rat CMVs S.D. rat CMVs
Rat Rat
KM 7.2 ± 2.4 M KI 9.2 ± 1.7 M
Sasabe et al. (1998) Sasabe et al. (1998)
EHBR CMVs
Rat
∼85%
Sasabe et al. (1998)
PKI166-G (ACU154)
MDCKII cells
Human
∼5×
Takada et al. (2004)
PKI166-G (ACU154) PKI166-G (ACU154)
Wistar rat CMVs TR− rat CMVs
Rat Rat
Takada et al. (2004) Takada et al. (2004)
PKI166-G (ACU154)
Wistar rat CMVs
Rat
Naphtol-G
Sf9 vesicles
Rabbit
KM ∼ 1 M Completely obliterated Conc. dependent ∼45% at 20 M ∼5% at 1 mM
Rat
Nitrophenol-G
TR− liver perfusion Sf9 vesicles
Rabbit
Valproate-G
TR− rat
Rat
UFX-G
EHBR rat
Rat
Estriol-16␣-G
Sf9 vesicles
Rat
Estradiol-3-G
Sf9 vesicles Sf9 vesicles
Rat Rat
Estradiol-3-S-17G
Sf9 vesicles
Rat
Sf9 vesicles
Rat
EHBR rat
Rat
Wistar erythrocyte vesicles EHBR rat
Rat
Rat
Biliary excretion modulation
EHBR rat
Rat
Ursodeoxycholate-G
EHBR rat
Rat
Taurolithocholate-G
EHBR rat
Rat
Chenodeoxycholate-G
EHBR rat
Rat
Estradiol-17-(DG)
MDCKII cells Sf9 vesicles Sf9 vesicles HEK293T vesicles
Human Human Rat Human
Impaired biliary excretion Impaired biliary excretion Enhanced biliary excretion Impaired biliary excretion Direct transport Direct transport Direct transport Direct transport
Cholate-G
Lithocholate-G
Impaired biliary excretion Impaired biliary excretion Uptake Inhibition of DNP-SG uptake Impaired uptake Enhanced apical excretion Uptake Impaired uptake Inhibition of E217G uptake Inhbition of E217G uptake Impaired biliary excretion Inhbition of E217G uptake Impaired biliary excretion Impaired biliary excretion Inhibition of E-3-G uptake Direct transport Inhibition of E217G uptake Inhibition of E217G uptake Inhibition of E-3-G uptake Impaired biliary excretion Impaired GSSG uptake
Takada et al. (2004) van Aubel et al. (1998)
∼90%
de Vries et al. (1989)
Not observed (1 mM)
van Aubel et al. (1998)
∼97%
Wright and Dickinson (2004) Yagi et al. (2003)
Complete obliteration IC50 ∼ 2 M KM ∼ 56 M Competitive IC50 ∼ 14 M Conc. dependent 20–50 M: >90% Competitive 5 M: increased E-3-G KM ∼ 2× Complete obliteration ∼5% at 10 M
∼40% decrease (1 nmol/min/g) ∼1.5× increase (1 nmol/min/g) ∼50–100% Complete obliteration ∼15.5× Complete obliteration Not determined KM >0.5 mM KM >160 M Not determined GSH independent
Gerk et al. (2004) Gerk et al. (2004) Gerk et al. (2004) Gerk et al. (2004) Gerk et al. (2004)
Morikawa et al. (2000) Heijn et al. (1992)
Takikawa et al. (1993)
Takikawa et al. (1991) Takikawa et al. (1992) Takikawa et al. (1991) Takikawa et al. (1991) Cui et al. (2001) Bodo et al. (2003) Gerk et al. (2004) Letourneau et al. (2005)
468
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3B (Continued ) X-glucuronide
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Stimulation of E217G uptake Inhibition of E-3-G uptake
Positive cooperativity Competitive IC50 ∼ 33 M 5–125 M: Increased E-3-G KM ∼ 50% IC50 13.3 ± 2.3 M
Gerk et al. (2004)
IC50 0.65 ± 0.12 M
Ito et al. (2001b)
Not determined KM 3.91 ± 0.73 M KM 7.46 ± 3.39 M KM 3.91 ± 0.93 M KM 4.81 ± 1.21 M 2 Binding sites KM 3.25 ± 0.10 M KM 75 M ∼5×
Ito et al. (2001c) Ito et al. (2005) Ito et al. (2001a) Ito et al. (2001b) Ninomiya et al. (2005) Ninomiya et al. (2005)
∼50% at 0.1 M ATP-dependent Not observed at 5 M
van Aubel et al. (1999) Zelcer et al. (2003c)
>20×
Spears et al. (2005)
Competely obliterated KM 6.32 ± 2.39 M Competitive KI 5.78 ± 1.20 M Dose dependent 180 pmol/g ∼90% 10 mol/g ∼65% Not determined Not determined Conc. dependent ∼85% at 200 M
Morikawa et al. (2000)
Sf9 vesicles
Rat
Sf9 vesicles
Rat
Sf9 vesicles
Rat
Sf9 vesicles
Rat
Sf9 vesicles Sf9 vesicles Sf9 vesicles Sf9 vesicles Sf9 Vesicles Sf9 vesicles
Human Rat Rat Rat Rat Dog
MDCKII cells
Human
Sf9 vesicles
Rabbit
Sf9 vesicles
Human
LLC-PK1 cells
Human
EHBR CMVs
Rat
S.D. rat CMVs S.D. rat CMVs
Rat Rat
EHBR rat
Rat
Sf9 vesicles Sf9 vesicles Sf9 vesicles
Rat Rat Human
Sf9 vesicles
Human
Yeast vesicles
Arabidopsis
Stimulation of DNP-SG uptake
Yeast vesicles
Arabidopsis
Yeast vesicles EHBR rat
Arabidopsis Rat
MDCKII Cells
Human
Inhibition of GSH uptake Direct transport Impaired biliary excretion Direct transport
Sf9 vesicles
Rat
Sf9 vesicles Sf9 vesicles Wistar CMVs
Rat Rabbit Rat
EHBR rat
Rat
HepG2 Cells
Human
Inhibition of DNP-SG uptake Inhibition of E217G uptake Direct transport Direct transport Direct transport Direct transport Direct transport Direct transport
Enhanced apical efflux Inhibition of GSH uptake Modulation of E217G uptake Enhanced apical efflux Impaired uptake Uptake Impaired DNP-SG uptake Impaired biliary excretion Direct transport Direct transport Inhibition of methotrexate uptake Direct transport
Inhibition of E217G uptake Direct transport Direct transport Inhibition of LTC4 uptake Impaired biliary excreion Inhibition of LTC4 transport
Gerk et al. (2004)
Ito et al. (2001b)
Sasaki et al. (2002)
Morikawa et al. (2000) Morikawa et al. (2000) Morikawa et al. (2000)
Ito et al. (2004) Xiong et al. (2002) Zelcer et al. (2003a,c)
KM ∼ 120 M homotropic cooperativity ∼5× decrease DNP-SG KM ∼ 6× cis stimulation Complete at 100 M
Zelcer et al. (2003c)
KM 752 ± 220 M ∼85%
Liu et al. (2001a,b) Takikawa et al. (1996)
Cl 3.56 ± 0.07 L/min/mg protein Competitive IC50 ∼ 14 M Not determined Not determined IC50 ∼ 0.10 M
Matsushima (2005)
Stieger et al. (2000) van Aubel et al. (1998) Jedlitschky et al. (1997)
∼80%
Sano et al. (1993)
IC50 ∼ 0.40 M
Jedlitschky et al. (1997)
Liu et al. (2001a)
Liu et al. (2001a)
Gerk et al. (2004)
469
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3C – Summary of reported interactions between glutathione conjugates and Mrp2 X-glutathione
Experimental system
Acetaminophen-SG
TR− rat
Rat
TR− rat liver perfusion
Rat
TR− rat
Rat
TR− rat liver perfusion
Rat
Acetaminophencysteinylglycine/cysteine
Acetaminophen-mercapturate TR− rat
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Impaired biliary excretion Impaired biliary excretion
Complete obliteration
Chen et al. (2003b)
Complete obliteration
Zamek-Gliszczynski et al. (2005)
Impaired biliary excretion Impaired biliary excretion
Not observed
Chen et al. (2003b)
∼90%
Zamek-Gliszczynski et al. (2005)
Rat
Metolachlor-SG Ethacrynic Acid-SG
Yeast vesicles Sf9 vesicles
Impaired biliary excretion Arabidopsis Direct transport Human Direct transport
Hydroxynonenal-SG
MDCKII Cells EHBR rat
Human Rat
N-ethylmaleimide-SG
Sf9 Vesicles Sf9 Plasma membranes
Human Human
Methylfluorescein-SG MDCKII cells Dinitrophenol-cysteinylglycine EHBR rat
Human Rat
Dinitrophenol-cysteine
EHBR rat
Rat
Dinitrophenol-mercapturate
EHBR rat
Rat
Curcumin-SG
MDCKII cells Sf9 Vesicles
Human Human
Methylmercury-SG
EHBR rat
Rat
Arsenite-SG
TR− rat
Rat
Decyl-SG
SD rat CMVs
Rat
Sulfobromophthalein-SG
TR−
Rat
S.D. rat CMVs
Rat
S.D. rat CMVs
Rat
Wistar rat CMVs EHBR rat
Rat Rat
Wistar rat erythrocyte vesicles EHBR rat liver perfusion MDCKII Cells S.D. Rat CMVs
Rat
Human Rat
EHBR rat CMVs
Rat
HEK293 vesicles LLC-PK1 vesicles Sf9 vesicles Sf9 vesicles HEK293T vesicles
Human Human Rat Human Human
Leokotriene C4
Rat
Enhanced apical efflux Impaired biliary excretion Direct transport Vanadate-sensitive ATPase stimulation
Complete obliteration
Chen et al. (2003b)
Not determined Not determined
Liu et al. (2001a) Wortelboer et al. (2003)
∼10× Complete obliteration
Ji et al. (2002) Ji et al. (2002)
KM ∼ 1.5 mM Concentrationdependent ∼3× at 10 mM EC50 ∼3–4 mM Enhanced cellular efflux Not determined Impaired biliary ∼85% excretion Impaired biliary ∼60% excretion Impaired biliary ∼70% excretion Enhanced apical efflux ∼3.5× Inhibition of ethacrynic IC50 ∼ 30 M acid-SG uptake Impaired biliary >98% excretion Impaired biliary ∼99.5% excretion (measured as As) Inhibition of DNP-SG KI ∼ 0.86 M uptake Impaired biliary ∼85% excretion Inhibition of DNP-SG KI ∼ 0.0461 M uptake cis and trans modulation Not observed 0–1 mM of GSH uptake Impaired BSP uptake ∼90% at 25 M Impaired biliary >95% excretion Impaired GSSG uptake Complete obliteration 1–10 M Impaired biliary excretion Direct transport MK-571 sensitive direct transport MK-571 Sensitive direct transport Direct transport Direct transport Direct transport Direct transport Direct transport
Bakos et al. (2000) Bakos et al. (2000)
Bogman et al. (2003) Gotoh et al. (2000) Gotoh et al. (2000) Gotoh et al. (2000) Wortelboer et al. (2003) Wortelboer et al. (2003) Ballatori et al. (1995) Dietrich et al. (2001a)
Horikawa et al. (2002a,b) Jansen et al. (1993) Horikawa et al. (2002a,b) Fernandez-Checa et al. (1992) Nishida et al. (1992a,b) Yamashita et al. (1993) Heijn et al. (1992)
Complete obliteration
Geng et al. (1998)
Not determined Not determined
Cui et al. (2001) Keppler et al. (1997)
Not observed
Keppler et al. (1997)
Not determined KM 0.26 ± 0.05 M Not determined Not determined Not determined GSH independent
Hashimoto et al. (2002) Chen et al. (1999) Ito et al. (2005) Ito et al. (2001c) Letourneau et al. (2005)
470
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3C (Continued ) X-glutathione
Dinitrophenol-SG
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Sf9 vesicles Sf9 vesicles
Rabbit Rabbit Human Human
MDCKII cells Sf9 vesicles Sf9 vesicles Sf9 vesicles
Human Rat Rabbit Rabbit
Not determined ∼75% at 5 M ATP dependent KM ∼ 1–1.4 M Concentrationdependent ∼1.5× at 20 mM ∼2× Not determined Not determined ∼80% at 10 M
van Aubel et al. (1999) van Aubel et al. (1999)
Sf9 vesicles Sf9 plasma membranes
Direct transport Inhibition of GSH uptake Direct transport Vanadate-sensitive ATPase stimulation
Wistar rat erythrocyte vesicles EHBR rat CMVs
Rat
∼20% at 1 M
Heijn et al. (1992)
Rat
Impaired uptake
Completely obliterated
Sf9 vesicles Sf9 vesicles EHBR rat
Rat Dog Rat
KM 2.05 ± 0.41 M KM 0.53 ± 0.03 M ∼80%
Xenopus laevis oocytes EHBR rat CMVs Sf9 vesicles
Rat
Direct transport Direct transport Impaired LTC4 biliary excretion Enhanced efflux
Fernandez-Checa et al. (1992) Ninomiya et al. (2005) Ninomiya et al. (2005) Kitaura et al. (1997)
∼2×
Madon et al. (1997)
Rat Rat
Impaired uptake Direct transport
∼98% Not determined
Keppler et al. (1997) Ito et al. (2001b)
MDCKII cells
Human Rat
Concentration dependent ∼75%
Cui et al. (2001)
EHBR rat CMVs
Hirouchi et al. (2005)
EHBR ratCMVs COS-7 cells Xenopus laevis oocytes S.D. rat CMVs
Rat Rat Rat
Inhibition of BSP apical excretion Impaired direct transport Impaired uptake Enhanced efflux Enhanced efflux
∼95% ∼9× ∼4×
Takenaka et al. (1995) Madon et al. (1997) Madon et al. (1997)
Conc. dependent ∼95% at 1 mM
Chu et al. (1997a)
KM 80.8 ± 7.0 M KM 62.6 ± 10.6 M IC50 19.3 ± 3.5 M
Ito et al. (2001b) Ito et al. (2001a) Ito et al. (2001b)
Conc. dependent ∼60% at 0.5 mM KM 126 ± 53 M ∼4× decrease E217G KM ∼ 3× cis stimulation ∼5–10× EC50 ∼ 1–7 M
Zelcer et al. (2003c)
KM 70 ± 12 M Not determined ∼3×
Paulusma et al. (1999) Zelcer et al. (2003c) Wortelboer et al. (2003)
∼95%
Gotoh et al. (2000)
∼50%
Gotoh et al. (2000)
Sf9 vesicles Sf9 vesicles Sf9 vesicles Sf9 vesicles Yeast vesicles Yeast vesicles Yeast vesicles MDCKII vesicles Sf9 vesicles MDCKII cells EHBR rat EHBR rat jejunum everted sac EHBR rat jejunum ussing chamber TR− rat liver perfusion
Enhanced apical efflux Direct transport Direct transport Inhibition of E217G uptake Inhibition of GSSG uptake
Inhibition of 5 M SN-38-G carboxylate uptake Rat Direct transport Rat Direct transport Rat Inhibition of E217G uptake Human Inhibition of E217G uptake Arabidopsis Direct transport Arabidopsis Stimulation of E217G uptake Arabidopsis Stimulation of E217G uptake Human Direct transport Human Direct transport Human Enhanced apical excretion Rat Impaired biliary excretion Rat Impaired secretion Rat
Bakos et al. (2000) Bakos et al. (2000)
Sasaki et al. (2002) Stieger et al. (2000) van Aubel et al. (1998) van Aubel et al. (1998)
Liu et al. (2001a) Liu et al. (2001a) Liu et al. (2001a)
Rat
Decreased BtoA/AtoB flux ratio
Decreased to ∼1
Gotoh et al. (2000)
Rat
Impaired biliary excretion
∼98%
Oude Elferink et al. (1989)
471
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3C (Continued ) X-glutathione
GSH
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Rat
Impaired efflux
∼80%
