Modulation of UDP-Glucuronosyltransferase Activity by Endogenous Compounds

Drug Metab. Pharmacokinet. 25 (2): 134–148 (2010).

Review Modulation of UDP-Glucuronosyltransferase Activity by Endogenous Compounds Yuji ISHII*, Arief NURROCHMAD** and Hideyuki YAMADA Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk

Summary: Glucuronidation is one of the major pathways of metabolism of endo- and xenobiotics. UDPGlucuronosyltransferase (UGT)-catalyzed glucuronidation accounts for up to 35z of phase II reactions. The expression and function of UGT is modulated by gene regulation, post-translational modifications and protein-protein association. Many studies have focused on drug-drug interactions involving UGT, and there are a number of reports describing the inhibition of UGT by xenobiotics. However, studies about the role of endogenous compounds as an inhibitor or activator of UGT are limited, and it is important to understand any change in the function and regulation of UGT by endogenous compounds. Recent studies in our laboratory have shown that fatty acyl-CoAs are endogenous activators of UGT, although fatty acyl-CoAs had been considered as inhibitors of UGT. Further, we have also suggested that adenine and related compounds are endogenous allosteric inhibitors of UGT. In this review, we summarize the endogenous modulators of UGT and discuss their relevance to UGT function. Keywords: UDP-glucuronosyltransferase; fatty acyl-CoA; fatty acid; inhibitor; activator; adenine; NADP; NAD; ATP

Conjugation with glucuronic acid is one of the major steps in the metabolism of endogenous substances and xenobiotics and is mediated by UGT (EC 2.4.1.17) isoforms belonging to the UGT multigene family. The substrates of UGTs include a number of drugs, environmental toxins, and carcinogens.3,5–10) The catalytic reaction uses UDP-glucuronic acid (UDPGA) as a co-substrate. While glucuronidation usually inactivates the target xenobiotics, there are exceptions such as morphine11) and retinoic acids12) which are converted to pharmacologically active glucuronides. As UGT is a member of the glycosyltransferase superfamily,7,9) this enzyme can be designated as UDP-glycosyltransferase. However, we refer to this enzyme here as UDP-glucuronosyltransferase because many papers and reviews use this terminology. The UGT superfamily is divided into many subfamilies on the basis of evolutionary divergence. Of the UGT superfamily, two main families, UGT1 and UGT2, are predominantly involved in glucuronidation. Human UGTs belong to 3 subfamilies (UGT1A, 2A, and 2B),7,9) although a recent study showed that UGT3A1 (UDP-N-acetylglucosaminyltransferase) is also involved in

Introduction Biotransformation is one of the important processes that determines the pharmacokinetic profile of an administered drug. Drug metabolizing enzymes play an important role in the biotransformation of many endogenous and exogenous compounds, giving products which are more soluble in water than their parent compounds. Drug metabolizing enzymes can be classified into two main groups: those involved in phase I and phase II reactions.1–3) Cytochrome P450 (P450, CYP) and UDP-glucuronosyltransferase (UGT) are the representative members of phase I and II enzymes, respectively. Both enzymes are localized on the endoplasmic reticulum (ER) where a vast number of drugs are sequentially metabolized. In particular, numerous studies have focused on the catalytic properties and regulation of the expression of P450, because the majority of drug interactions occur through the inhibition and/or induction of this enzyme. However, phase II enzymes also play important roles, because many drugs and phase I metabolites undergo changes by conjugation.4)

Received; October 23, 2009, Accepted; January 7, 2010 *To whom correspondence should be addressed: Yuji ISHII, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Tel. ＋81-92-642-6586, Fax. ＋81-92-642-6588, E-mail: ishii＠phar.kyushu-u.ac.jp **Present address: Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, Indonesia

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Modulation of UDP-Glucuronosyltransferase Activity by Endogenous Compounds

glucuronidation to a minor extent.13) Enzymes in each family are at least 50% homologous in their cDNA sequences, whereas enzymes in each subfamiliy are more than 60% homologous.14) The single UGT1A gene locus is located on chromosome 2q37 and encodes 9 functional proteins: UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, and 1A10.9,15) The UGT2 family has multiple gene loci located on chromosome 4q13 and consists of the following functional proteins: UGT2A1, 2B4, 2B7, 2B10, 2B11, 2B15, 2B17, and 2B28.16) UGT is anchored at its C-terminal to the ER membrane, and the main body, including the catalytic domain, is located within the ER.17,18) Because of this orientation, UGT has a diagnostic feature, so called ``latency,'' whereby treating tissue microsomes with detergent greatly enhances the activity.19) In addition, UDPGA, a co-substrate, must be supplied from the cytosol to the luminal side of the ER for UGT reaction.20) UDPGalactose transporter-related isozyme7 (UGTrel7) has been shown to facilitate UDPGA transport from cytosol into the ER.21,22) The glucuronides formed in the ER lumen appear to be rapidly translocated to the cytosol. However, the transporter(s) involved in this step has not yet been identified. Finally, glucuronides are transported from cytosol into the bile or the blood. Glucuronide transport across the plasma membrane has been characterized in detail, and several members of the multidrug resistance-associated protein family (MRP1, 2, and 3)23,24) and organic anion transporters (OATP2, 4, and 8)25–27) have been shown to be involved. UGT-catalyzed glucuronidation is thought to account for up to 35% of phase II reactions.28) The expression and function of UGT is modulated by gene regulation,29–33) phosphorylation,34,35) glycosylation,36) homo/ hetero-oligomerization,37–45) and protein-protein association with cytochrome P450.46–51) For these subjects, please refer to other reviews.10,15,51–55) Further, as there are a number of reports about the inhibition of UGT by xenobiotics,56, references therein) drug-drug interactions due to UGT inhibition have attracted the interest of many researchers. Several pieces of evidence have suggested that endogenous substances also modulate UGT catalysis. Although we have much to learn about this from future studies, we summarize here the endogenous compoundproduced modulation of UGT function reported thus far, and discuss its significance and mechanism.