Oude Elferink et al. (1989) Oude Elferink et al. (1990) Nishida et al. (1992b)
TR− rat hepatocytes TR− rat hepatocytes Wistar rat CMVs
Rat
Impaired efflux
∼65%
Rat
Wistar rat CMVs Sf9 vesicles S.D. rat CMVs S.D. rat CMVs
Rat Rat Rat Rat
Impaired bilirubin-diG uptake Impaired BSP uptake Direct transport Uptake Inhibition of E3040G uptake
EHBR rat CMVs
Rat
∼40% at 200 M competitive KI ∼ 41 M competitive Not determined KM 17.6 ± 4.9 M Competitive, KI 17.1 ± 5.3 M Inhibition incomplete Not observed
EHBR rat CMVs Wistar rat erythrocyte vesicles S.D. rat CMVs
Rat Rat
Rat
S.D. Rat CMVs
Rat
S.D. Rat CMVs
Rat
Dubin–Johnson erythrocute vesicles TR− rat erythrocyte vesicles LLC-PK1 vesicles S.D. rat CMVs HEK293T vesicles
Human
HEK293T vesicles
Human
HEK293T vesicles
Human
TR− rat
Rat
TR− rat
Rat
MDCKII vesicles
Human
MDCKII cells Sf9 vesicles
Human Rabbit
Sf9 vesicles
Rabbit
Sf9 vesicles
Rabbit
MDCKII cells
Human
Sf9 vesicles
Human
MDCKII cells Sf9 vesicles Wistar rat CMVs
Human Human Rat
Inhibition of E3040G uptake Impaired uptake Impaired GSSG uptake
Impaired temocaprilat uptake cis Stimulation of GSH uptake
Nishida et al. (1992b) Ito et al. (2004) Niinuma et al. (1997) Niinuma et al. (1997)
Niinuma et al. (1997)
Complete obliteration Competitive KI 2.6 ± 1.4 M
Niinuma et al. (1997) Heijn et al. (1992)
KI ∼ 25.8 M
Ishizuka et al. (1997)
Human
No ATP: conc. dependent stimulation >30% 0.25–1 mM trans stimulation of GSH Conc. dependent ∼3× at uptake 1 mM Modulation of transport Not observed
Fernandez-Checa et al. (1992) Board et al. (1992)
Rat
Modulation of transport Not observed
Board et al. (1992)
Human Rat
Direct transport Inhibition of 5-CH3 -H4 PteGlu uptake Inhibition of NNAL-G uptake Modulation of LTC4 uptake Modulation of E217G uptake Impaired biliary excretion Impaired biliary excretion Inhibition of DNP-SG transport Enhanced apical efflux Stimulation of vinblastine uptake Direct transport
Not determined KI 34.5 ± 4.2 M
Chen et al. (1999) Kusuhara et al. (1998b)
∼86% at 3 mM
Leslie et al. (2001)
Not observed at 3 mM
Letourneau et al. (2005)
Not Observed at 3 mM
Letourneau et al. (2005)
∼40%
Paulusma et al. (1999)
∼99.9%
Paulusma et al. (1999)
Competitive KI 20 ± 0.6 mM ∼11× ∼5× at 5 mM ED50 1.9 ± 0.1 mM Not determined, ATP-independent Conc. dependent (0.1–5 mM) >90% at 5 mM ∼6×
Paulusma et al. (1999)
Potentiated vinblastine inhibition of LTC4 uptake Enhanced apical excretion Stimulationn of E217G uptake Enhanced apical efflux Direct transport Impaired bilirubin-diG uptake
Fernandez-Checa et al. (1992)
Paulusma et al. (1999) van Aubel et al. (1999) van Aubel et al. (1999) van Aubel et al. (1999)
Wortelboer et al. (2003)
∼20% at 0.1–10 mM
Zelcer et al. (2003c)
∼60% Not determined ∼20% at 5 mM
Ito et al. (2004) Zelcer et al. (2003c) Nishida et al. (1992b)
472
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 3C (Continued ) X-glutathione
GSSG
Methyl-SG
Experimental system
Species of Mrp2 origin
Interaction with Mrp2
Affinity
Reference
Modulation of BSP uptake Impaired uptake
Not Observed 3 mM
Nishida et al. (1992a)
Not observed ATP-independent GSH trans stimulated same KM VMAX KM ∼ 16 mM ∼97%
Fernandez-Checa et al. (1992)
Complete obliteration Complete obliteration
Oude Elferink et al. (1989) Dietrich et al. (2001a,b)
>99%
Koeppel et al. (1998)
∼99.6%
Lu et al. (1996)
∼90%
Johnson et al. (2002)
>98%
Ballartori et al. (1995)
Not determined Not observed 1–10 mM
Liu et al. (2001a) Liu et al. (2001a)
Wistar rat CMVs
Rat
EHBR rat CMVs
Rat
EHBR rat
Rat
TR− rat
Rat
TR− rat
Rat
TR− rat liver perfusion EHBR rat
Rat
EHBR rat
Rat
EHBR rat
Rat
Yeast vesicles Yeast vesicles
Arabidopsis Arabidopsis
Yeast vesicles
Arabidopsis
Yeast vesicles
Arabidopsis
Yeast vesicles
Arabidopsis
Yeast vesicles Yeast vesicles
Arabidopsis Arabidopsis
Sf9 Vesicles MDCKII vesicles
Rat Human
Sf9 vesicles
Human
Sf9 vesicles
Human
TR− rat CMVs Wistar rat CMVs
Rat Rat
Wistar rat CMVs TR− rat
Rat Rat
Dubin–Johnson erythrocute vesicles TR− rat erythrocyte vesicles TR− rat erythrocyte vesicles EHBR rat CMVs
Human
Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Impaired biliary excretion Direct transport Modulation of DNP-SG uptake Stimulation of E217G uptake Inhibition of DNP-SG uptake Stimulation of E217G uptake Direct transport Inhibition of E217G uptake Direct transport Inhibition of DNP-SG transport Inhibition of E217G uptake Inhibition of methotrexate uptake Impaired uptake Impaired bilirubin-diG uptake Impaired BSP uptake Impaired biliary excretion Modulation of transport
Rat
Yeast vesicles Yeast vesicles
Arabidopsis Direct transport Arabidopsis Inhibition of DNP-SG uptake Arabidopsis Stimulation of E217G uptake Rabbit Stimulation of vinblastine uptake
Yeast vesicles Sf9 vesicles
Rat
Sugawara et al. (1996)
Conc. dependent ∼3× at Liu et al. (2001a) 10 mM EC50 4.7 ± 1.3 mM Not observed 1–10 mM Liu et al. (2001a) Conc. dependent ∼2.5× at 10 mM Not determined Conc. dependent ∼25% at 200 M Not determined Conc. dependent ∼25% at 100 M Conc. dependent ∼60% at 1 mM Conc. dependent ∼50% at 1 mM Complete obliteration ∼50% at 100 M ∼60% at 25 M >99.7%
Liu et al. (2001a) Liu et al. (2001a) Liu et al. (2001a) Stieger et al. (2000) Paulusma et al. (1999) Zelcer et al. (2003c) Zelcer et al. (2003c) Nishida et al. (1992a) Nishida et al. (1992b)
Not observed
Nishida et al. (1992a) Oude Elferink et al. (1989) Board et al. (1992)
Impaired uptake
Not observed
Board et al. (1992)
Rat
Impaired uptake
∼45%
Heijn et al. (1992)
Rat
Impaired uptake
Completely obliterated
Fernandez-Checa et al. (1992)
Not determined Not observed 1–10 mM
Liu et al. (2001a) Liu et al. (2001a)
Conc. dependent ∼2.5× Liu et al. (2001a) at 10 mM ∼3× at 5 mM van Aubel et al. (1999)
473
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 4A – Summary of reported interactions between sulfate conjugates and Bcrp X-sulfate
Experimental system
Species of Bcrp origin
Interaction with Bcrp
Affinity
Reference
Acetaminophen-S
MDCKII cells
Mouse
A/B ratio ∼6–8
MDCKII Cells
Mouse
Liver perfsuion
Rat
Abcg2−/− mouse liver perfusion
Mouse
Enhanced apical excretion GF120918 inhibition of apical excretion GF120918 inhibition of biliary excretion Impaired biliary excretion
Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005)
Caco-2 Cells
Human
TC7 (Caco-2 subclone) cells TC7 (Caco-2 subclone) cells
Human
Aminomethylphenylimidazopyridine-S
Estrone-3-S
Estradiol-3-S
Dehydroepiandrosterone-S
Taurolithocholate-S
4-Methylumbelliferone-S
Human
K562 vesicles Sf9 vesicles
Human Human
K562 vesicles P388 Vesicles LLC-PK1 cells
Human Human Human
Caco-2 cells
Human
Caco-2 cells
Human
MDCKII cells
Human
K562 vesicles
Human
P388 vesicles
Human
LLC-PK1 cells
Human
K562 vesicles
Human
P388 Vesicles P388 vesicles
Human Human
P388 vesicles P388 vesicles
Human Human
K562 vesicles
Human
P388 vesicles
Human
P388 vesicles P388 vesicles
Human Human
MDCKII cells
Mouse
MDCKII cells
Mouse
Abcg2−/− mouse perfused intestine Abcg2−/− mouse
Mouse
Wistar rat liver perfusion
Mouse Rat
Ko143 inhibition of apical efflux Ko143 inhibition of apical efflux Enhanced apical excretion after BCRP induction Direct transport Direct transport Direct transport Direct transport Enhanced apical excretion Enhanced apical excretion Ko143, GF120918, prazosin inhibition of apical efflux Direct transport
A/B ratio ∼1 ∼50% ∼90% ∼20% at 5 M Ko143
Ebert et al. (2005)
∼40% at 5 M Ko143
Ebert et al. (2005)
<2×
Ebert et al. (2005)
KM 6.8 ± 1.4 M KM ∼ 40 M Not determined KM 16.6 ± 3.4 M ∼2×
Imai et al. (2003) Krishnamurthy et al. (2004) Yanase et al. (2004) Suzuki et al. (2003) Imai et al. (2003)
A/B ratio ∼8–16
Xia et al. (2005)
A/B ratio ∼1
Xia et al. (2005)
Cl = 2.31 ± 0.02 L/min/mg Matsushima et al. protein (2005)
Estrone-3-sulfate uptake inhibition Estrone-3-sulfate uptake inhibition Enhanced apical excretion Estrone-3-sulfate uptake inhibition Direct transport Estrone-3-sulfate uptake inhibition Direct transport Estrone-3-sulfate uptake inhibition Estrone-3-sulfate uptake inhibition Direct transport
Conc. dependent ∼60% at 30 M IC50 ∼ 14 M
Imai et al. (2003)
<40%
Imai et al. (2003)
Conc. dependent ∼50% at 30 M Not determined IC50 ∼ 55 M
Imai et al. (2003) Suzuki et al. (2003) Suzuki et al. (2003)
Not observed IC50 ∼ 37 M
Suzuki et al. (2003) Suzuki et al. (2003)
Conc. dependent ∼70% at 30 M KM 12.9 ± 2.1 M
Imai et al. (2003)
Direct transport Estrone-3-sulfate uptake inhibition Enhanced apical excretion GF120918 inhibition of apical excretion Impaired luminal excretion
Not determined IC50 ∼ 6 M
Suzuki et al. (2003) Suzuki et al. (2003)
A/B ratio ∼2
Complete obliteration
Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005) Adachi et al. (2005)
Not observed
Mizuno et al. (2004)
∼50%
Zamek-Gliszczynski et al. (2005)
Renal clearance modulation GF120918 inhibition of biliary excretion
A/B ratio ∼1
Suzuki et al. (2003)
Suzuki et al. (2003)
474
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 4A (Continued ) X-sulfate
Experimental system
Species of Bcrp origin
tInteraction with Bcrp
Affinity
Reference
Abcg2−/− mouse liver perfusion
Mouse
Impaired biliary excretion
∼99.9%
Zamek-Gliszczynski et al. (2005)
Harmol-S
Abcg2−/− mouse liver perfusion
Mouse
Impaired biliary excretion
∼99%
Zamek-Gliszczynski et al. (2005)
E3040-S
P388 vesicles P388 vesicles P388 vesicles
Human Human Human
KM 26.9 ± 4.0 M Not determined IC50 ∼ 10 M
Suzuki et al. (2003) Suzuki et al. (2003) Suzuki et al. (2003)
Abcg2−/− mouse
Mouse
∼4× Lower
Mizuno et al. (2004)
P388 vesicles
Human
IC50 ∼ 53 M
Suzuki et al. (2003)
MDCKII cells
Mouse
A/B ratio ∼5
MDCKII cells
Mouse
Direct transport Direct transport Estrone-3-sulfate uptake inhibition Impaired renal clearance Estrone-3-sulfate uptake inhibition Enhanced apical excretion GF120918 inhibition of apical excretion
Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005)
p-Nitrophenol-S
fate conjugates is impaired, but partially maintained. Biliary excretion of sulfate conjugates of acetaminophen and 4-methylumbelliferone is reduced to negligible levels in Mrp2deficient rats with GF120918 co-administration. Subsequent in vitro assays in Abcg2 and Mdr1a/Mdr1b gene knockout mouse liver perfusions demonstrated that the GF120918-sensitive component of sulfate conjugate biliary excretion was mediated by Bcrp, and not P-gp (Zamek-Gliszczynski et al., 2005, 2006b). Phase II metabolites, such as acetaminophen- and 4methylumbelliferyl sulfate demonstrate how in vitro assays with a single recombinant transport protein, such as Mrp2 or Bcrp, could mislead the investigator into concluding that in the absence of one of these protein, the sulfate metabolite would not be excreted into bile, when in fact this process would be partially maintained. The potential pitfalls of extending recombinant in vitro and transport gene knockout data from other organs to the liver is perhaps best exemplified by two P-glycoprotein substrates. Estradiol-17-(-d-glucuronide) is transported by recombinant P-glycoprotein in vitro (Huang et al., 1998), but in the intact liver, the absence of P-glycoprotein has no impact on the biliary excretion of this conjugate (Huang et al., 2000). [d-Penicillamine]2,5 enkephalin is an opioid pentapeptide whose CNS penetration is limited by P-glycoprotein at the blood–brain barrier (Chen and Pollack, 1997b, 1998, 1999). Despite the importance of P-glycoprotein in limiting access of this opioid to the CNS, elimination via biliary excretion was not impaired in Mdr1a gene knockout mice or by coadministration of GF120918 (Chen and Pollack, 1997a, 1998, 1999). However, in Mrp2-deficient rat livers, biliary excretion of [d-penicillamine]2,5 enkephalin was partially impaired, and fully impaired in the presence of a P-glycoprotein inhibitor (Hoffmaster et al., 2004). Collectively, these studies exemplify the potential pitfalls associated with predicting mechanisms of biliary excretion in the intact liver based on in vitro or other organ findings, and indicate that a more comprehensive approach is needed to elucidate the complexities of hepatic transport.