Endogenous inhibitors of UGT Many endogenous substances such as nucleotides, hormones, and fatty acyl-CoAs have been shown to inhibit or down-regulate UGT (Table 1). UDP is a competitive inhibitor of UGT, and it competitively inhibits the binding of co-substrate UDPGA to UGT.57,58) However, recent studies in our laboratory have shown that adenine and related compounds are non-competitive

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inhibitors of the substrate and UDPGA.59) We shall discuss this topic later. Other examples of endogenous UGT inhibitors reported thus far are: cytokines (interleukin1a, IL-1a),61,62) fibroblast growth factors (FGFs),63) estrogen,64–66) testosterone,67) thyroid hormones,68) and ursodeoxycholic acid (UDCA).69) Of the endogenous inhibitors listed above, the effects of acyl-CoAs have been studied in more detail than the others. Long chain fatty acyl-CoAs are capable of modulating UGT activity. Previous studies, including one conducted by this laboratory, have suggested that addition of fatty acyl-CoA to rat hepatic microsomes pretreated with detergent inhibits UGT activity.71–73) Regarding the mechanism, an early study suggested that oleoyl-CoA alters suggested the functional state of UGT.74) Palmitoyland oleoyl-CoAs cause a concentration-dependent inhibition only in microsomes permeabilized by alamethicin. The extent of inhibition depends on the level of permeability, and the effect reaches a maximum in fully permeabilized microsomes. It is also known that arachidonoyl-CoA reduces the UGT activity toward testosterone catalyzed by partially purified enzymes.72) Furthermore, 20 mM palmitoyl-CoA reduced UGT activities in permeabilized rat liver microsomes toward various endogenous and exogenous substrates to 30–60% of the control. The concentration of acyl-CoA required for the half-maximal inhibition (IC50) was approximately 20–30 mM for various substrates. Kinetic studies have suggested that acyl-CoAs act on UGT non-competitively for each substrate.72) A previous study observed that the acylation of UGT isoforms by acyl-CoA occurred during incubation in the absence of acyltransferase. Thus, non-enzymatic autoacylation is suggested to be involved in the mechanism. However, it is also suggested that autoacylation is not the sole mechanism underlying the inhibition of UGT activity.75) Because the effect of acyl-CoA was observed for various substrates, the acyl-CoA binding site seems not to be located in the variable domain for the substrate but in the commonly used domain, i.e., the C-terminal half of UGT. However, this would not be the binding site of UDPGA, because acylCoA reduces UDPGA utility in a non-competitive mode. The result described above suggests that the specific binding of acyl-CoA to UGT induces a conformational change of the enzyme to inhibit UGT.75) Taking these reports into consideration, it seems likely that fatty acylCoA inhibits UGT when the membrane of the ER is disrupted. Adenine nucleotide as an allosteric inhibitor of UGT: The effects of nucleotides other than UDP on UGT activity have received little attention. We provided evidence that nucleotides such as ATP, ADP, adenine, CTP, NAD＋, and NADP＋ are endogenous inhibitors of UGTs.59) In this laboratory, we are now focusing on the functional interaction between P450 and UGT, and have

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Table 1. Endogenous inhibitors of UDP-glucuronosyltransferase reported so far Dose/ concentration

Compound

Substrate (aglycon)

Animal/ enzyme source

a

Inhibition (%)/IC50b (mM)

Apparent Ki (mM)

References

ATP (15.3c, 9.4d); NADP＋ (13.1c, 8.1d); ＋ NAD (9.5c, 5.7d)

59)

ATP, CTP, NAD＋ , NADP＋

4-MU

Permeabilized rat liver microsomes

ATP (15.4b); CTP (5.9b); NAD＋ (9.0b); ＋ NADP (10.0b)

ATP, CTP, NAD＋ , ＋ NADP

E3G

Permeabilized rat liver microsomes

ATP (35.2b); CTP (55.8b); ＋ NAD (32.1b); NADP＋ (25.2b)

59)

E17G

Permeabilized rat liver microsomes

59)

1 mM

E3G

Human UGT1A1

ATP (11.7b); CTP (34.7b); NAD＋ (11.8b); ＋ NADP (8.0b) ¿100a

0.4 mM

E3G

Human UGT1A1

¿100a

59)

1 mM

E3G

Human UGT1A1

¿100a

59)

1 mM

1-Naphthol

Purified rat UGT (phenol)

90a

57)

0–1.4 mM

1-Naphthol

Rat intestinal microsomes (latent)

UTP

1 mM

1-Naphthol

Purified rat UGT (phenol UGT)

42a

57)

CDP

1 mM

1-Naphthol

Purified rat UGT (phenol UGT)

44a

57)

IL-1a

1–10 ng/mL

DHT

LNCaP cells

70a

61)

FGF

10 ng/mL

DHT

LNCaP cells

33–51a

Ethynyl estradiol

2.5 mg/kg

AZT

Human liver microsomes

38c

67)

Testosterone

AZT

Human liver microsomes

250c

61)

Estradiol benzoate

Androsterone

Wistar rats

70–80a

65)

Bilirubin

Wistar rat

27a

70)

Bilirubin

Rat liver microsomes (digitonin activated)

Bilirubin

Rat liver microsomes (digitonin activated)

＋

ATP, CTP, NAD , NADP＋ ATP NAD

＋

NADP

＋

UDP

UDCA

1 mmol/min/100 ge

TUDCA Acyl-CoAs (C14:0; C18:0; C18:1; C18:2; C20:4)

20 mM and C20:4: 11 mM

Palmitoyl-CoA

Oleoyl-CoA, Palmitoyl-CoA Oleoyl-CoA and Palmitoyl-CoA

20 mM 20 mM 0–50 mM

59)

100d

63)

346c, 206d

69)

201c, 188d

69)

a

72)

Testosterone

Purified rat UGT

p-Nitrophenol

Permeabilized rat liver microsomes

Testosterone p-Nitrophenol

Purified rat UGT

71a

Permeabilized rat liver microsomes

50a

71)

Permeabilized rat liver microsomes and human UGT1A6

0¿100a (concentrationdependent manner)

73)

4-MU

50–71

60)

15c

72)

DHT, dihydrotestosterone; AZT, zidovudine; 4-MU, 4-methylumbelliferone; E3G, formation of estradiol 3 b-D-glucuronide; E17G, formation of estradiol 17bD-glucuronide; UDCA, ursodeoxycholic acid; TUDCA, tauroursodeoxycholic acid a Inhibition (%); bIC50 (mM); cKi for substrate; dKi for UDPGA; eInfusion rate.

provided evidence supporting this concept.46,48–51) In one of a series of studies on UGT-P450 interactions, we examined whether microsomal UGT activity is affected by the NAD(P)H-generating system. The purpose of this experiment was to determine whether the catalytic activity of P450 is needed for functional P450-UGT interaction. The preliminary data suggested that the NADPH-generating system inhibited UGT activity only in the presence of detergents such as Brij 58 and Tween 20, which are generally used in UGT assays. Since the NADPH-generating system consists of NADP＋, glucose-6-phosphate (G6P), and G6P dehydrogenase, we further investigated

which component is a potent inhibitor of UGT. The results showed that NADP＋ exhibits a strong inhibitory effect on UGT, while G6P exhibits a weak effect.59) Some NADP＋-dependent oxidoreductases76,77) as well as NADP＋ 78) exist within the ER. A strong inhibitory effect on UGT was also observed for ATP, ADP, NAD＋, and adenine as well as NADP＋. Although the concentration of smaller nucleotides within the ER has not been characterized in detail, many sorts of nucleotides and related substances including ATP are likely to be present in this organelle (Fig. 1).79) An early study conducted by Hallinan et al.80) reported

Modulation of UDP-Glucuronosyltransferase Activity by Endogenous Compounds

Fig. 1. Possible inhibition of UGT by adenine nucleotides in the lumen of the endoplasmic reticulum In the lumen of the ER are molecular chaperones such as glucoseregulated protein (GRP)78 and GRP94, which need ATP for their function. In addition, NAD(P)＋, the other potent inhibitor of UGT, is formed by oxidoreductases.

for the first time that UGT activity can be reduced by nucleotides. They used ultrasonicated liver microsomes from guinea pigs as the enzyme source and observed a significant reduction in UGT activity toward pnitrophenol, estradiol, and estrone by 4 mM ATP. In contrast, our study indicated that UGT inhibition by ATP and related nucleotides, including NADP, occurs at much lower concentrations [IC50, º20 mM (Table 1); detergent-treated rat liver microsomes]. Although the reason for the above inconsistency remains unknown, it may be due to the difference in the method for removing UGT latency (ultrasonication vs. detergent treatment). In connection with this assumption, quite a different finding has been reported by Yan and Caldwell,81) For example, they observed that untreated liver microsomes are insensitive toward 1 mM NADP＋ in terms of UGT inhibition. Because their study used acetaminophen and trifluoperazine as the substrates, it cannot be ruled out that the difference between the studies is due to the use of different substrates. Keeping this in mind, it seems likely that UGT inhibition by nucleotides depends on the nature of the microsomes used in the assay. In agreement with the observation made by Yan and Caldwell,81) our data also showed that ATP and NADP＋ have little effect on 4-MU glucuronidation catalyzed by untreated microsomes prepared from rat liver. However, detergent-treated microsomes exhibited quite a different response to nucleotides, and 4-MU UGT activity was strongly inhibited by ATP, NAD＋, and NADP＋.59) This fact strongly suggests that only nucleotides accessible directly to UGT inhibit the enzymatic activity. In other words, while nucleotides present in the ER only are suggested to be active inhibitors, cytosolic nucleotides cannot inhibit UGT. UGT is a type-I membrane-bound en-