A/B ratio ∼1
4.7. Model systems for studying hepatic excretion of sulfate, glucuronide, and glutathione conjugates The hepatic excretion of sulfate, glucuronide and glutathione conjugates was first investigated in vivo in humans and animals by measuring urinary excretion with the requisite assumption that all conjugates recovered in urine were formed in the liver and traversed the hepatic basolateral membrane, moving from blood perfusing the hepatic sinusoids to the kidney for ultimate excretion in the urine; conjugates recovered in feces were assumed to be excreted from the bile and/or intestines. When access to bile was possible (T-tube in patients; bile duct cannulation in animals), biliary excretion of conjugates was measured directly. As discussed above, diseases that involved loss of specific hepatic transport functions [e.g., patients with Dubin–Johnson syndrome that lack canalicular MRP2 and exhibit impaired biliary excretion of sulfate, glucuronide, or glutathione conjugates of drugs or endogenous compounds (Kartenbeck et al., 1996; Paulusma et al., 1997)] have provided important insights regarding the role of transport proteins in disposition of conjugates. Naturally-occurring mutant rats that are deficient in canalicular Mrp2 allowed for early characterization of the substrate specificity for Mrp2 (Keppler and Konig, 1997; Oude Elferink and Jansen, 1994). More recently, the generation of knockout mouse models to examine the role of specific transport proteins in the hepatobiliary disposition of conjugates has proved very useful. However, data generated from naturally-occurring or generated knockout models must be interpreted cautiously because compensatory upregulation of other genes encoding different proteins involved in hepatic metabolism or transport may occur [e.g., increased Mrp3 expression in Mrp2 knockout models (Xiong et al., 2002b)], or other indirect alterations in hepatic disposition of conjugates (accumulation of endogenous substrates that compete for other routes of conjugate excretion) may confound data interpretation. The lack of specific inhibitors for individual hepatic transport proteins has been a major limitation in elu-
475
e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 447–486
Table 4B – Summary of reported interactions between glucuronide and glutathione conjugates and Bcrp Conjugate
Experimental system
Species of Bcrp origin
Interaction with Bcrp
Affinity
Reference
K562 vesicles MDCKII cells
Human Human
Direct transport Direct transport
P388 vesicles HEK293 vesicles K562 vesicles
Human Human Human
Imai et al. (2003) Matsushima et al. (2005) Suzuki et al. (2003) Chen et al. (2003b) Imai et al. (2003)
P388 vesicles
Human
Estrone-3-G
K562 vesicles
Human
∼10% at 30 M
Imai et al. (2003)
Estradiol-3-G
K562 vesicles
Human
Not observed
Imai et al. (2003)
4-Methylumbelliferone-G
P388 vesicles
Human
Direct transport Direct transport Estrone-3-sulfate uptake inhibition Estrone-3-sulfate uptake inhibition Estrone-3-sulfate uptake inhibition Estrone-3-sulfate uptake inhibition Direct transport
Not observed Cl = 0.383 ± 0.059 L/min/mg protein Not determined KM 44.2 ± 4.3 M Conc. dependent ∼20% at 30 M ∼7% at 75 M
Not determined
Suzuki et al. (2003)
P388 vesicles
Human
∼16% at 500 M
Suzuki et al. (2003)
Abcg2−/− mouse perfused intestine Wistar rat liver perfusion Abcg2−/− mouse liver perfusion
Mouse
∼80% lower
Adachi et al. (2005)
Not observed
Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005)
X-Glucuronide Estradiol-17-(G)
Rat Mouse
Estrone-3-sulfate uptake inhibition Impaired luminal excretion GF120918 modulation of biliary excretion Impaired biliary excretion
∼60%
Suzuki et al. (2003)
Harmol-G
Abcg2−/− mouse liver perfusion
Mouse
Impaired biliary excretion
∼95%
Zamek-Gliszczynski et al. (2005)
E3040-G
P388 vesicles P388 vesicles
Human Human
Not determined ∼24% at 250 M
Suzuki et al. (2003) Suzuki et al. (2003)
Abcg2−/− mouse perfused intestine Wistar rat liver perfusion Abcg2−/− mouse liver perfusion
Mouse
Direct transport Estrone-3-sulfate uptake inhibition Impaired luminal excretion GF120918 inhibition of biliary excretion Impaired biliary excretion
∼50% lower
Adachi et al. (2005)
Not observed
Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005)
SN-38-G
PC-6 vesicles HEK293 vesicles
Human Human
Direct transport Direct transport
KM ∼ 26 M Not determined
Nakatomi et al. (2001) Yoshikawa et al. (2004)
Aminomethylphenylimidazopyridine-G
TC7 (Caco-2 subclone) cells
Human
<2×
Ebert et al. (2005)
TC7 cells
Human
Enhanced apical excretion after BCRP induction Ko143 inhibition of apical efflux
∼20% at 5 M Ko143
Ebert et al. (2005)
P388 vesicles
Human
Not observed (2 M)
Suzuki et al. (2003)
Dinitrophenol-SG
P388 vesicles P388 vesicles
Human Human
Not determined ∼22% at 80 M
Suzuki et al. (2003) Suzuki et al. (2003)
Acetaminophen-SG
TR− rat liver perfusion TR− rat liver perfusion
Rat
Not observed
Zamek-Gliszczynski et al. (2005) Zamek-Gliszczynski et al. (2005)
Acetaminophen-G
X-Glutathione Leukotriene C4
Acetaminophencysteinylglycine/cysteine
Rat Mouse
Rat
cidating the role of individual transporters in overall disposition of sulfate, glucuronide and glutathione conjugates in vivo or in the isolated organ system. These model systems, with intact metabolic machinery and physiologically-relevant expression levels of transport proteins, may provide the best
Estrone-3-sulfate uptake inhibition Direct transport Estrone-3-sulfate uptake inhibition GF120918 modulation of biliary excretion GF120918 modulation of biliary excretion
∼80%
Not observed
overall description of hepatic disposition and the kinetics of hepatobiliary excretion of conjugates despite the multiplicity of transporters. Hepatocytes cultured between two layers of gelled collagen in a sandwich configuration maintain liverspecific functions including induction of metabolic enzymes
476
european journal of pharmaceutical sciences
to levels representative of in vivo expression and function (LeCluyse et al., 1996), develop intact canaliculi, maintain hepatic transport protein expression and function, and reestablish polarized excretory function (Liu et al., 1999a,b,c). Hepatocytes may offer some advantages over the intact liver with respect to compound requirements and higher throughput. However, molecular and functional characterization of the transport systems involved in the hepatic excretion of conjugates is challenging for cellular systems due to numerous practical limitations. Accurate kinetic characterization requires knowledge of the intracellular concentrations, which often are difficult to alter without influencing normal cellular processes. For example, preloading hepatocytes or transfected/expressed cells at precise substrate and/or inhibitor concentrations for efflux studies is problematic. If the conjugates are not taken up readily by the cells, intracellular concentrations of conjugates may be dependent on the formation rate of conjugates. Of course, transfected/expressed systems require pre-formed conjugates, which may not be readily available. The development of cell lines transfected with multiple transport proteins to facilitate vectorial transport of conjugates may circumvent some of these problems. Recently, Kopplow et al. (2005) demonstrated the utility of quadruple-transfected cells to study the transcellular transport of estrone 3-sulfate. The expression level of transport proteins between the transfected cells and whole liver must be considered in order to quantitatively predict biliary or basolateral excretion of conjugates in these artificial systems (Sasaki et al., 2004). Isolated basolateral or canalicular membrane vesicles would appear to be the least useful in vitro system for studying hepatic transport of conjugates. These membranes not only express the full complement of transport proteins, which makes it challenging to identify the specific transporters primarily responsible for excretion, but lack the metabolic machinery necessary to form conjugates. Furthermore, the directionality of transport may be lost in membrane vesicle systems, and the sidedness of vesicles (inside-out versus right side-out) may confound data interpretation. Clearly, the appropriate selection of a model system to study the hepatic excretion of conjugates depends on the study objectives. Important considerations include species differences in the transport proteins and the availability of preformed conjugate. For a more complete discussion of hepatic clearance models the reader is referred to ZamekGliszczynski and Brouwer (2004). If the objective is to examine the overall hepatobiliary disposition of the generated conjugate, in vivo, isolated perfused liver or sandwich-cultured hepatocyte studies would be appropriate. Transfected/expressed systems or knockout models would be more useful to characterize the specific protein(s) involved in transport of conjugates. The next decade promises to be an exciting era in the field of hepatic transport. As our knowledge of drug transport proteins increases, model systems will continue to be developed and refined to determine the extent of hepatic excretion of sulfate, glucuronide and glutathione conjugates in humans, to explore the interplay between metabolism and transport, to elucidate the mechanisms involved in cellular processing of conjugates, and to predict drug–drug interactions. A greater understanding of the regulatory mechanisms
27
( 2 0 0 6 ) 447–486
that govern transport and metabolic processes, and how disease states alter these processes, will undoubtedly evolve. One of the greatest challenges appears to be the major species differences that exist in the hepatic handling of sulfate, glucuronide and glutathione conjugates. If potent inhibitors of specific transport processes can be identified, many important questions can be addressed in a systematic fashion in humans. This knowledge will be particularly useful for conjugates that exhibit therapeutic efficacy and/or toxicity.
Acknowledgments The authors would like to sincerely thank Dr. Philip C. Smith and Rong Zhao for their constructive and insightful comments, which were instrumental in the prepatration of this manuscript. This work was funded by grant R01 GM41935 from the National Institutes of Health. Maciej J. Zamek-Gliszczynski was supported by a pre-doctoral fellowship in pharmacokinetics and drug disposition from the Eli Lilly and Company Foundation.
references
Abernethy, D.R., Greenblatt, D.J., Ameer, B., Shader, R.I., 1985. Probenecid impairment of acetaminophen and lorazepam clearance: direct inhibition of ether glucuronide formation. J. Pharmacol. Exp. Ther. 234, 345–349. Adachi, Y., Suzuki, H., Schinkel, A.H., Sugiyama, Y., 2005. Role of breast cancer resistance protein (bcrp1/abcg2) in the extrusion of glucuronide and sulfate conjugates from enterocytes to intestinal lumen. Mol. Pharmacol. 67, 923–928. Adachi, Y., Kobayashi, H., Shouji, M., Kitano, M., Okuyama, Y., Yamamoto, T., 1993. Functional integrity of hepatocyte canalicular membrane transport of taurocholate and bilirubin diglucuronide in eisai hyperbilirubinuria rats. Life Sci. 52, 777–784. Akita, H., Suzuki, H., Hirohashi, T., Takikawa, H., Sugiyama, Y., 2002. Transport activity of human mrp3 expressed in sf9 cells: comparative studies with rat mrp3. Pharm. Res. 19, 34–41. Akita, H., Suzuki, H., Ito, K., Kinoshita, S., Sato, N., Takikawa, H., Sugiyama, Y., 2001. Characterization of bile acid transport mediated by multidrug resistance associated protein 2 and bile salt export pump. Biochim. Biophys. Acta 1511, 7–16. Ameen, M., Musthapa, M.S., Abidi, P., Ahmad, I., Rahman, Q., 2003. Garlic attenuates chrysotile-mediated pulmonary toxicity in rats by altering the phase I and phase II drug metabolizing enzyme system. J. Biochem. Mol. Toxicol. 17, 366–371. Assem, M., Schuetz, E.G., Leggas, M., Sun, D., Yasuda, K., Reid, G., Zelcer, N., Adachi, M., Strom, S., Evans, R.M., Moore, D.D., Borst, P., Schuetz, J.D., 2004. Interactions between hepatic mrp4 and sult2a as revealed by the constitutive androstane receptor and mrp4 knockout mice. J. Biol. Chem.. Bai, J., Lai, L., Yeo, H.C., Goh, B.C., Tan, T.M., 2004. Multidrug resistance protein 4 (mrp4/abcc4) mediates efflux of bimane-glutathione. Int. J. Biochem. Cell. Biol. 36, 247–257. Bakos, E., Evers, R., Sinko, E., Varadi, A., Borst, P., Sarkadi, B., 2000. Interactions of the human multidrug resistance proteins mrp1 and mrp2 with organic anions. Mol. Pharmacol. 57, 760–768.
european journal of pharmaceutical sciences
Ballatori, N., Gatmaitan, Z., Truong, A.T., 1995. Impaired biliary excretion and whole body elimination of methylmercury in rats with congenital defect in biliary glutathione excretion. Hepatology 22, 1469–1473. Bandurski, R.S., Wilson, L.G., Squires, C.L., 1956. The mechanism of ’active sulfate’ formation. J. Am. Chem. Soc. 78, 6408–6409. Barbier, O., Villeneuve, L., Bocher, V., Fontaine, C., Torra, I.P., Duhem, C., Kosykh, V., Fruchart, J.C., Guillemette, C., Staels, B., 2003. The UDP-glucuronosyltransferase 1a9 enzyme is a peroxisome proliferator-activated receptor alpha and gamma target gene. J. Biol. Chem. 278, 13975–13983. Bates, S.E., Robey, R., Miyake, K., Rao, K., Ross, D.D., Litman, T., 2001. The role of half-transporters in multidrug resistance. J. Bioenerg. Biomembr. 33, 503–511. Belinsky, M.G., Chen, Z.S., Shchaveleva, I., Zeng, H., Kruh, G.D., 2002. Characterization of the drug resistance and transport properties of multidrug resistance protein 6 (mrp6, abcc6). Cancer Res. 62, 6172–6177. Belinsky, M.G., Dawson, P.A., Shchaveleva, I., Bain, L.J., Wang, R., Ling, V., Chen, Z.S., Grinberg, A., Westphal, H., Klein-Szanto, A., Lerro, A., Kruh, G.D., 2005. Analysis of the in vivo functions of mrp3. Mol. Pharmacol. 68, 160–168. Beyer, K.H., Russo, H.F., Tillson, E.K., Miller, A.K., Verwey, W.F., Gass, S.R., 1951. ‘benemid,’ p-(di-n-propylsulfamyl)-benzoic acid; its renal affinity and its elimination. Am. J. Physiol. 166, 625–640. Board, P., Nishida, T., Gatmaitan, Z., Che, M., Arias, I.M., 1992. Erythrocyte membrane transport of glutathione conjugates and oxidized glutathione in the Dubin–Johnson syndrome and in rats with hereditary hyperbilirubinemia. Hepatology 15, 722–725. Boberg, E.W., Miller, E.C., Miller, J.A., Poland, A., Liem, A., 1983. Strong evidence from studies with brachymorphic mice and pentachlorophenol that 1 -sulfooxysafrole is the major ultimate electrophilic and carcinogenic metabolite of 1 -hydroxysafrole in mouse liver. Cancer Res. 43, 5163– 5173. Bodo, A., Bakos, E., Szeri, F., Varadi, A., Sarkadi, B., 2003. Differential modulation of the human liver conjugate transporters mrp2 and mrp3 by bile acids and organic anions. J. Biol. Chem. 278, 23529–23537. Bogman, K., Erne-Brand, F., Alsenz, J., Drewe, J., 2003. The role of surfactants in the reversal of active transport mediated by multidrug resistance proteins. J. Pharm. Sci. 92, 1250–1261. Bohan, A., Boyer, J.L., 2002. Mechanisms of hepatic transport of drugs: implications for cholestatic drug reactions. Semin. Liver Dis. 22, 123–136. Bosma, P.J., Seppen, J., Goldhoorn, B., Bakker, C., Oude Elferink, R.P., Chowdhury, J.R., Chowdhury, N.R., Jansen, P.L., 1994. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J. Biol. Chem. 269, 17960–17964. Bosma, P.J., Chowdhury, J.R., Bakker, C., Gantla, S., de Boer, A., Oostra, B.A., Lindhout, D., Tytgat, G.N., Jansen, P.L., Oude Elferink, R.P., et al., 1995. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in gilbert’s syndrome. N. Engl. J. Med. 333, 1171–1175. Brouwer, K.L., Jones, J.A., 1990. Altered hepatobiliary disposition of acetaminophen metabolites after phenobarbital pretreatment and renal ligation: evidence for impaired biliary excretion and a diffusional barrier. J. Pharmacol. Exp. Ther. 252, 657–664. Buesen, R., Mock, M., Seidel, A., Jacob, J., Lampen, A., 2002. Interaction between metabolism and transport of benzo[a]pyrene and its metabolites in enterocytes. Toxicol. Appl. Pharmacol. 183, 168–178.
27
( 2 0 0 6 ) 447–486
477
Buhl, A.E., Waldon, D.J., Baker, C.A., Johnson, G.A., 1990. Minoxidil sulfate is the active metabolite that stimulates hair follicles. J. Invest. Dermatol. 95, 553–557. Byrne, J.A., Strautnieks, S.S., Mieli-Vergani, G., Higgins, C.F., Linton, K.J., Thompson, R.J., 2002. The human bile salt export pump: characterization of substrate specificity and identification of inhibitors. Gastroenterology 123, 1649–1658. Cappiello, M., Giuliani, L., Pacifici, G.M., 1991. Distribution of UDP-glucuronosyltransferase and its endogenous substrate uridine 5 -diphosphoglucuronic acid in human tissues. Eur. J. Clin. Pharmacol. 41, 345–350. Cappiello, M., Franchi, M., Giuliani, L., Pacifici, G.M., 1989. Distribution of 2-naphthol sulphotransferase and its endogenous substrate adenosine 3 -phosphate 5 -phosphosulphate in human tissues. Eur. J. Clin. Pharmacol. 37, 317–320. Carrella, M., Roda, E., 1999. Evolving concepts in the pathophysiology of biliary lipid secretion. Ital. J. Gastroenterol. Hepatol. 31, 643–648. Chen, C., Pollack, G.M., 1997a. Extensive biliary excretion of the model opioid peptide [d-pen2,5] enkephalin in rats. Pharm. Res. 14, 345–350. Chen, C., Pollack, G.M., 1997b. Blood–brain disposition and antinociceptive effects of d-penicillamine2,5-enkephalin in the mouse. J. Pharmacol. Exp. Ther. 283, 1151–1159. Chen, C., Pollack, G.M., 1998. Altered disposition and antinociception of [d-penicillamine(2,5)] enkephalin in mdr1a-gene-deficient mice. J. Pharmacol. Exp. Ther. 287, 545–552. Chen, C., Pollack, G.M., 1999. Enhanced antinociception of the model opioid peptide [d-penicillamine] enkephalin by P-glycoprotein modulation. Pharm. Res. 16, 296–301. Chen, C., Hennig, G.E., Manautou, J.E., 2003a. Hepatobiliary excretion of acetaminophen glutathione conjugate and its derivatives in transport-deficient (TR− ) hyperbilirubinemic rats. Drug Metab. Dispos. 31, 798–804. Chen, C., Slitt, A.L., Dieter, M.Z., Tanaka, Y., Scheffer, G.L., Klaassen, C.D., 2005. Up-regulation of mrp4 expression in kidney of mrp2-deficient tr− rats. Biochem. Pharmacol. 70, 1088–1095. Chen, Z.S., Lee, K., Kruh, G.D., 2001. Transport of cyclic nucleotides and estradiol 17-beta-d-glucuronide by multidrug resistance protein. 4. Resistance to 6-mercaptopurine and 6-thioguanine. J. Biol. Chem. 276, 33747–33754. Chen, Z.S., Lee, K., Walther, S., Raftogianis, R.B., Kuwano, M., Zeng, H., Kruh, G.D., 2002. Analysis of methotrexate and folate transport by multidrug resistance protein 4 (abcc4): Mrp4 is a component of the methotrexate efflux system. Cancer Res. 62, 3144–3150. Chen, Z.S., Robey, R.W., Belinsky, M.G., Shchaveleva, I., Ren, X.Q., Sugimoto, Y., Ross, D.D., Bates, S.E., Kruh, G.D., 2003b. Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-d-glucuronide) by abcg2: effects of acquired mutations at r482 on methotrexate transport. Cancer Res. 63, 4048–4054. Chen, Z.S., Kawabe, T., Ono, M., Aoki, S., Sumizawa, T., Furukawa, T., Uchiumi, T., Wada, M., Kuwano, M., Akiyama, S.I., 1999. Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter. Mol. Pharmacol. 56, 1219–1228. Chu, X.Y., Kato, Y., Sugiyama, Y., 1997a. Multiplicity of biliary excretion mechanisms for irinotecan, cpt-11, and its metabolites in rats. Cancer Res. 57, 1934–1938. Chu, X.Y., Kato, Y., Niinuma, K., Sudo, K.I., Hakusui, H., Sugiyama, Y., 1997b. Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J.
478
european journal of pharmaceutical sciences
Pharmacol. Exp. Ther. 281, 304–314. Chu, X.Y., Huskey, S.E., Braun, M.P., Sarkadi, B., Evans, D.C., Evers, R., 2004. Transport of ethinylestradiol glucuronide and ethinylestradiol sulfate by the multidrug resistance proteins mrp1, mrp2, and mrp3. J. Pharmacol. Exp. Ther. 309, 156–164. Clarke, D., Burchell, B., 1994. The uridine diphosphate glucuronosyltransferase multigene family: function and regulation. In: Kauffman, F. (Ed.), Conjugation–Deconjugation Reactions in Drug Metabolism and Toxicity. Springer-Verlag, Berlin, pp. 3–43. Coffman, B.L., Rios, G.R., King, C.D., Tephly, T.R., 1997. Human ugt2b7 catalyzes morphine glucuronidation. Drug Metab. Dispos. 25, 1–4. Court, M.H., Duan, S.X., von Moltke, L.L., Greenblatt, D.J., Patten, C.J., Miners, J.O., Mackenzie, P.I., 2001. Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J. Pharmacol. Exp. Ther. 299, 998–1006. Crayford, J.V., Hutson, D.H., 1980. Comperative metabolism of phenobarbital in the rat (cfe) and mouse (cf1). Food Cosmet. Toxicol. 18, 503–509. Cui, Y., Konig, J., Keppler, D., 2001. Vectorial transport by double-transfected cells expressing the human uptake transporter slc21a8 and the apical export pump abcc2. Mol. Pharmacol. 60, 934–943. Cummings, J., Zelcer, N., Allen, J.D., Yao, D., Boyd, G., Maliepaard, M., Friedberg, T.H., Smyth, J.F., Jodrell, D.I., 2004. Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins. Biochem. Pharmacol. 67, 31–39. de Vries, M.H., Redegeld, F.A., Koster, A.S., Noordhoek, J., de Haan, J.G., Oude Elferink, R.P., Jansen, P.L., 1989. Hepatic, intestinal and renal transport of 1-naphthol-beta-d-glucuronide in mutant rats with hereditary-conjugated hyperbilirubinemia. Naunyn. Schmiedebergs Arch. Pharmacol. 340, 588–592. Denk, G.U., Soroka, C.J., Takeyama, Y., Chen, W.S., Schuetz, J.D., Boyer, J.L., 2004. Multidrug resistance-associated protein 4 is up-regulated in liver but down-regulated in kidney in obstructive cholestasis in the rat. J. Hepatol. 40, 585–591. DePierre, J.W., Seidegard, J., Morgenstern, R., Balk, L., Meijer, J., Astrom, A., Norelius, I., Ernster, L., 1984. Induction of cytosolic glutathione transferase and microsomal epoxide hydrolase activities in extrahepatic organs of the rat by phenobarbital, 3-methylcholanthrene and trans-stilbene oxide. Xenobiotica 14, 295–301. Desmond, P.V., Smyth, F.E., Mashford, M.L., 1994. Release of latent glucuronosyltransferase activity contributes to the sparing of glucuronidation in experimental liver injuries. J. Gastroenterol. Hepatol. 9, 350–354. Dietrich, C.G., Ottenhoff, R., de Waart, D.R., Oude Elferink, R.P., 2001a. Role of mrp2 and gsh in intrahepatic cycling of toxins. Toxicology 167, 73–81. Dietrich, C.G., de Waart, D.R., Ottenhoff, R., Bootsma, A.H., van Gennip, A.H., Elferink, R.P., 2001b. Mrp2-deficiency in the rat impairs biliary and intestinal excretion and influences metabolism and disposition of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo. Carcinogenesis 22, 805–811. Doerge, D.R., Chang, H.C., Churchwell, M.I., Holder, C.L., 2000. Analysis of soy isoflavone conjugation in vitro and in human blood using liquid chromatography-mass spectrometry. Drug Metab. Dispos. 28, 298–307. Donner, M.G., Keppler, D., 2001. Up-regulation of basolateral multidrug resistance protein 3 (mrp3) in cholestatic rat liver. Hepatology 34, 351–359.
27
( 2 0 0 6 ) 447–486
Donner, M.G., Warskulat, U., Saha, N., Haussinger, D., 2004. Enhanced expression of basolateral multidrug resistance protein isoforms mrp3 and mrp5 in rat liver by lps. Biol. Chem. 385, 331–339. Duanmu, Z., Kocarek, T.A., Runge-Morris, M., 2001. Transcriptional regulation of rat hepatic aryl sulfotransferase (sult1a1) gene expression by glucocorticoids. Drug Metab. Dispos. 29, 1130–1135. Duanmu, Z., Dunbar, J., Falany, C.N., Runge-Morris, M., 2000. Induction of rat hepatic aryl sulfotransferase (sult1a1) gene expression by triamcinolone acetonide: impact on minoxidil-mediated hypotension. Toxicol. Appl. Pharmacol. 164, 312–320. Duanmu, Z., Locke, D., Smigelski, J., Wu, W., Dahn, M.S., Falany, C.N., Kocarek, T.A., Runge-Morris, M., 2002. Effects of dexamethasone on aryl (sult1a1)- and hydroxysteroid (sult2a1)-sulfotransferase gene expression in primary cultured human hepatocytes. Drug Metab. Dispos. 30, 997–1004. Dutton, G.J., 1980. Glucuronidation of Drugs and other Compounds. CRC Press, Boca Raton. Ebert, B., Seidel, A., Lampen, A., 2005. Identification of bcrp as transporter of benzo[a]pyrene conjugates metabolically formed in caco-2 cells and its induction by ah-receptor agonists. Carcinogenesis 26, 1754–1763. Ejendal, K.F., Hrycyna, C.A., 2002. Multidrug resistance and cancer: the role of the human abc transporter abcg2. Curr. Protein Pept. Sci. 3, 503–511. Elferink, R.P., Tytgat, G.N., Groen, A.K., 1997. Hepatic canalicular membrane. 1. The role of mdr2 P-glycoprotein in hepatobiliary lipid transport. FASEB J. 11, 19–28. Elferink, R.P., Ottenhoff, R., Liefting, W., de Haan, J., Jansen, P.L., 1989. Hepatobiliary transport of glutathione and glutathione conjugate in rats with hereditary hyperbilirubinemia. J. Clin. Invest. 84, 476–483. Eriksson, G., Strath, D., 1981. Decreased UDP-glucuronic acid in rat liver after ether narcosis: an isotachophoretic study. FEBS Lett. 124, 39–42. Ethell, B.T., Anderson, G.D., Burchell, B., 2003. The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases. Biochem. Pharmacol. 65, 1441–1449. Evans, W.E., Johnson, J.A., 2001. Pharmacogenomics: the inherited basis for interindividual differences in drug response. Annu. Rev. Genomics Hum. Genet. 2, 9–39. Falany, C.N., Comer, K.A., Dooley, T.P., Glatt, H., 1995. Human dehydroepiandrosterone sulfotransferase. Purification, molecular cloning, and characterization. Ann. N.Y. Acad. Sci. 774, 59–72. Falany, C.N., Xie, X., Wang, J., Ferrer, J., Falany, J.L., 2000. Molecular cloning and expression of novel sulphotransferase-like cdnas from human and rat brain. Biochem. J. 346 (Pt 3), 857–864. Fattinger, K., Funk, C., Pantze, M., Weber, C., Reichen, J., Stieger, B., Meier, P.J., 2001. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin. Pharmacol. Ther. 69, 223–231. Fernandez-Checa, J.C., Takikawa, H., Horie, T., Ookhtens, M., Kaplowitz, N., 1992. Canalicular transport of reduced glutathione in normal and mutant eisai hyperbilirubinemic rats. J. Biol. Chem. 267, 1667–1673. Fisher, M.B., Paine, M.F., Strelevitz, T.J., Wrighton, S.A., 2001. The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism. Drug Metab. Rev. 33, 273–297. Fouassier, L., Kinnman, N., Lefevre, G., Lasnier, E., Rey, C., Poupon, R., Elferink, R.P., Housset, C., 2002. Contribution of
european journal of pharmaceutical sciences
mrp2 in alterations of canalicular bile formation by the endothelin antagonist bosentan. J. Hepatol. 37, 184– 191. Funk, C., Ponelle, C., Scheuermann, G., Pantze, M., 2001. Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (bsep) in the rat. Mol. Pharmacol. 59, 627–635. Galinsky, R.E., Levy, G., 1981. Dose- and time-dependent elimination of acetaminophen in rats: pharmacokinetic implications of cosubstrate depletion. J. Pharmacol. Exp. Ther. 219, 14–20. Geng, W., Schwab, A.J., Horie, T., Goresky, C.A., Pang, K.S., 1998. Hepatic uptake of bromosulfophthalein–glutathione in perfused eisai hyperbilirubinemic mutant rat liver: a multiple-indicator dilution study. J. Pharmacol. Exp. Ther. 284, 480–492. Gerk, P.M., Li, W., Vore, M., 2004. Estradiol 3-glucuronide is transported by the multidrug resistance-associated protein 2 but does not activate the allosteric site bound by estradiol 17-glucuronide. Drug Metab. Dispos. 32, 1139– 1145. Glatt, H., Davis, W., Meinl, W., Hermersdorfer, H., Venitt, S., Phillips, D.H., 1998. Rat, but not human, sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture. Carcinogenesis 19, 1709–1713. Golden, P.L., Pollack, G.M., 2003. Blood–brain barrier efflux transport. J. Pharm. Sci. 92, 1739–1753. Gotoh, Y., Suzuki, H., Kinoshita, S., Hirohashi, T., Kato, Y., Sugiyama, Y., 2000. Involvement of an organic anion transporter (canalicular multispecific organic anion transporter/multidrug resistance-associated protein 2) in gastrointestinal secretion of glutathione conjugates in rats. J. Pharmacol. Exp. Ther. 292, 433–439. Gram, T.E., Gillette, J.R., 1971. Biotransformation of drugs. In: Bacq, Z.M. (Ed.), Fundamentals of Biochemical Pharmacology. Pergamon Press Ltd., New York, pp. 571–609. Gregus, Z., Madhu, C., Klaassen, C.D., 1990. Effect of microsomal enzyme inducers on biliary and urinary excretion of acetaminophen metabolites in rats. Decreased hepatobiliary and increased hepatovascular transport of acetaminophen-glucuronide after microsomal enzyme induction. Drug Metab. Dispos. 18, 10–19. Gregus, Z., Oguro, T., Klaassen, C.D., 1994a. Nutritionally and chemically induced impairment of sulfate activation and sulfation of xenobiotics in vivo. Chem. Biol. Interact. 92, 169–177. Gregus, Z., Watkins, J.B., Thompson, T.N., Klaassen, C.D., 1983. Depletion of hepatic uridine diphosphoglucuronic acid decreases the biliary excretion of drugs. J. Pharmacol. Exp. Ther. 225, 256–262. Gregus, Z., Kim, H.J., Madhu, C., Liu, Y., Rozman, P., Klaassen, C.D., 1994b. Sulfation of acetaminophen and acetaminophen-induced alterations in sulfate and 3 -phosphoadenosine 5 -phosphosulfate homeostasis in rats with deficient dietary intake of sulfur. Drug Metab. Dispos. 22, 725–730. Guarino, A.M., Conway, W.D., Fales, H.M., 1969. Mass spectral identification of probenecid metabolites in rat bile. Eur. J. Pharmacol. 8, 244–252. Guillemette, C., 2003. Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenom. J. 3, 136–158. Haimeur, A., Conseil, G., Deeley, R.G., Cole, S.P., 2004. The mrp-related and bcrp/abcg2 multidrug resistance proteins: biology, substrate specificity and regulation. Curr. Drug Metab. 5, 21–53.