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zyme, and its main body, including the catalytic domain, is localized in the ER lumen.17) Only the C-terminal of UGT, consisting of approximately 20 amino acid residues, extrudes into the cytosol, and this portion is often termed the ``cytosolic tail.'' Taking such topology into consideration, inhibitory nucleotides would interact with UGT at the region present in its main body, which is present inside the ER. The UGT specificity for nucleotide-produced inhibition remains to be established. Conceivably, only particular UGT isoforms may be sensitive to the inhibition. Regarding this issue, our study assessed the ability of nucleotides to inhibit UGT using 4-MU and estradiol. The glucuronidation of 4-MU is catalyzed by multiple isoforms belonging to the UGT1A and 2B subfamilies.82) Despite such a situation, 4-MU UGT activity is completely inhibited when a sufficient concentration of nucleotide is used. Furthermore, estradiol glucuronidation giving estradiol-3-glucuronide (E3G) and 17-glucuronide (E17G) is also mediated by different UGT isoforms; that is, the former is catalyzed by UGT1A183) and the latter is mediated by several isoforms including UGT2B1and 2B3.84,85) Nevertheless, adenine nucleotides and related substances suppress both reactions. Accordingly, UGT inhibition by nucleotides appears to occur ubiquitously in the case of many isoforms of UGT, although the sensitivity to inhibitors may differ from one isoform to another. The inhibitory effect of ATP, NADP＋, and NAD＋ on E3G formation was observed for recombinant human UGT1A1.59) The inhibitory effect of ATP, NADP＋, and related nucleotides on 4-MU glucuronidation was also observed for recombinant UGT2B7 (Nishimura et al., unpublished data). As mentioned before, such inhibitory effects are thought to be a direct effect on UGT. The nucleotidyl inhibitors suppress the activity of recombinant forms of UGT, even when the enzymes are not pretreated with detergent. This would probably be because recombinant UGTs lose their latency86,87) or are expressed with an abnormal topology. Human UGT1A1 catalyzes the glucuronidation of bilirubin88) and therapeutic drugs such as etoposide89) and SN-38, an active metabolite of irinotecan.90) Similarly, UGT2B7 catalyzes a number of reactions including the glucuronidation of morphine91) and zidovudine.92) Thus, any alteration in these enzymatic activities may cause unexpected adverse effects during chemotherapy. In contrast to ATP and ADP, AMP does not inhibit 4-MU glucuronidation.59) However, AMP suppresses the ATP-produced inhibition of 4-MU glucuronidation in a concentration-dependent manner.59) It is, therefore, likely that AMP can bind to the allosteric effector site of UGT and antagonize the inhibitory effects caused by ATP. A similar phenomenon was observed for adenine-, NAD＋-, and NADP＋-induced inhibition of 4-MU and E3 glucuronide formation.59) It is, therefore, suggested that

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AMP as well as adenine-related compounds such as ATP and NADP＋, bind to a common allosteric effector site on UGT to exert their effects. One of the minimum requirements for binding to the effector site is thought to be the adenine-skeleton. Like AMP, adenosine has no inhibitory effect on UGT catalysis.59) Thus, a di- or triphosphate substituent attached to the ribose seems to be needed as one of the other structural requirements for an active inhibitor. However, very confusingly, adenine shows an ability to inhibit UGT, although it lacks a phosphate group. The structure-effect relationships involving UGT inhibition by adenine and related substances remain to be clarified. Considering the guanine nucleotide, while GTP is a potent inhibitor of UGT, other derivatives including guanosine, GMP, and GDP have little effect on UGT.59) The IC50 value of GTP toward 4-MU and estradiol glucuronidation is 7-fold higher than that of ATP. Similarly, among the cytidine derivatives, only CTP had an inhibitory effect on UGT activity. Probably, GTP and CTP inhibit UGT by a mechanism different from that of adenine-related inhibitors. This is because, in contrast to adenine, both guanine and cytidine do not have any inhibitory effect on UGT. The inhibition by adenine-related compounds (ATP, NAD＋, and NADP＋) is non-competitive.59) These substances do not appear to compete either with the substrate (aglycon) or UDPGA at the binding site. The Ki values (º20 mM) of adenine-related substances for UGT inhibition are lower than the Km values for the substrate (aglycon) and co-substrate (UDPGA, 782 mM, our data). Therefore, the affinities of inhibitors for the specific site of UGT seem to be higher than those of substrates and co-substrate. Since only nucleotides present in the ER can inhibit UGT function, their concentrations and dynamics in the ER lumen are of interest. The luminal concentrations of NADH plus NAD＋ and NADPH plus NADP＋ in rat liver microsomes are estimated to be 240 and 55 mM, respectively.93) Other workers have demonstrated that the luminal concentration of reduced pyridine nucleotides (NADPH and NADH) is 400 mM.94) Furthermore, the concentration of oxidized pyridine nucleotides (NADP＋ and NAD＋) is assumed to be 50 mM.94) Thus, both the IC50 and Ki values of NADP＋/NAD＋ are less than their estimated concentrations in the ER. This strongly suggests that UGT activity is controlled by oxidized forms of pyridine nucleotides under physiological conditions. The concentration of ATP in the lumen of the ER has not yet been determined, but the presence of ATP within the ER is implicated by studies detecting light from cells expressing ER-targeted firefly luciferase, which requires ATP for function.79) In agreement with this evidence, some proteins on the luminal side of the ER are phosphorylated,34,35,95) and ER chaperones, such as GRP78 and GRP94, have affinities for ATP.96,97) Purified GRP78 is known to bind ATP (Kd, 5.4 mM) and hydrolyze ATP (Km, 28.6

mM).96) Protein disulfide isomerase is another example of an ER protein: it also binds to and hydrolyses ATP (Kd and Km are 9.7 and 7.1 mM, respectively).98) In addition, ATP can be delivered into the ER of rat liver with an apparent Km of 3–4 mM and Vmax of 3–7 pmol/min/mg protein.99) The above pieces of evidence would support the view that ATP and related nucleotides are physiological regulators of UGT function and that their activity is dynamically altered according to changes in the concentration of nucleotidyl regulators in the ER. If UGT inhibition by nucleotides really takes place in the ER, what is the physiological significance? The ER lumen of hepatocytes is the place where the conversion of cortisol to cortisone or the reverse reaction occurs. The former reaction needs 11b-hydroxysteroid dehydrogenase (11b-HSD), which is a membrane-bound enzyme located in the ER, and NADP＋ as the obligate cofactor.100) Cortisol delivered into the ER is converted to cortisone by 11b-HSD depending on the in situ concentration of NADP＋. Formation of cortisone consumes NADP＋, and reduces its concentration to a level which is insufficient for the inhibition of UGT. Such a condition would facilitate the inactivation of excess cortisol by glucuronidation. Thus, the progress of the 11b-HSD reaction results in the facilitation of UGT catalysis. As cortisol is the most active glucocorticoid in humans, this synergism may be an important mechanism to achieve the rapid and effective inactivation of cortisol. Conversely, the formation of cortisone would increase the NADPH concentration to a level which favors the reverse reaction of 11b-HSD, i.e., reduction of cortisone to cortisol.100) Taken together, the inhibition of UGT by NADP＋ is suggested to be one of the key mechanisms modulating glucocorticoid levels. In this context, cortisol glucuronide has been detected in human urine.101) UGT inhibition by nucleotides may rationalize the ``latency'' of UGT. As mentioned previously, treating tissue microsomes with detergent greatly enhances UGT activity. The traditional explanation for this phenomenon is that an increase in the permeability of microsomes caused by the detergent allows the UGT substrate free access to the enzyme. However, the disruption of the ER membrane by detergent treatment probably reduces the luminal concentrations of UGT inhibitors such as ATP, NAD＋, and NADP＋. A reduction in the concentration of inhibitory nucleotides would be attributable to the apparent increase in UGT activity caused by the detergent. Therefore, the inhibition of UGT by adenine-related substances may be one of the reasons why microsomal UGT is latent. Endogenous activators of UGT In contrast to the endogenous inhibitors of UGT, the endogenous activators have been poorly understood, except for the role of UDP-sugars (Table 2). Many studies

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Modulation of UDP-Glucuronosyltransferase Activity by Endogenous Compounds

Table 2. Endogenous activators of UDP-glucuronosyltransferase reported so far Compound UDP-GlcNAc

Dose/ concentration

Aglycon

Animal/ enzyme source

1–1.8 mM

p-Nitrophenol

Rat liver microsomes

1.4 mM

o-Aminophenol

Guinea pig liver microsomes

Activation (fold)

References

2.5–3.2

102)

86%

102) 103)

2.5 mM

p-Nitrophenol

Guinea pig liver microsomes

4

1 mM

Estrone

Guinea pig liver microsomes

2.8–4.9

104)

1 mM

Bilirubin

Primate liver microsomes

105)

2 mM

Bilirubin

Rat liver microsomes

63% À3

UDP-Xylose

2 mM

4-MU

Rat liver microsomes

2–5

108)

Estrogen

10 nM

DHT

ER-positive breast cancer cells mMCF-7, BT474, T47D, and ZR-75)

6

109)

73)

106)

Decanoyl-CoA

15 mM

4-MU

Rat liver microsomes

3.2

Myristoyl-CoA

22.5 mM

4-MU

Rat liver microsomes

7

73)

Stearoyl-CoA

7.5 mM 15 mM

4-MU

Rat liver microsomes

9

73)

4-MU

Rat liver microsomes

7.7

73)

15 mM 15 mM

4-MU

Rat liver microsomes

7.5

73)

4-MU

Rat liver microsomes

7

73)

Oleoyl-CoA Palmitoyl-CoA Arachidonoyl-CoA

have shown that UDP-N-acetylglucosamine (UDPGlcNAc) is an endogenous activator of UGT.102–107) Similar to UDP-GlcNAc, UDP-xylose has an ability to activate UGT.108) Further, recent studies in our laboratory showed that fatty acyl-CoAs are endogenous activators of UGT,73,110) although other investigators have claimed to show an inhibitory effect of acyl-CoAs on UGT function. UDP-N-Acetylglucosamine as an endogenous activator: The activation of UGT catalysis by an endogenous substance, UDP-GlcNAc, was reported for the first time by Pogell and Leloir.102) This sugar increases pnitrophenol glucuronidation by rat liver microsomes, and the maximal activation is achieved at as much as 0.3 mM. The relative specificity of this activation has been confirmed by the observation that UDP-glucose, GDP-mannose, and uridine produce no activation. UDP-GlcNAc activates the glucuronidation of not only p-nitrophenol but also o-aminophenol, 4-MU, and phenolphthalein mediated by freshly prepared hepatic microsomes from mice and rats. However, no further activation occurs upon addition of UDP-GlcNAc when Triton X-100-purturbed microsomes were used. Glucuronidation of estrone and estradiol by liver microsomes from guinea pigs is also stimulated 2.8–4.9-fold by 1 mM UDP-GlcNAc.104) There are controversial reports about the effect of ATP on the UDP-GlcNAc-dependent activation of UGT. For example, Pogell and Leloir (1961) showed that ATP enhances UDP-GlcNAc-dependent activation,102) whereas Winsnes (1969) claimed no such activation.19) Hauser et al. (1988) have investigated the mechanism whereby UDPGA interacts with microsomal UGT.105) This was conducted by analyzing the kinetics of bilirubin UGT in the monkey. Following fitting of the data to mathematical models, it was suggested that native micro-