27
( 2 0 0 6 ) 447–486
479
Hamaguchi, H., Yamaguchi, Y., Goto, M., Misumi, M., Hisama, N., Miyanari, N., Mori, K., Ogawa, M., 1994. Hepatic biliary transport after hepatocyte transplantation in eizai hyperbilirubinemic rats. Hepatology 20, 220–224. Hashimoto, K., Uchiumi, T., Konno, T., Ebihara, T., Nakamura, T., Wada, M., Sakisaka, S., Maniwa, F., Amachi, T., Ueda, K., Kuwano, M., 2002. Trafficking and functional defects by mutations of the ATP-binding domains in mrp2 in patients with Dubin–Johnson syndrome. Hepatology 36, 1236–1245. Hauser, S.C., Ziurys, J.C., Gollan, J.L., 1988. A membrane transporter mediates access of uridine 5 -diphosphoglucuronic acid from the cytosol into the endoplasmic reticulum of rat hepatocytes: implications for glucuronidation reactions. Biochim. Biophys. Acta 967, 149–157. Heijn, M., Oude Elferink, R.P., Jansen, P.L., 1992. ATP-dependent multispecific organic anion transport system in rat erythrocyte membrane vesicles. Am. J. Physiol. 262, C104–C110. Her, C., Wood, T.C., Eichler, E.E., Mohrenweiser, H.W., Ramagli, L.S., Siciliano, M.J., Weinshilboum, R.M., 1998. Human hydroxysteroid sulfotransferase sult2b1: two enzymes encoded by a single chromosome 19 gene. Genomics 53, 284–295. Hirano, M., Maeda, K., Shitara, Y., Sugiyama, Y., 2004. Contribution of oatp2 (oatp1b1) and oatp8 (oatp1b3) to the hepatic uptake of pitavastatin in humans. J. Pharmacol. Exp. Ther. 311, 139–146. Hirohashi, T., Suzuki, H., Sugiyama, Y., 1999. Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (mrp3). J. Biol. Chem. 274, 15181–15185. Hirohashi, T., Suzuki, H., Takikawa, H., Sugiyama, Y., 2000a. ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 (mrp3). J. Biol. Chem. 275, 2905–2910. Hirohashi, T., Suzuki, H., Chu, X.Y., Tamai, I., Tsuji, A., Sugiyama, Y., 2000b. Function and expression of multidrug resistance-associated protein family in human colon adenocarcinoma cells (caco-2). J. Pharmacol. Exp. Ther. 292, 265–270. Hirouchi, M., Suzuki, H., Sugiyama, Y., 2005. Treatment of hyperbilirubinemia in eisai hyperbilirubinemic rat by transfecting human mrp2/abcc2 gene. Pharm. Res. 22, 661–666. Hjelle, J.J., Hazelton, G.A., Klaassen, C.D., 1985. Acetaminophen decreases adenosine 3 -phosphate 5 -phosphosulfate and uridine diphosphoglucuronic acid in rat liver. Drug Metab. Dispos. 13, 35–41. Hoffmaster, K.A., Zamek-Gliszczynski, M.J., Pollack, G.M., Brouwer, K.L., 2004. Hepatobiliary disposition of the metabolically stable opioid peptide [d-penicillamine2,5]enkephalin (dpdpe): pharmacokinetic consequences of the interplay between multiple transport systems. J. Pharmacol. Exp. Ther. 311, 1203–1210. Homolya, L., Varadi, A., Sarkadi, B., 2003. Multidrug resistance-associated proteins: export pumps for conjugates with glutathione, glucuronate or sulfate. Biofactors 17, 103–114. Horikawa, M., Kato, Y., Sugiyama, Y., 2002a. Reduced gastrointestinal toxicity following inhibition of the biliary excretion of irinotecan and its metabolites by probenecid in rats. Pharm. Res. 19, 1345–1353. Horikawa, M., Kato, Y., Tyson, C.A., Sugiyama, Y., 2002b. The potential for an interaction between mrp2 (abcc2) and various therapeutic agents: probenecid as a candidate inhibitor of the biliary excretion of irinotecan metabolites. Drug Metab. Pharmacokinet. 17, 23–33.
480
european journal of pharmaceutical sciences
Huang, L., Vore, M., 2001. Multidrug resistance P-glycoprotein 2 is essential for the biliary excretion of indocyanine green. Drug Metab. Dispos. 29, 634–637. Huang, L., Hoffman, T., Vore, M., 1998. Adenosine triphosphate-dependent transport of estradiol-17beta(beta-d-glucuronide) in membrane vesicles by mdr1 expressed in insect cells. Hepatology 28, 1371–1377. Huang, L., Smit, J.W., Meijer, D.K., Vore, M., 2000. Mrp2 is essential for estradiol-17beta(beta-d-glucuronide)-induced cholestasis in rats. Hepatology 32, 66–72. Iida, S., Mizuma, T., Sakuma, N., Hayashi, M., Awazu, S., 1989. Transport of acetaminophen conjugates in isolated rat hepatocytes. Drug Metab. Dispos. 17, 341–344. Ikeda, H., Nishi, S., Sakai, M., 2004. Transcription factor nrf2/mafk regulates rat placental glutathione S-transferase gene during hepatocarcinogenesis. Biochem. J. 380, 515–521. Ilias, A., Urban, Z., Seidl, T.L., Le Saux, O., Sinko, E., Boyd, C.D., Sarkadi, B., Varadi, A., 2002. Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human abcc6 (mrp6). J. Biol. Chem. 277, 16860–16867. Imai, Y., Asada, S., Tsukahara, S., Ishikawa, E., Tsuruo, T., Sugimoto, Y., 2003. Breast cancer resistance protein exports sulfated estrogens but not free estrogens. Mol. Pharmacol. 64, 610–618. Inoue, H., Tsuruta, A., Kudo, S., Ishii, T., Fukushima, Y., Iwano, H., Yokota, H., Kato, S., 2005. Bisphenol a glucuronidation and excretion in liver of pregnant and non-pregnant female rats. Drug Metab. Dispos. 33, 55–59. Ishizuka, H., Konno, K., Naganuma, H., Sasahara, K., Kawahara, Y., Niinuma, K., Suzuki, H., Sugiyama, Y., 1997. Temocaprilat, a novel angiotensin-converting enzyme inhibitor, is excreted in bile via an ATP-dependent active transporter (cmoat) that is deficient in eisai hyperbilirubinemic mutant rats (ehbr). J. Pharmacol. Exp. Ther. 280, 1304–1311. Ishizuka, H., Konno, K., Shiina, T., Naganuma, H., Nishimura, K., Ito, K., Suzuki, H., Sugiyama, Y., 1999. Species differences in the transport activity for organic anions across the bile canalicular membrane. J. Pharmacol. Exp. Ther. 290, 1324–1330. Ito, K., Suzuki, H., Sugiyama, Y., 2001a. Single amino acid substitution of rat mrp2 results in acquired transport activity for taurocholate. Am. J. Physiol. Gastrointest. Liver Physiol. 281, G1034–G1040. Ito, K., Suzuki, H., Sugiyama, Y., 2001b. Charged amino acids in the transmembrane domains are involved in the determination of the substrate specificity of rat mrp2. Mol. Pharmacol. 59, 1077–1085. Ito, K., Wakabayashi, T., Horie, T., 2005. Mrp2/abcc2 transport activity is stimulated by protein kinase calpha in a baculo virus co-expression system. Life Sci. 77, 539–550. Ito, K., Koresawa, T., Nakano, K., Horie, T., 2004. Mrp2 is involved in benzylpenicillin-induced choleresis. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G42–G49. Ito, K., Oleschuk, C.J., Westlake, C., Vasa, M.Z., Deeley, R.G., Cole, S.P., 2001c. Mutation of trp1254 in the multispecific organic anion transporter, multidrug resistance protein 2 (mrp2) (abcc2), alters substrate specificity and results in loss of methotrexate transport activity. J. Biol. Chem. 276, 38108–38114. Jansen, P.L., van Klinken, J.W., van Gelder, M., Ottenhoff, R., Elferink, R.P., 1993. Preserved organic anion transport in mutant TR− rats with a hepatobiliary secretion defect. Am. J. Physiol. 265, G445–G450. Jedlitschky, G., Cassidy, A.J., Sales, M., Pratt, N., Burchell, B., 1999. Cloning and characterization of a novel human olfactory UDP-glucuronosyltransferase. Biochem. J. 340 (Pt 3), 837–843.
27
( 2 0 0 6 ) 447–486
Jedlitschky, G., Leier, I., Buchholz, U., Hummel-Eisenbeiss, J., Burchell, B., Keppler, D., 1997. ATP-dependent transport of bilirubin glucuronides by the multidrug resistance protein mrp1 and its hepatocyte canalicular isoform mrp2. Biochem. J. 327 (Pt 1), 305–310. Ji, B., Ito, K., Suzuki, H., Sugiyama, Y., Horie, T., 2002. Multidrug resistance-associated protein2 (mrp2) plays an important role in the biliary excretion of glutathione conjugates of 4-hydroxynonenal. Free Radic. Biol. Med. 33, 370–378. Ji, B., Ito, K., Sekine, S., Tajima, A., Horie, T., 2004. Ethacrynic-acid-induced glutathione depletion and oxidative stress in normal and mrp2-deficient rat liver. Free Radic. Biol. Med. 37, 1718–1729. Johnson, D.R., Habeebu, S.S., Klaassen, C.D., 2002. Increase in bile flow and biliary excretion of glutathione-derived sulfhydryls in rats by drug-metabolizing enzyme inducers is mediated by multidrug resistance protein 2. Toxicol. Sci. 66, 16–26. Kamali, F., 1993. The effect of probenecid on paracetamol metabolism and pharmacokinetics. Eur. J. Clin. Pharmacol. 45, 551–553. Kartenbeck, J., Leuschner, U., Mayer, R., Keppler, D., 1996. Absence of the canalicular isoform of the mrp gene-encoded conjugate export pump from the hepatocytes in Dubin–Johnson syndrome. Hepatology 23, 1061–1066. Kato, Y., Suzuki, H., Sugiyama, Y., 2002. Toxicological implications of hepatobiliary transporters. Toxicology 181–182, 287–290. Kawai, K., Kawasaki-Tokui, Y., Odaka, T., Tsuruta, F., Kazui, M., Iwabuchi, H., Nakamura, T., Kinoshita, T., Ikeda, T., Yoshioka, T., Komai, T., Nakamura, K., 1997. Disposition and metabolism of the new oral antidiabetic drug troglitazone in rats, mice and dogs. Arzneimittelforschung 47, 356–368. Keppler, D., Konig, J., 1997. Hepatic canalicular membrane 5: expression and localization of the conjugate export pump encoded by the mrp2 (cmrp/cmoat) gene in liver. FASEB J. 11, 509–516. Keppler, D., Konig, J., Buchler, M., 1997. The canalicular multidrug resistance protein, cmrp/mrp2, a novel conjugate export pump expressed in the apical membrane of hepatocytes. Adv. Enz. Regul. 37, 321–333. Kim, H.J., Rozman, P., Madhu, C., Klaassen, C.D., 1992. Homeostasis of sulfate and 3 -phosphoadenosine 5 -phosphosulfate in rats after acetaminophen administration. J. Pharmacol. Exp. Ther. 261, 1015–1021. Kitaura, K., Takikawa, H., Yamanaka, M., 1997. Effects of organic anions and bile acid conjugates on biliary excretion of ltc4 in the rat. Prostaglandins 54, 745–755. Klokouzas, A., Wu, C.P., van Veen, H.W., Barrand, M.A., Hladky, S.B., 2003. Cgmp and glutathione-conjugate transport in human erythrocytes. Eur. J. Biochem. 270, 3696–3708. Koeppel, T.A., Trauner, M., Mennone, A., Arrese, M., Rios-Velez, L., Boyer, J.L., 1998. Role of glutathione in hepatic bile formation during reperfusion after cold ischemia of the rat liver. J. Hepatol. 28, 812–819. Konig, J., Rost, D., Cui, Y., Keppler, D., 1999. Characterization of the human multidrug resistance protein isoform mrp3 localized to the basolateral hepatocyte membrane. Hepatology 29, 1156–1163. Kool, M., van der Linden, M., de Haas, M., Scheffer, G.L., de Vree, J.M., Smith, A.J., Jansen, G., Peters, G.J., Ponne, N., Scheper, R.J., Elferink, R.P., Baas, F., Borst, P., 1999. Mrp3, an organic anion transporter able to transport anti-cancer drugs. Proc. Natl. Acad. Sci. U.S.A. 96, 6914–6919. Kopplow, K., Letschert, K., Konig, J., Walter, B., Keppler, D., 2005. Human hepatobiliary transport of organic anions analyzed by quadruple-transfected cells. Mol. Pharmacol. 68, 1031–1038.
european journal of pharmaceutical sciences
Koster, H., Scholtens, E., Mulder, G.J., 1979. Inhibition of sulfation of phenols in vivo by 2,6-dichloro-4-nitrophenol: selectivity of its action in relation to other conjugations in the rat in vivo. Med. Biol. 57, 340–344. Koster, H., Halsema, I., Scholtens, E., Meerman, J.H., Pang, K.S., Mulder, G.J., 1982. Selective inhibition of sulfate conjugation in the rat: pharmacokinetics and characterization of the inhibitory effect of 2,6-dichloro-4-nitrophenol. Biochem. Pharmacol. 31, 1919–1924. Kostrubsky, V.E., Vore, M., Kindt, E., Burliegh, J., Rogers, K., Peter, G., Altrogge, D., Sinz, M.W., 2001. The effect of troglitazone biliary excretion on metabolite distribution and cholestasis in transporter-deficient rats. Drug Metab. Dispos. 29, 1561–1566. Kouzuki, H., Suzuki, H., Sugiyama, Y., 2000. Pharmacokinetic study of the hepatobiliary transport of indomethacin. Pharm. Res. 17, 432–438. Krajka-Kuzniak, V., Szaefer, H., Baer-Dubowska, W., 2004. Modulation of 3-methylcholanthrene-induced rat hepatic and renal cytochrome p450 and phase ii enzymes by plant phenols: protocatechuic and tannic acids. Toxicol. Lett. 152, 117–126. Krishnamurthy, P., Ross, D.D., Nakanishi, T., Bailey-Dell, K., Zhou, S., Mercer, K.E., Sarkadi, B., Sorrentino, B.P., Schuetz, J.D., 2004. The stem cell marker bcrp/abcg2 enhances hypoxic cell survival through interactions with heme. J. Biol. Chem. 279, 24218–24225. Kullak-Ublick, G.A., Stieger, B., Hagenbuch, B., Meier, P.J., 2000. Hepatic transport of bile salts. Semin. Liver Dis. 20, 273–292. Kuroda, M., Kobayashi, Y., Tanaka, Y., Itani, T., Mifuji, R., Araki, J., Kaito, M., Adachi, Y., 2004. Increased hepatic and renal expressions of multidrug resistance-associated protein 3 in eisai hyperbilirubinuria rats. J. Gastroenterol. Hepatol. 19, 146–153. Kusuhara, H., Suzuki, H., Sugiyama, Y., 1998a. The role of P-glycoprotein and canalicular multispecific organic anion transporter in the hepatobiliary excretion of drugs. J. Pharm. Sci. 87, 1025–1040. Kusuhara, H., Han, Y.H., Shimoda, M., Kokue, E., Suzuki, H., Sugiyama, Y., 1998b. Reduced folate derivatives are endogenous substrates for cmoat in rats. Am. J. Physiol. 275, G789–G790. Le, H.T., Franklin, M.R., 1997. Selective induction of phase ii drug metabolizing enzyme activities by quinolines and isoquinolines. Chem. Biol. Interact. 103, 167–178. LeCluyse, E.L., Bullock, P.L., Parkinson, A., Hochman, J.H., 1996. Cultured rat hepatocytes. Pharm. Biotechnol. 8, 121–159. Lee, Y.J., Kusuhara, H., Sugiyama, Y., 2004a. Do multidrug resistance-associated protein-1 and -2 play any role in the elimination of estradiol-17 beta-glucuronide and 2,4-dinitrophenyl-S-glutathione across the blood–cerebrospinal fluid barrier? J. Pharm. Sci. 93, 99–107. Lee, Y.M., Cui, Y., Konig, J., Risch, A., Jager, B., Drings, P., Bartsch, H., Keppler, D., Nies, A.T., 2004b. Identification and functional characterization of the natural variant mrp3-arg1297his of human multidrug resistance protein 3 (mrp3/abcc3). Pharmacogenetics 14, 213–223. Leslie, E.M., Ito, K., Upadhyaya, P., Hecht, S.S., Deeley, R.G., Cole, S.P., 2001. Transport of the beta-o-glucuronide conjugate of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (nnal) by the multidrug resistance protein 1 (mrp1). Requirement for glutathione or a non-sulfur-containing analog. J. Biol. Chem. 276, 27846–27854. Letourneau, I.J., Bowers, R.J., Deeley, R.G., Cole, S.P., 2005. Limited modulation of the transport activity of the human multidrug resistance proteins mrp1, mrp2 and mrp3 by nicotine glucuronide metabolites. Toxicol. Lett. 157, 9–19.