somes have a single binding site for UDPGA with a Km of 2.8 mM. In contrast, UDP-GlcNAc at a physiological concentration (1 mM) changes the kinetics; the new kinetics fit a non-interactive two-binding site (or process) model, which is characterized by the appearance of a high-affinity site (Km, 0.14 mM) in addition to a lowaffinity site (Km, 5.13 mM). Consequently, the intrinsic clearance (Vmax/Km) of bilirubin glucuronidation was increased by approximately 10-fold due to the high-affinity site that was newly formed in the presence of UDPGlcNAc. This observation suggests that UDP-GlcNAc enhances glucuronidation by altering the manner of the interaction between UDPGA and UGT. It is widely accepted that UDP-GlcNAc acts as a physiological activator of hepatic glucuronidation, but the mechanism of this effect remains elusive. In 1995, Bossuyt and Blanckaert proposed a model for the facilitation of UDPGA translocation into the ER by UDP-GlcNAc. The model consisted of two asymmetric pathways: UDPGA influx into the ER coupled with the concomitant efflux of UDP-GlcNAc. The model also suggested that UDP-GlcNAc in the ER lumen needed for UDPGA influx is supplied by coupling with UMP efflux. Although the mechanism in uncertain, exogenous UDP-GlcNAc added to the reaction mixture is assumed to enhance UDPGA uptake into the ER where the catalytic centre of UGT exists, resulting in the activation of UGT. The UGT reaction forms UDP as the inevitable by-product, and this is further hydrolyzed to UMP and inorganic phosphate by nucleotide diphosphatase. As mentioned above, UMP is ejected from the lumen of the ER in exchange for UDPGlcNAc which enters the ER. UDP-GlcNAc accumulated in the ER lumen then becomes available as a driving force for UDPGA influx. In this way, UDP-GlcNAc shuttles be-

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tween the ER lumen and the cytosol, once in exchange with UMP to enter the ER lumen and once in exchange with UDPGA to leave the ER lumen. These transport systems, together with intravesicular metabolism of UDPGA, would be changed when the UDP-GlcNAc-induced stimulation of glucuronidation occurs.107) UDP-Xylose as an endogenous activator: UDPXylose is also one of the uridine nucleotides which acts as an endogenous activator of UGT.108) UDP-Xylose stimulates 4-MU glucuronidation assayed with the ER membrane under non-denaturing conditions. When assayed with Staphylococcus aureus a-toxin-permeabilized microsomes, UDP-xylose does not affect 4-MU glucuronidation. This sugar stimulates both glucuronidation and UDPGA uptake. Similar to the case for UDPGlcNAc, UMP formed from UDP, a by-product of the UGT reaction, is released from the lumen of the ER in exchange for UDP-xylose, which enters the ER lumen. The internalized UDP-xylose then becomes available as a counter-substrate for UDPGA influx. Thus, it is also likely that UDP-xylose enhances glucuronidation by affecting UDPGA transportation107). Fatty acyl-CoA as an endogenous activator of UGT: Fatty acyl-CoAs have a number of physiological roles within cells, including incorporation into triacylglycerol and membrane phospholipids. They are also used as substrates for b-oxidation and protein acylation, and function as ligands for transcription factors.111) Other cellular processes are also regulated by acyl-CoA: these include cytosolic enzymes, ion channels, ion pumps, translocators, membrane fusion, and gene regulation.100) Fatty acid precursors need to be activated to fatty acylCoAs by acyl-CoA synthetases (ACSs) before being used. The active site of microsomal ACS faces the cytosol.112) Since acyl-CoAs are fairly water-soluble and are amphiphilic, they can exist either in membranes or in the cytosol. In liver cytosol, most of the fatty acyl-CoA is believed to bind to fatty acyl-CoA-binding protein (FACBP) and to fatty acid-binding protein (FABP).113–116) It is also suggested that fatty acyl-CoAs are involved in gene regulation as the ligands of peroxisome proliferator-activated receptor a (PPARa) and hepatocyte nuclear factor-4 (HNF-4).117) PPARa has been shown to upregulate UGT1A1 and UGT1A6.118) HNF-4 is also involved in the regulation of UGT1A6 and UGT1A9.31–33) Therefore, it is possible that fatty acyl-CoA affects glucuronidation by inducing UGT. Several previous studies have demonstrated that fatty acyl-CoAs are inhibitors of UGT.71,72) These studies used microsomes under denaturing conditions or partially purified enzyme.71,72) To elucidate in more detail the effect of fatty-acyl-CoA on intact microsomes, we evaluated the effect of acyl-CoAs on UGT activity toward 4-MU using rat liver microsomes. When microsomes are treated with Brij 58, oleoyl- and palmitoyl-CoA reduces UGT