27
( 2 0 0 6 ) 447–486
481
Liu, G., Sanchez-Fernandez, R., Li, Z.S., Rea, P.A., 2001a. Enhanced multispecificity of arabidopsis vacuolar multidrug resistance-associated protein-type ATP-binding cassette transporter, atmrp2. J. Biol. Chem. 276, 8648–8656. Liu, J., Chen, H., Miller, D.S., Saavedra, J.E., Keefer, L.K., Johnson, D.R., Klaassen, C.D., Waalkes, M.P., 2001b. Overexpression of glutathione S-transferase ii and multidrug resistance transport proteins is associated with acquired tolerance to inorganic arsenic. Mol. Pharmacol. 60, 302–309. Liu, J.H., Smith, P.C., 2006. Predicting the pharmacokinetics of acyl glucuronides and their parent compounds in disease states. Curr. Drug Metab. 7. Liu, L., Klaassen, C.D., 1996. Regulation of hepatic sulfotransferases by steroidal chemicals in rats. Drug Metab. Dispos. 24, 854–858. Liu, X., Chism, J.P., LeCluyse, E.L., Brouwer, K.R., Brouwer, K.L., 1999a. Correlation of biliary excretion in sandwich-cultured rat hepatocytes and in vivo in rats. Drug Metab. Dispos. 27, 637–644. Liu, X., LeCluyse, E.L., Brouwer, K.R., Lightfoot, R.M., Lee, J.I., Brouwer, K.L., 1999b. Use of ca2+ modulation to evaluate biliary excretion in sandwich-cultured rat hepatocytes. J. Pharmacol. Exp. Ther. 289, 1592–1599. Liu, X., LeCluyse, E.L., Brouwer, K.R., Gan, L.S., Lemasters, J.J., Stieger, B., Meier, P.J., Brouwer, K.L., 1999c. Biliary excretion in primary rat hepatocytes cultured in a collagen-sandwich configuration. Am. J. Physiol. 277, G12–G21. Loeser, W., Siegers, C.P., 1985. Effects of phenobarbital, phorone and carbon tetrachloride pretreatment on the biliary excretion of acetaminophen in rats. Arch. Int. Pharmacodyn. Ther. 275, 180–188. Low, L.K., 1998. Metabolic changes of drugs and related organic compounds. In: Delgado, J.N., Remers, W.A. (Eds.), Wilson and gisvold’s textbook of organic medicinal and pharmaceutical chemistry. Lippincott-Raven, Philadelphia, pp. 43–122. Lu, S.C., Cai, J., Kuhlenkamp, J., Sun, W.M., Takikawa, H., Takenaka, O., Horie, T., Yi, J., Kaplowitz, N., 1996. Alterations in glutathione homeostasis in mutant eisai hyperbilirubinemic rats. Hepatology 24, 253–258. Madon, J., Eckhardt, U., Gerloff, T., Stieger, B., Meier, P.J., 1997. Functional expression of the rat liver canalicular isoform of the multidrug resistance-associated protein. FEBS Lett. 406, 75–78. Madon, J., Hagenbuch, B., Landmann, L., Meier, P.J., Stieger, B., 2000. Transport function and hepatocellular localization of mrp6 in rat liver. Mol. Pharmacol. 57, 634–641. Manautou, J.E., de Waart, D.R., Kunne, C., Zelcer, N., Goedken, M., Borst, P., Elferink, R.O., 2005. Altered disposition of acetaminophen in mice with a disruption of the mrp3 gene. Hepatology 42, 1091–1098. Markovich, D., 2001. Physiological roles and regulation of mammalian sulfate transporters. Physiol. Rev. 81, 1499–1533. Mason, J., Cardin, C.J., 1977. The competition of molybdate and sulphate ions for a transport system in the ovine small intestine. Res. Vet. Sci. 22, 313–315. Matsushima, S., Maeda, K., Kondo, C., Hirano, M., Sasaki, M., Suzuki, H., Sugiyama, Y., 2005. Identification of the hepatic efflux transporters of organic anions using double-transfected madin-darby canine kidney ii cells expressing human organic anion-transporting polypeptide 1b1 (oatp1b1)/multidrug resistance-associated protein 2, oatp1b1/multidrug resistance 1, and oatp1b1/breast cancer resistance protein. J. Pharmacol. Exp. Ther. 314, 1059–1067. Meerman, J.H., Sterenborg, H.M., Mulder, G.J., 1983. Use of pentachlorophenol as long-term inhibitor of sulfation of phenols and hydroxamic acids in the rat in vivo. Biochem. Pharmacol. 32, 1587–1593.
482
european journal of pharmaceutical sciences
Meier, P.J., 1995. Molecular mechanisms of hepatic bile salt transport from sinusoidal blood into bile. Am. J. Physiol. 269, G801–G812. Meijer, D.K.F., Smit, J.W., Muller, M., 1997. Hepatobiliary elimination of cationic drugs: the role of P-glycoprotein and other ATP-dependent transporters. Adv. Drug Del. Rev. 25, 159–200. Meisheri, K.D., Johnson, G.A., Puddington, L., 1993. Enzymatic and non-enzymatic sulfation mechanisms in the biological actions of minoxidil. Biochem. Pharmacol. 45, 271–279. Miyauchi, S., Sugiyama, Y., Iga, T., Hanano, M., 1988. Membrane-limited hepatic transport of the conjugative metabolites of 4-methylumbelliferone in rats. J. Pharm. Sci. 77, 688–692. Miyazaki, K., Takemoto, C., Satoh, T., Ueno, K., Igarashi, T., Kitagawa, H., 1983. Toxicity and biotransformation of acetaminophen in rat hepatocytes. (i). Uptake and release. Res. Commun. Chem. Pathol. Pharmacol. 39, 77–86. Mizuno, N., Suzuki, M., Kusuhara, H., Suzuki, H., Takeuchi, K., Niwa, T., Jonker, J.W., Sugiyama, Y., 2004. Impaired renal excretion of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (e3040) sulfate in breast cancer resistance protein (bcrp1/abcg2) knockout mice. Drug Metab. Dispos. 32, 898–901. Monaghan, G., Clarke, D.J., Povey, S., See, C.G., Boxer, M., Burchell, B., 1994. Isolation of a human yac contig encompassing a cluster of ugt2 genes and its regional localization to chromosome 4q13. Genomics 23, 496–499. Moran, T.D., Smith, P.A., 2002. Morphine-3beta-d-glucuronide suppresses inhibitory synaptic transmission in rat substantia gelatinosa. J. Pharmacol. Exp. Ther. 302, 568–576. Morgenstern, R., Lundqvist, G., Andersson, G., Balk, L., DePierre, J.W., 1984. The distribution of microsomal glutathione transferase among different organelles, different organs, and different organisms. Biochem. Pharmacol. 33, 3609–3614. Morikawa, A., Goto, Y., Suzuki, H., Hirohashi, T., Sugiyama, Y., 2000. Biliary excretion of 17beta-estradiol 17beta-d-glucuronide is predominantly mediated by cmoat/mrp2. Pharm. Res. 17, 546–552. Morris, M.E., Yuen, V., Tang, B.K., Pang, K.S., 1988. Competing pathways in drug metabolism. I. Effect of input concentration on the conjugation of gentisamide in the once-through in situ perfused rat liver preparation. J. Pharmacol. Exp. Ther. 245, 614–624. Mulder, G.J., Scholtens, E., 1978. The availability of inorganic sulphate in blood for sulphate conjugation of drugs in rat liver in vivo. (35s)sulphate incorporation into harmol sulphate. Biochem. J. 172, 247–251. Mulder, G.J., Hinson, J.A., Gillette, J.R., 1977. Generation of reactive metabolites of n-hydroxy-phenacetin by glucoronidation and sulfation. Biochem. Pharmacol. 26, 189–196. Murata, M., Tamai, I., Sai, Y., Nagata, O., Kato, H., Sugiyama, Y., Tsuji, A., 1998. Hepatobiliary transport kinetics of hsr-903, a new quinolone antibacterial agent. Drug Metab. Dispos. 26, 1113–1119. Naderer, O.J., Dupuis, R.E., Heinzen, E.L., Wiwattanawongsa, K., Johnson, M.W., Smith, P.C., 2005. The influence of norfloxacin and metronidazole on the disposition of mycophenolate mofetil. J. Clin. Pharmacol. 45, 219–226. Nagata, K., Ozawa, S., Miyata, M., Shimada, M., Gong, D.W., Yamazoe, Y., Kato, R., 1993. Isolation and expression of a cdna encoding a male-specific rat sulfotransferase that catalyzes activation of n-hydroxy-2-acetylaminofluorene. J. Biol. Chem. 268, 24720–24725. Nakatomi, K., Yoshikawa, M., Oka, M., Ikegami, Y., Hayasaka, S., Sano, K., Shiozawa, K., Kawabata, S., Soda, H., Ishikawa, T.,
27
( 2 0 0 6 ) 447–486
Tanabe, S., Kohno, S., 2001. Transport of 7-ethyl-10-hydroxycamptothecin (sn-38) by breast cancer resistance protein abcg2 in human lung cancer cells. Biochem. Biophys. Res. Commun. 288, 827–832. Niinuma, K., Takenaka, O., Horie, T., Kobayashi, K., Kato, Y., Suzuki, H., Sugiyama, Y., 1997. Kinetic analysis of the primary active transport of conjugated metabolites across the bile canalicular membrane: comparative study of S-(2,4-dinitrophenyl)-glutathione and 6-hydroxy-5,7dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole glucuronide. J. Pharmacol. Exp. Ther. 282, 866–872. Ninomiya, M., Ito, K., Horie, T., 2005. Functional analysis of dog multidrug resistance-associated protein 2 (mrp2) in comparison with rat mrp2. Drug Metab. Dispos. 33, 225–232. Nishida, T., Hardenbrook, C., Gatmaitan, Z., Arias, I.M., 1992a. ATP-dependent organic anion transport system in normal and TR− rat liver canalicular membranes. Am. J. Physiol. 262, G629–G635. Nishida, T., Gatmaitan, Z., Roy-Chowdhry, J., Arias, I.M., 1992b. Two distinct mechanisms for bilirubin glucuronide transport by rat bile canalicular membrane vesicles. Demonstration of defective ATP-dependent transport in rats (tr−) with inherited conjugated hyperbilirubinemia. J. Clin. Invest. 90, 2130–2135. Nishino, A., Kato, Y., Igarashi, T., Sugiyama, Y., 2000. Both cmoat/mrp2 and another unknown transporter(s) are responsible for the biliary excretion of glucuronide conjugate of the non-peptide angiotensin ii antagonist, telmisaltan. Drug Metab. Dispos. 28, 1146–1148. Ogasawara, T., Takikawa, H., 2001. Biliary excretion of phenolphthalein glucuronide in the rat. Hepatol. Res. 20, 221–231. Ogawa, K., Suzuki, H., Hirohashi, T., Ishikawa, T., Meier, P.J., Hirose, K., Akizawa, T., Yoshioka, M., Sugiyama, Y., 2000. Characterization of inducible nature of mrp3 in rat liver. Am. J. Physiol. Gastrointest. Liver Physiol. 278, G438–G440. Oguro, T., Gregus, Z., Madhu, C., Liu, L., Klaassen, C.D., 1994. Molybdate depletes hepatic 3-phosphoadenosine 5-phosphosulfate and impairs the sulfation of acetaminophen in rats. J. Pharmacol. Exp. Ther. 270, 1145–1151. Otterness, D.M., Wieben, E.D., Wood, T.C., Watson, W.G., Madden, B.J., McCormick, D.J., Weinshilboum, R.M., 1992. Human liver dehydroepiandrosterone sulfotransferase: molecular cloning and expression of cdna. Mol. Pharmacol. 41, 865–872. Oude Elferink, R.P., Jansen, P.L., 1994. The role of the canalicular multispecific organic anion transporter in the disposal of endo- and xenobiotics. Pharmacol. Ther. 64, 77–97. Oude Elferink, R.P., de Haan, J., Lambert, K.J., Hagey, L.R., Hofmann, A.F., Jansen, P.L., 1989. Selective hepatobiliary transport of nordeoxycholate side chain conjugates in mutant rats with a canalicular transport defect. Hepatology 9, 861–865. Oude Elferink, R.P., Ottenhoff, R., Liefting, W.G., Schoemaker, B., Groen, A.K., Jansen, P.L., 1990. ATP-dependent efflux of gssg and gs-conjugate from isolated rat hepatocytes. Am. J. Physiol. 258, G699–G706. Pang, K.S., Terrell, J.A., 1981. Retrograde perfusion to probe the heterogeneous distribution of hepatic drug metabolizing enzymes in rats. J. Pharmacol. Exp. Ther. 216, 339–346. Pang, K.S., Schwab, A.J., Goresky, C.A., Chiba, M., 1994. Transport, binding, and metabolism of sulfate conjugates in the liver. Chem. Biol. Interact. 92, 179–207. Pang, K.S., Koster, H., Halsema, I.C., Scholtens, E., Mulder, G.J., 1981. Aberrant pharmacokinetics of harmol in the perfused rat liver preparation: sulfate and glucuronide conjugations. J. Pharmacol. Exp. Ther. 219, 134–140.