activity in a dose-dependent manner. This result agrees with previous reports that suggested a dose-dependent inhibition of UGT activity by acyl-CoAs.71,72,75) However, we have provided evidence for the first time that medium- and long-chain acyl-CoAs activate UGT activity catalyzed by microsomes not treated by detergent,73) even though under these conditions acyl-CoA at increased concentrations inhibits UGT function. The maximal activation by acyl-CoA takes place at around 15 mM, which is less than that needed for inhibition (at least 30 mM) (Table 2). Acyl-CoA consists of a hydrophilic moiety (CoA) and a hydrophobic region (acyl chain). Therefore, long-chain acyl-CoAs appear to act as a detergent.119) For example, palmitoyl-CoA is suggested to have a critical micelle concentration of 70–80 mM.120) At higher concentrations, acyl-CoAs are thought to inhibit UGT in microsomes owing to their detergent-like nature and also their inhibitory effect on UGTs. The above pieces of information suggest that the intact nature of the ER membrane is an important determinant for the acyl-CoAdependent enhancement of UGT activity. Since fatty acids can be released from acyl-CoAs, they may partially contribute to UGT inhibition. Indeed, unsaturated fatty acids markedly increase UGT activity, whereas saturated fatty acids and CoA do not exhibit such effects. However, the concentration needed for UGT activation and inhibition differs between free fatty acids and acyl-CoAs.73) This difference suggests that the mechanisms governing the effect on UGT function of the above two groups of substances are different. Thus, acyl-CoA itself is considered to have the ability to activate microsomal UGT, although free fatty acids may make a minor contribution. Unsaturated fatty acids have been reported to inhibit 4-MU glucuronidation by human kidney microsomes or human recombinant UGT1A9 at 1–3 mM.121,122) In our study, unsaturated fatty acids at a concentration greater than 20 mM increased 4-MU glucuronidation catalyzed by rat liver microsomes.73) Although the reason for this discrepancy is unknown, the presence of such a difference suggests that the activation or inhibition effect of acylCoA may again depend on the nature of the UGT membrane environment. Based on kinetic analyses, acyl-CoAs enhance the velocity of glucuronidation, although they reduce the affinity of UGT toward substrate 4-MU. An increase in affinity toward UDPGA and an increased in Vmax, the kinetics of which are assessed by varying the UDPGA concentration, are also assumed to contribute to the acylCoA-produced activation of UGT.73) The transportation of UDPGA from the cytoplasm to the luminal side of the ER is thought to be mediated by a specific transporter.20) In fact, human nucleotidyl sugar transporter, capable of transporting both UDPGA and UDP-N-acetylgalactosamine, exists on the ER membrane.21,22) Therefore, acylCoAs may enhance UGT activity through activation of

Modulation of UDP-Glucuronosyltransferase Activity by Endogenous Compounds

UDPGA transportation. We shall discuss this issue later in more detail. As described above, the main body of UGT except for its cytosolic tail is located within the ER, and it is protected by the ER membrane. Therefore, trypsin fails to hydrolyze UGT when intact microsomes are incubated with this digestive enzyme. However, microsomal UGTs pretreated with 50 mM oleoyl-CoA can be digested by trypsin, although no tryptic digestion occurs for microsomal UGTs treated with 15 mM oleoyl-CoA.73) This evidence supports the hypothesis that acyl-CoA at higher concentrations acts as a detergent. Thus, acylCoAs seem to require increased permeability of the membrane to access the luminal domain of UGT for inhibition. The observation that acyl-CoAs inhibit UGT in detergent-treated microsomes agrees with the above assumption71,72,75). The cytosolic tail of UGT2B1 is truncated by treating microsomes not previously exposed to detergent with trypsin, whereas the main body of UGT is resistant to digestion under identical conditions. The same is true even when microsomes pretreated with 15 mM oleoyl-CoA are used.73) The C-terminal sequence of UGTs is relatively conserved.123) Therefore, it is likely that the cytosolic tails of UGTs other than UGT2B1 are also sensitive to tryptic digestion. The activation of UGT by 15 mM oleoyl-CoA takes place even when trypsintreated microsomes are used as the enzyme source. This fact does not support the view that the cytosolic tail plays a role in acyl-CoA-dependent activation of UGT. However, it should be noted that the activation of microsomal UGT may occur through a mechanism whereby acyl-CoAs affect the cytosolic region remaining even after tryptic digestion. The cytosolic tail of UGT2B1 has six residues of lysine, which is the target amino acid of trypsin. Three cysteine residues are also present in the cytosolic tail. It is of interest whether these cysteine residues remain after tryptic digestion, because there is evidence for the important role of the SH group in acylCoA-produced activation of UGT.73) It is possible that an acyl-CoA-sensitive cysteine residue (or residues) is present in UGT2B1 if the most upstream site for the trypsin target is K519. This is because cysteine residues in the cytosolic tail are located at sites earlier than K519. As described before, our series of studies has provided evidence for protein-protein interactions between UGT and P450.46,48–51) Some of the above interactions cause the suppression of UGT function.48,49) P450 is localized in the ER membrane and almost the entire molecule extrudes into the cytoplasm. Owing to this topology of expression, P450s are thought to be sensitive to digestion by trypsin. In relation to this, trypsin-treated microsomes exhibit a higher UGT activity than untreated microsomes.73) Conceivably, tryptic digestion of microsomes may activate UGT function through removing P450, a suppressor of UGT. On the other hand, recombinant