european journal of pharmaceutical sciences
Pang, K.S., Koster, H., Halsema, I.C., Scholtens, E., Mulder, G.J., Stillwell, R.N., 1983. Normal and retrograde perfusion to probe the zonal distribution of sulfation and glucuronidation activities of harmol in the perfused rat liver preparation. J. Pharmacol. Exp. Ther. 224, 647–653. Parkinson, A., 2001. Biotransformation of xenobiotics. In: Klaassen, C.D., Thomas, M.J., Hazucha, M.J. (Eds.), Casarett and Doull’s Toxicology: The Basic Science of Poisons. McGraw-Hill Medical Publishing Division, New York, pp. 113–186. Patel, N.J., Zamek-Gliszczynski, M.J., Zhang, P., Han, Y.H., Jansen, P.L., Meier, P.J., Stieger, B., Brouwer, K.L., 2003. Phenobarbital alters hepatic mrp2 function by direct and indirect interactions. Mol. Pharmacol. 64, 154–159. Patten, E.J., DeLong, M.J., 1999. Effects of sulindac, sulindac metabolites, and aspirin on the activity of detoxification enzymes in ht-29 human colon adenocarcinoma cells. Cancer Lett. 147, 95–100. Paulusma, C.C., van Geer, M.A., Evers, R., Heijn, M., Ottenhoff, R., Borst, P., Oude Elferink, R.P., 1999. Canalicular multispecific organic anion transporter/multidrug resistance protein 2 mediates low-affinity transport of reduced glutathione. Biochem. J. 338 (Pt 2), 393–401. Paulusma, C.C., Kool, M., Bosma, P.J., Scheffer, G.L., ter Borg, F., Scheper, R.J., Tytgat, G.N., Borst, P., Baas, F., Oude Elferink, R.P., 1997. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin–Johnson syndrome. Hepatology 25, 1539–1542. Paumi, C.M., Wright, M., Townsend, A.J., Morrow, C.S., 2003. Multidrug resistance protein (mrp) 1 and mrp3 attenuate cytotoxic and transactivating effects of the cyclopentenone prostaglandin, 15-deoxy-delta(12,14)prostaglandin j2 in mcf7 breast cancer cells. Biochemistry 42, 5429–5437. Prochaska, H.J., Talalay, P., 1988. Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver. Cancer Res. 48, 4776–4782. Radominska, A., Comer, K.A., Zimniak, P., Falany, J., Iscan, M., Falany, C.N., 1990. Human liver steroid sulphotransferase sulphates bile acids. Biochem. J. 272, 597–604. Radominska-Pandya, A., Czernik, P.J., Little, J.M., Battaglia, E., Mackenzie, P.I., 1999. Structural and functional studies of UDP-glucuronosyltransferases. Drug Metab. Rev. 31, 817–899. Rae, J.M., Johnson, M.D., Lippman, M.E., Flockhart, D.A., 2001. Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cdna and oligonucleotide expression arrays. J. Pharmacol. Exp. Ther. 299, 849–857. Ratna, S., Chiba, M., Bandyopadhyay, L., Pang, K.S., 1993. Futile cycling between 4-methylumbelliferone and its conjugates in perfused rat liver. Hepatology 17, 838–853. Raub, T.J., Irizarry, A., Gao, H., Ryan, T.P., 2005. In: Brouwer, K.L.R., Zamek-Gliszczynski, M.J., Nezasa, K., Tian, X. (Eds.), Pathology of Acetaminophen-treated Wild-type and abcc2−/− mice. Indianapolis, IN. Rendic, S., Di Carlo, F.J., 1997. Human cytochrome p450 enzymes: a status report summmarizing their reactions, substrates, inducers, and inhibitors. Drug Metab. Rev. 29, 413–580. Reuter, S., Mayer, D., 1995. Transport of dehydroepiandrosterone and dehydroepiandrosterone sulphate into rat hepatocytes. J. Steroid Biochem. Mol. Biol. 54, 227–235. Ritter, J.K., Chen, F., Sheen, Y.Y., Tran, H.M., Kimura, S., Yeatman, M.T., Owens, I.S., 1992. A novel complex locus ugt1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini. J. Biol. Chem. 267, 3257–3261. Rius, M., Nies, A.T., Hummel-Eisenbeiss, J., Jedlitschky, G., Keppler, D., 2003. Cotransport of reduced glutathione with
27
( 2 0 0 6 ) 447–486
483
bile salts by mrp4 (abcc4) localized to the basolateral hepatocyte membrane. Hepatology 38, 374–384. Roberts, M.S., Magnusson, B.M., Burczynski, F.J., Weiss, M., 2002. Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin. Pharmacokinet. 41, 751–790. Romberg, R., Olofsen, E., Sarton, E., den Hartigh, J., Taschner, P.E., Dahan, A., 2004. Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences. Anesthesiology 100, 120–133. Runge-Morris, M., Rose, K., Kocarek, T.A., 1996. Regulation of rat hepatic sulfotransferase gene expression by glucocorticoid hormones. Drug Metab. Dispos. 24, 1095– 1101. Runge-Morris, M., Wu, W., Kocarek, T.A., 1999. Regulation of rat hepatic hydroxysteroid sulfotransferase (sult2-40/41) gene expression by glucocorticoids: evidence for a dual mechanism of transcriptional control. Mol. Pharmacol. 56, 1198–1206. Runge-Morris, M., Rose, K., Falany, C.N., Kocarek, T.A., 1998. Differential regulation of individual sulfotransferase isoforms by phenobarbital in male rat liver. Drug Metab. Dispos. 26, 795–801. Rushmore, T.H., Pickett, C.B., 1990. Transcriptional regulation of the rat glutathione S-transferase ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. J. Biol. Chem. 265, 14648–14653. Said, M., Noort, D., Magdalou, J., Ziegler, J.C., van der Marel, G.A., van Boom, J.H., Mulder, G.J., Siest, G., 1992. Selective and potent inhibition of different hepatic UDP-glucuronosyltransferase activities by omega, omega, omega-triphenylalcohols and UDP derivatives. Biochem. Biophys. Res. Commun. 187, 140–145. Sampath, J., Adachi, M., Hatse, S., Naesens, L., Balzarini, J., Flatley, R.M., Matherly, L.H., Schuetz, J.D., 2002. Role of mrp4 and mrp5 in biology and chemotherapy. AAPS Pharm. Sci. 4, E14. Sano, N., Takikawa, H., Yamanaka, M., 1993. Estradiol-17 beta-glucuronide-induced cholestasis. Effects of ursodeoxycholate-3-o-glucuronide and 3,7-disulfate. J. Hepatol. 17, 241–246. Sasabe, H., Tsuji, A., Sugiyama, Y., 1998. Carrier-mediated mechanism for the biliary excretion of the quinolone antibiotic grepafloxacin and its glucuronide in rats. J. Pharmacol. Exp. Ther. 284, 1033–1039. Sasaki, M., Suzuki, H., Ito, K., Abe, T., Sugiyama, Y., 2002. Transcellular transport of organic anions across a double-transfected madin-darby canine kidney ii cell monolayer expressing both human organic anion-transporting polypeptide (oatp2/slc21a6) and multidrug resistance-associated protein 2 (mrp2/abcc2). J. Biol. Chem. 277, 6497–6503. Sasaki, M., Suzuki, H., Aoki, J., Ito, K., Meier, P.J., Sugiyama, Y., 2004. Prediction of in vivo biliary clearance from the in vitro transcellular transport of organic anions across a double-transfected madin-darby canine kidney ii monolayer expressing both rat organic anion transporting polypeptide 4 and multidrug resistance associated protein 2. Mol. Pharmacol. 66, 450–459. Savina, P.M., Brouwer, K.L., 1992. Probenecid-impaired biliary excretion of acetaminophen glucuronide and sulfate in the rat. Drug Metab. Dispos. 20, 496–501. Scheffer, G.L., Hu, X., Pijnenborg, A.C., Wijnholds, J., Bergen, A.A., Scheper, R.J., 2002. Mrp6 (abcc6) detection in normal human tissues and tumors. Lab Invest. 82, 515–518. Schneider, E.G., Durham, J.C., Sacktor, B., 1984. Sodium-dependent transport of inorganic sulfate by rabbit
484
european journal of pharmaceutical sciences
renal brush-border membrane vesicles. Effects of other ions. J. Biol. Chem. 259, 14591–14599. Schuetz, E.G., Strom, S., Yasuda, K., Lecureur, V., Assem, M., Brimer, C., Lamba, J., Kim, R.B., Ramachandran, V., Komoroski, B.J., Venkataramanan, R., Cai, H., Sinal, C.J., Gonzalez, F.J., Schuetz, J.D., 2001. Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome p450. J. Biol. Chem. 276, 39411–39418. Seah, V.M., Wong, K.P., 1994. 2,6-dichloro-4-nitrophenol (dcnp), an alternate-substrate inhibitor of phenolsulfotransferase. Biochem. Pharmacol. 47, 1743–1749. Seitz, S., Kretz-Rommel, A., Oude Elferink, R.P., Boelsterli, U.A., 1998. Selective protein adduct formation of diclofenac glucuronide is critically dependent on the rat canalicular conjugate export pump (mrp2). Chem. Res. Toxicol. 11, 513–519. Shibayama, Y., Ikeda, R., Motoya, T., Yamada, K., 2004. St. John’s wort (hypericum perforatum) induces overexpression of multidrug resistance protein 2 (mrp2) in rats: a 30-day ingestion study. Food Chem. Toxicol. 42, 995–1002. Shimamura, H., Suzuki, H., Tagaya, O., Horie, T., Sugiyama, Y., 1996. Biliary excretion of glycyrrhizin in rats: kinetic basis for multiplicity in bile canalicular transport of organic anions. Pharm. Res. 13, 1833–1837. Silverman, J.A., Schrenk, D., 1997. Hepatic canalicular membrane. 4. Expression of the multidrug resistance genes in the liver. FASEB J. 11, 308–313. Singer, S.S., Ansel, A.Z., Van Brunt, N., Torres, J., Galaska, E.G., 1984. Enzymatic sulfation of steroids–xx. Effects of ten drugs on the hepatic glucocorticoid sulfotransferase activity of rats in vitro and in vivo. Biochem. Pharmacol. 33, 3485–3490. Slattery, J.T., Levy, G., 1979. Acetaminophen kinetics in acutely poisoned patients. Clin. Pharmacol. Ther. 25, 184–195. Slitt, A.L., Cherrington, N.J., Maher, J.M., Klaassen, C.D., 2003. Induction of multidrug resistance protein 3 in rat liver is associated with altered vectorial excretion of acetaminophen metabolites. Drug Metab. Dispos. 31, 1176–1186. Smith, A.J., van Helvoort, A., van Meer, G., Szabo, K., Welker, E., Szakacs, G., Varadi, A., Sarkadi, B., Borst, P., 2000. Mdr3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J. Biol. Chem. 275, 23530–23539. Smith, M.T., 2003. Mechanisms of troglitazone hepatotoxicity. Chem. Res. Toxicol. 16, 679–687. Smith, P.C., Benet, L.Z., McDonagh, A.F., 1990a. Covalent binding of zomepirac glucuronide to proteins: evidence for a schiff base mechanism. Drug Metab. Dispos. 18, 639–644. Smith, P.C., McDonagh, A.F., Benet, L.Z., 1990b. Effect of esterase inhibition on the disposition of zomepirac glucuronide and its covalent binding to plasma proteins in the guinea pig. J. Pharmacol. Exp. Ther. 252, 218–224. Smith, P.C., Langendijk, P.N., Bosso, J.A., Benet, L.Z., 1985. Effect of probenecid on the formation and elimination of acyl glucuronides: studies with zomepirac. Clin. Pharmacol. Ther. 38, 121–127. Soars, M.G., Ring, B.J., Wrighton, S.A., 2003. The effect of incubation conditions on the enzyme kinetics of UDP-glucuronosyltransferases. Drug Metab. Dispos. 31, 762–767. Sonoda, J., Xie, W., Rosenfeld, J.M., Barwick, J.L., Guzelian, P.S., Evans, R.M., 2002. Regulation of a xenobiotic sulfonation cascade by nuclear pregnane x receptor (pxr). Proc. Natl. Acad. Sci. U.S.A. 99, 13801–13806. Soroka, C.J., Lee, J.M., Azzaroli, F., Boyer, J.L., 2001. Cellular localization and up-regulation of multidrug
27
( 2 0 0 6 ) 447–486
resistance-associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver. Hepatology 33, 783–791. Spahn-Langguth, H., Benet, L.Z., 1992. Acyl glucuronides revisited: is the glucuronidation process a toxification as well as a detoxification mechanism? Drug Metab. Rev. 24, 5–47. Spears, K.J., Ross, J., Stenhouse, A., Ward, C.J., Goh, L.B., Wolf, C.R., Morgan, P., Ayrton, A., Friedberg, T.H., 2005. Directional trans-epithelial transport of organic anions in porcine llc-pk1 cells that co-express human oatp1b1 (oatp-c) and mrp2. Biochem. Pharmacol. 69, 415–423. Stieger, B., Fattinger, K., Madon, J., Kullak-Ublick, G.A., Meier, P.J., 2000. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (bsep) of rat liver. Gastroenterology 118, 422–430. Strautnieks, S.S., Bull, L.N., Knisely, A.S., Kocoshis, S.A., Dahl, N., Arnell, H., Sokal, E., Dahan, K., Childs, S., Ling, V., Tanner, M.S., Kagalwalla, A.F., Nemeth, A., Pawlowska, J., Baker, A., Mieli-Vergani, G., Freimer, N.B., Gardiner, R.M., Thompson, R.J., 1998. A gene encoding a liver-specific abc transporter is mutated in progressive familial intrahepatic cholestasis. Nat. Genet. 20, 233–238. Strott, C.A., 2002. Sulfonation and molecular action. Endocr Rev. 23, 703–732. Sugatani, J., Nishitani, S., Yamakawa, K., Yoshinari, K., Sueyoshi, T., Negishi, M., Miwa, M., 2005. Transcriptional regulation of human ugt1a1 gene expression: activated glucocorticoid receptor enhances constitutive androstane receptor/pregnane × receptor-mediated UDP-glucuronosyltransferase 1a1 regulation with glucocorticoid receptor-interacting protein 1. Mol. Pharmacol. 67, 845–855. Sugatani, J., Kojima, H., Ueda, A., Kakizaki, S., Yoshinari, K., Gong, Q.H., Owens, I.S., Negishi, M., Sueyoshi, T., 2001. The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase ugt1a1 gene and regulation by the nuclear receptor car. Hepatology 33, 1232–1238. Sugawara, N., Lai, Y., Yuasa, M., Dhar, S.K., Arizono, K., 1996. Biliary excretion of copper, manganese, and horseradish peroxidase in eisai hyperbilirubinemic mutant rats (ehbrs) with defective biliary excretion of glutathione. Biol. Trace Elem. Res. 55, 181–189. Sugiyama, D., Kusuhara, H., Shitara, Y., Abe, T., Meier, P.J., Sekine, T., Endou, H., Suzuki, H., Sugiyama, Y., 2001. Characterization of the efflux transport of 17beta-estradiol-d-17beta-glucuronide from the brain across the blood–brain barrier. J. Pharmacol. Exp. Ther. 298, 316–322. Suzuki, M., Suzuki, H., Sugimoto, Y., Sugiyama, Y., 2003. Abcg2 transports sulfated conjugates of steroids and xenobiotics. J. Biol. Chem. 278, 22644–22649. Sweeny, D.J., Reinke, L.A., 1988. Sulfation of acetaminophen in isolated rat hepatocytes. Relationship to sulfate ion concentrations and intracellular levels of 3 -phosphoadenosine-5 -phosphosulfate. Drug Metab. Dispos. 16, 712–715. Takada, T., Weiss, H.M., Kretz, O., Gross, G., Sugiyama, Y., 2004. Hepatic transport of pki166, an epidermal growth factor receptor kinase inhibitor of the pyrrolo-pyrimidine class, and its main metabolite, acu154. Drug Metab. Dispos. 32, 1272–1278. Takenaka, O., Horie, T., Suzuki, H., Sugiyama, Y., 1995a. Different biliary excretion systems for glucuronide and sulfate of a model compound; study using eisai hyperbilirubinemic rats. J. Pharmacol. Exp. Ther. 274, 1362–1369.
european journal of pharmaceutical sciences
Takenaka, O., Horie, T., Kobayashi, K., Suzuki, H., Sugiyama, Y., 1995b. Kinetic analysis of hepatobiliary transport for conjugated metabolites in the perfused liver of mutant rats (ehbr) with hereditary conjugated hyperbilirubinemia. Pharm. Res. 12, 1746–1755. Takikawa, H., Sano, N., Minagawa, K., Yamanaka, M., 1992. Effects of ursodeoxycholate, its glucuronide and disulfate and beta-muricholate on biliary bicarbonate concentration and biliary lipid excretion. J. Hepatol. 15, 77–84. Takikawa, H., Minagawa, K., Sano, N., Yamanaka, M., 1993. Lithocholate-3-o-glucuronide-induced cholestasis. A study with congenital hyperbilirubinemic rats and effects of ursodeoxycholate conjugates. Dig. Dis. Sci. 38, 1543–1548. Takikawa, H., Yamazaki, R., Sano, N., Yamanaka, M., 1996. Biliary excretion of estradiol-17 beta-glucuronide in the rat. Hepatology 23, 607–613. Takikawa, H., Sano, N., Ogasawara, T., Yamanaka, M., 1998. Enhanced biliary excretion of lithocholate-3-sulfate by ursodeoxycholate-3,7-disulfate infusion in eisai hyperbilirubinemic rat (ehbr). Dig. Dis. Sci. 43, 188–192. Takikawa, H., Nishikawa, K., Sano, N., Yamanaka, M., Horie, T., 1995. Mechanisms of biliary excretion of lithocholate-3-sulfate in eisai hyperbilirubinemic rats (ehbr). Dig. Dis. Sci. 40, 1792–1797. Takikawa, H., Sano, N., Narita, T., Uchida, Y., Yamanaka, M., Horie, T., Mikami, T., Tagaya, O., 1991. Biliary excretion of bile acid conjugates in a hyperbilirubinemic mutant Sprague-Dawley rat. Hepatology 14, 352–360. Tan, E., Pang, K.S., 2001. Sulfation is rate limiting in the futile cycling between estrone and estrone sulfate in enriched periportal and perivenous rat hepatocytes. Drug Metab. Dispos. 29, 335–346. Tanaka, H., Sano, N., Takikawa, H., 2003. Biliary excretion of phenolphthalein sulfate in rats. Pharmacology 68, 177–182. Tanaka, Y., Kobayashi, Y., Gabazza, E.C., Higuchi, K., Kamisako, T., Kuroda, M., Takeuchi, K., Iwasa, M., Kaito, M., Adachi, Y., 2002. Increased renal expression of bilirubin glucuronide transporters in a rat model of obstructive jaundice. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G656–G660. Thompson, R., Strautnieks, S., 2000. Inherited disorders of transport in the liver. Curr. Opin. Genet. Dev. 10, 310–313. Tosh, D., Borthwick, E.B., Sharp, S., Burchell, A., Burchell, B., Coughtrie, M.W., 1996. Heterogeneous expression of sulphotransferases in periportal and perivenous hepatocytes prepared from male and female rat liver. Biochem. Pharmacol. 51, 369–374. Tukey, R.H., Strassburg, C.P., 2000. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu. Rev. Pharmacol. Toxicol. 40, 581–616. Tukey, R.H., Strassburg, C.P., 2001. Genetic multiplicity of the human UDP-glucuronosyltransferases and regulation in the gastrointestinal tract. Mol. Pharmacol. 59, 405–414. Turner, K.C., Brouwer, K.L., 1997. In vitro mechanisms of probenecid-associated alterations in acetaminophen glucuronide hepatic disposition. Drug Metab. Dispos. 25, 1017–1021. van Aubel, R.A., Koenderink, J.B., Peters, J.G., Van Os, C.H., Russel, F.G., 1999. Mechanisms and interaction of vinblastine and reduced glutathione transport in membrane vesicles by the rabbit multidrug resistance protein mrp2 expressed in insect cells. Mol. Pharmacol. 56, 714–719. van Aubel, R.A., Smeets, P.H., Peters, J.G., Bindels, R.J., Russel, F.G., 2002. The mrp4/abcc4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary camp and cgmp. J. Am. Soc. Nephrol. 13, 595–603. van Aubel, R.A., van Kuijck, M.A., Koenderink, J.B., Deen, P.M., van Os, C.H., Russel, F.G., 1998. Adenosine
27
( 2 0 0 6 ) 447–486
485
triphosphate-dependent transport of anionic conjugates by the rabbit multidrug resistance-associated protein mrp2 expressed in insect cells. Mol. Pharmacol. 53, 1062–1067. Wacher, V.J., Salphati, L., Benet, L.Z., 2001. Active secretion and enterocytic drug metabolism barriers to drug absorption. Adv. Drug Deliv. Rev. 46, 89–102. Watkins, J.B., Klaassen, C.D., 1982. Effect of inducers and inhibitors of glucuronidation on the biliary excretion and choleretic action of valproic acid in the rat. J. Pharmacol. Exp. Ther. 220, 305–310. Wei, P., Zhang, J., Egan-Hafley, M., Liang, S., Moore, D.D., 2000. The nuclear receptor car mediates specific xenobiotic induction of drug metabolism. Nature 407, 920–923. Weinshilboum, R.M., Otterness, D.M., Aksoy, I.A., Wood, T.C., Her, C., Raftogianis, R.B., 1997. Sulfation and sulfotransferases. 1. Sulfotransferase molecular biology: Cdnas and genes. FASEB J. 11, 3–14. Wielinga, P.R., van der Heijden, I., Reid, G., Beijnen, J.H., Wijnholds, J., Borst, P., 2003. Characterization of the mrp4and mrp5-mediated transport of cyclic nucleotides from intact cells. J. Biol. Chem. 278, 17664–17671. Wijnholds, J., Mol, C.A., van Deemter, L., de Haas, M., Scheffer, G.L., Baas, F., Beijnen, J.H., Scheper, R.J., Hatse, S., De Clercq, E., Balzarini, J., Borst, P., 2000. Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc. Natl. Acad. Sci. U.S.A. 97, 7476–7481. Williams, J.A., Stone, E.M., Fakis, G., Johnson, N., Cordell, J.A., Meinl, W., Glatt, H., Sim, E., Phillips, D.H., 2001. N-acetyltransferases, sulfotransferases and heterocyclic amine activation in the breast. Pharmacogenetics 11, 373–388. Williams, J.A., Hyland, R., Jones, B.C., Smith, D.A., Hurst, S., Goosen, T.C., Peterkin, V., Koup, J.R., Ball, S.E., 2004. Drug–drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (auci/auc) ratios. Drug Metab. Dispos. 32, 1201–1208. Wittenburg, H., Carey, M.C., 2002. Biliary cholesterol secretion by the twinned sterol half-transporters abcg5 and abcg8. J. Clin. Invest. 110, 605–609. Wood, T.C., Aksoy, I.A., Aksoy, S., Weinshilboum, R.M., 1994. Human liver thermolabile phenol sulfotransferase: Cdna cloning, expression and characterization. Biochem. Biophys. Res. Commun. 198, 1119–1127. Wortelboer, H.M., Usta, M., van der Velde, A.E., Boersma, M.G., Spenkelink, B., van Zanden, J.J., Rietjens, I.M., van Bladeren, P.J., Cnubben, N.H., 2003. Interplay between mrp inhibition and metabolism of mrp inhibitors: the case of curcumin. Chem. Res. Toxicol. 16, 1642–1651. Wright, A.W., Dickinson, R.G., 2004. Abolition of valproate-derived choleresis in the mrp2 transporter-deficient rat. J. Pharmacol. Exp. Ther. 310, 584–588. Xia, C.Q., Liu, N., Yang, D., Miwa, G., Gan, L.S., 2005. Expression, localization, and functional characteristics of breast cancer resistance protein in caco-2 cells. Drug Metab. Dispos. 33, 637–643. Xie, W., Yeuh, M.F., Radominska-Pandya, A., Saini, S.P., Negishi, Y., Bottroff, B.S., Cabrera, G.Y., Tukey, R.H., Evans, R.M., 2003. Control of steroid, heme, and carcinogen metabolism by nuclear pregnane x receptor and constitutive androstane receptor. Proc. Natl. Acad. Sci. U.S.A. 100, 4150– 4155. Xiong, H., Yoshinari, K., Brouwer, K.L., Negishi, M., 2002a. Role of constitutive androstane receptor in the in vivo induction of mrp3 and cyp2b1/2 by phenobarbital. Drug Metab. Dispos. 30, 918–923.
486
european journal of pharmaceutical sciences
Xiong, H., Turner, K.C., Ward, E.S., Jansen, P.L., Brouwer, K.L., 2000. Altered hepatobiliary disposition of acetaminophen glucuronide in isolated perfused livers from multidrug resistance-associated protein 2-deficient tr(−) rats. J. Pharmacol. Exp. Ther. 295, 512–518. Xiong, H., Suzuki, H., Sugiyama, Y., Meier, P.J., Pollack, G.M., Brouwer, K.L., 2002b. Mechanisms of impaired biliary excretion of acetaminophen glucuronide after acute phenobarbital treatment or phenobarbital pretreatment. Drug Metab. Dispos. 30, 962–969. Xu, C., Li, C.Y., Kong, A.N., 2005. Induction of phase i, ii and iii drug metabolism/transport by xenobiotics. Arch. Pharm. Res. 28, 249–268. Yagi, Y., Shibutani, S., Hodoshima, N., Ishiwata, K., Okudaira, N., Li, Q., Sai, Y., Kato, Y., Tsuji, A., 2003. Involvement of multiple transport systems in the disposition of an active metabolite of a prodrug-type new quinolone antibiotic, prulifloxacin. Drug Metab. Pharmacokinet. 18, 381–389. Yamaguchi, Y., Hamaguchi, H., Yamada, S., Fujiwara, K., Higashio, K., Miyanari, N., Ichiguchi, O., Goto, M., Mori, K., Ogawa, M., 1997. Recombinant human hepatocyte growth factor facilitates biliary transport after hepatocyte transplantation in eisai hyperbilirubinemic rats. Dig. Dis. Sci. 42, 522–528. Yamashita, G., Tazuma, S., Horikawa, K., Aihara, N., Ochi, H., Teramen, K., Yamashita, Y., Sasaki, M., Ohya, T., Kajiyama, G., 1993. Partial characterization of mechanism(s) by which sulphobromophthalein reduces biliary lipid secretion. Biochem. J. 291 (Pt 1), 173–177. Yamazoe, Y., Manabe, S., Murayama, N., Kato, R., 1987. Regulation of hepatic sulfotransferase catalyzing the activation of n-hydroxyarylamide and n-hydroxyarylamine by growth hormone. Mol. Pharmacol. 32, 536–541. Yamazoe, Y., Nagata, K., Ozawa, S., Kato, R., 1994. Structural similarity and diversity of sulfotransferases. Chem. Biol. Interact. 92, 107–117. Yamazoe, Y., Gong, D., Murayama, N., Abu-Zeid, M., Kato, R., 1989. Regulation of hepatic cortisol sulfotransferase in rats by pituitary growth hormone. Mol. Pharmacol. 35, 707–712. Yanase, K., Tsukahara, S., Asada, S., Ishikawa, E., Imai, Y., Sugimoto, Y., 2004. Gefitinib reverses breast cancer resistance protein-mediated drug resistance. Mol. Cancer Ther. 3, 1119–1125. Yeh, S.Y., 1975. Urinary excretion of morphine and its metabolites in morphine-dependent subjects. J. Pharmacol. Exp. Ther. 192, 201–210. Yoshikawa, M., Ikegami, Y., Hayasaka, S., Ishii, K., Ito, A., Sano, K., Suzuki, T., Togawa, T., Yoshida, H., Soda, H., Oka, M., Kohno, S., Sawada, S., Ishikawa, T., Tanabe, S., 2004. Novel camptothecin analogues that circumvent abcg2-associated drug resistance in human tumor cells. Int. J. Cancer 110, 921–927. Zamek-Gliszczynski, M.J., Brouwer, K.L.R., 2004. In vitro models for estimating hepatobiliary clearance. In: Borchardt, R.T., Kerns, E.H., Lipinski, C.A., Thakker, D.R., Wang, B. (Eds.), Pharmaceutical Profiling in Drug Discovery for Lead Selection. AAPS Press, Arlington, VA, pp. 259–292. Zamek-Gliszczynski, M.J., Xiong, H., Patel, N.J., Turncliff, R.Z., Pollack, G.M., Brouwer, K.L.R., 2003. Pharmacokinetics of 5 (and 6)-carboxy-2 ,7 -dichlorofluorescein and its diacetate promoiety in the liver. J. Pharmacol. Exp. Ther. 304, 801– 809. Zamek-Gliszczynski, M.J., Hoffmaster, K.A., Nezasa, K., Tian, X., Brouwer, K.L.R., 2006a. Species differences in mechanisms of biliary excretion of harmol sulfate and glucuronide in rats and mice. Biochem. Pharmacol., submitted for publication.
27
( 2 0 0 6 ) 447–486
Zamek-Gliszczynski, M.J., Hoffmaster, K.A., Humphreys, J.E., Brouwer, K.L.R., 2006b. Differential involvement of mrp2 (abcc2) and bcrp1 (abcg2) in biliary excretion of 4-methylumbelliferyl glucuronide and sulfate in the rat. J. Pharmacol. Exp. Ther. 317, submitted for publication. Zamek-Gliszczynski, M.J., Nezasa, K., Tian, X., Kalvass, J.C., Patel, N.J., Raub, T.J., Brouwer, K.L.R., 2006c. Biliary excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in abcc2(−/−), abcg2(−/−), and mdr1a(−/−)/mdr1b(−/−) mice. Mol. Pharmacol. submitted for publication. Zamek-Gliszczynski, M.J., Nezasa, K., Tian, X., Bridges, A.S., Belinsky, M.G., Kruh, G.D., Brouwer, K.L.R., 2006d. Elucidation of the role of mrp3 and mrp4 in hepatic basolateral excretion of sulfate and glucuronide conjugates of acetaminophen, 4-methylumbelliferone, and harmol using abcc3(−/−) and abcc4(−/−) mice. Mol. Pharmacol, submitted for publication. Zamek-Gliszczynski, M.J., Hoffmaster, K.A., Tian, X., Zhao, R., Polli, J.W., Humphreys, J.E., Webster, L.O., Bridges, A.S., Kalvass, J.C., Brouwer, K.L., 2005. Multiple mechanisms are involved in the biliary excretion of acetaminophen sulfate in the rat: role of mrp2 and bcrp1. Drug Metab. Dispos. 33, 1158–1165. Zelcer, N., Saeki, T., Reid, G., Beijnen, J.H., Borst, P., 2001. Characterization of drug transport by the human multidrug resistance protein 3 (abcc3). J. Biol. Chem. 276, 46400–46407. Zelcer, N., Saeki, T., Bot, I., Kuil, A., Borst, P., 2003a. Transport of bile acids in multidrug-resistance-protein 3-overexpressing cells co-transfected with the ileal na+-dependent bile-acid transporter. Biochem. J. 369, 23–30. Zelcer, N., Reid, G., Wielinga, P., Kuil, A., van der Heijden, I., Schuetz, J.D., Borst, P., 2003b. Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (mrp) 4 (ATP-binding cassette c4). Biochem. J. 371, 361–367. Zelcer, N., Huisman, M.T., Reid, G., Wielinga, P., Breedveld, P., Kuil, A., Knipscheer, P., Schellens, J.H., Schinkel, A.H., Borst, P., 2003c. Evidence for two interacting ligand binding sites in human multidrug resistance protein 2 (ATP-binding cassette c2). J. Biol. Chem. 278, 23538–23544. Zelcer, N., van de Wetering, K., Hillebrand, M., Sarton, E., Kuil, A., Wielinga, P.R., Tephly, T., Dahan, A., Beijnen, J.H., Borst, P., 2005. Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Proc. Natl. Acad. Sci. U.S.A. 102, 7274–7279. Zeng, H., Liu, G., Rea, P.A., Kruh, G.D., 2000. Transport of amphipathic anions by human multidrug resistance protein 3. Cancer Res. 60, 4779–4784. Zhang, J., Ye, Z., Lou, Y., 2004. Metabolism of chlorambucil by rat liver microsomal glutathione S-transferase. Chem. Biol. Interact. 149, 61–67. Zhang, J., Ye, Z., Lou, Y., 2005. Metabolism of melphalan by rat liver microsomal glutathione S-transferase. Chem. Biol. Interact. 152, 101–106. Zhu, X., Veronese, M.E., Sansom, L.N., McManus, M.E., 1993a. Molecular characterisation of a human aryl sulfotransferase cdna. Biochem. Biophys. Res. Commun. 192, 671–676. Zhu, X., Veronese, M.E., Iocco, P., McManus, M.E., 1996. Cdna cloning and expression of a new form of human aryl sulfotransferase. Int. J. Biochem. Cell. Biol. 28, 565–571. Zhu, X., Veronese, M.E., Bernard, C.C., Sansom, L.N., McManus, M.E., 1993b. Identification of two human brain aryl sulfotransferase cdnas. Biochem. Biophys. Res. Commun. 195, 120–127.