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UGT2B1 possessing a truncated cytosolic tail exhibits a lower catalytic activity than wild-type UGT2B1.87) Therefore, it may be true that liver microsomal UGTs are suppressed by microsomal proteins including P450s. Treating liver microsomes with N-ethylmaleimide (NEM) and 5,5?-dithiobis(2-nitrobenzoic acid) (DTNB) renders UGTs resistant to activation with 15 mM oleoylCoA, although no such effect was observed with dithiothreitol (DTT).73) A previous report has shown the positive role of the SH moiety in the binding of acyl-CoAs to UGTs.75) All isoforms of rat and human UGT other than UGT2A1 have at least one cysteine residue in the cytosolic tail. The cysteine residues present in the cytosolic tail may be targets for activation by acyl-CoAs. If this is true, it would be reasonable to consider that the acylation of the cysteine residues is a prerequisite for the acyl-CoA-mediated activation of UGT. However, it remains to be clarified whether UGTs are directly modified by acyl-CoAs. The activity of recombinant UGT1A6 expressed in insect cells is always inhibited rather than facilitated by oleoyl-CoA, both in the absence and presence of Brij 58.73) Such a picture resembles the effect observed in Brij 58-pertubed rat liver microsomes. Since the intact membrane is assumed to be necessary for the oleoyl CoA-dependent activation of liver microsomal UGT, the absence of an enhancing effect of acyl-CoA on the catalysis by recombinant UGT may be due to the difference in membrane integrity. The environment of the insect ER would differ from that of mammalian cells. Thus, the different circumstances of recombinant UGT may be the reason why it lacks acyl-CoA-dependent activation. An alternative possibility is that factor(s) other than UGT itself and the expression conditions are a target of acyl-CoA for the activation. For example, the UDPGA transporter may be activated through the acylation of its SH-group (Fig. 2). The SH-modifying reagents NEM, DTNB, and DTT inhibit UGT in the presence of 50 mM oleoyl-CoA.73) Since oleoyl-CoA at this concentration seems to disrupt the ER membrane, the above thiol-modifying reagents and oleoyl-CoA would be able to interact directly with the luminal domain of UGT under the conditions used. On the other hand, studies using site-directed mutagenesis have provided evidence that UGT needs the cysteine residue(s) of the luminal domain to acquire its full function.124–126) Therefore, the modification of luminal cysteine residues by NEM and DTNB appears to lead to the enhancement of UGT inhibition by 50 mM oleoyl-CoA. This is supported by the observation that NEM and DTNB greatly impair or abolish microsomal UGT activity in the presence of Brij 58. It is widely known that DTT has a protective effect against protein denaturation. Nevertheless, this substance is also inhibitory to UGT function when the activity is assayed in the presence of 50 mM oleoyl-CoA.73) This abnormality suggests that DTT

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Fig. 2. Hypothetical model for the activation of UGT by fatty acyl-CoA The modification of an SH group may be a prerequisite for the fatty acyl-CoA-dependent activation of UGT. In the figure, nucleotide sugar transporter (NST) and the cytosolic tail of UGT are assumed to be candidates having acyl-CoA-sensitive SH groups. The modification of the SH group of NST by fatty acyl-CoA would facilitate UDPGA uptake into the ER from the cytosol. The modulation of UDPGA uptake by an effector protein, the function of which needs the acylation of its SH group, may also be possible. The acylation of the cytosolic tail of UGT is another possibility explaining the acyl-CoAmediated activation of UGT.

may reduce the disulfide to free SH, which is the target of oleoyl-CoA. The cytoplasmic concentration of long-chain acylCoAs in rat liver is estimated to be around 30 mM.127) If we simply assume the significance for UGT function, acyl-CoAs would enhance glucuronidation rather than inhibit it under physiological conditions. However, the cytosol contains acyl-CoA-binding protein, which serves to mask the effect of long-chain acyl-CoAs.116) The authors of that report demonstrated that the intracellular concentrations of free acyl-CoAs are in the low nanomolar region because of the presence of the binding protein. However, as the concentrations of cellular components vary dynamically, the conditions surrounding the ER will not be constant. Indeed, the levels of long-chain acylCoAs and CoA in rats are increased under a number of conditions, such as fasting,115,127,128) diabetes,127,128) and treatment with hypolipidemic drugs.115,127,129) Therefore, it is reasonable to suppose that in vivo UGT activity toward various drugs and their metabolites alters along with changes in long-chain acyl-CoA levels, which are affected markedly by nutrition and health conditions. Although the above discussion about acyl-CoAproduced modulation of UGT activity is based on the findings obtained from animal studies, it would be of great interest to know if the same is true for clinicallyimportant drugs or human UGTs. Concerning this issue, our recent study has suggested that fatty acyl-CoA activates morphine glucuronidation mediated by human as well as rat UGTs.110) According to the three-step treatment for pain relief proposed by the World Health

Organization, morphine is widely used for opioid treatment of patients.130) This drug is prescribed mainly for cancer patients suffering from moderate to severe pain. Morphine is metabolized mainly to its 3- and 6glucuronides (M-3-G and M-6-G, respectively).131,132) M-3-G is a major metabolite, with no analgesic activity, in many species.133,134) In contrast, M-6-G exhibits a more potent analgesic effect than the parent morphine.11) The strong analgesic effect of M-6-G is also supported by clinical studies.135–142) While M-3-G formation occurs ubiquitously in many animal species, M-6-G production is rather specific to humans and guinea pigs.133,134) In humans, UGT2B7 plays a crucial role in the metabolism of morphine, and this isoform has the ability to produce both glucuronides.91) It seems to be true without exception that there are great inter-individual differences in the pharmacological effects of medicines in humans. This is also the case for morphine, and its analgesic effect and toxicity vary extensively between individuals.143) Previous studies have suggested that genetic polymorphism in ATP-binding cassette transporter B1 [ABCB1, multidrug resistance 1 (MDR1)], m-opioid receptor, or their combination correlates with the inter-individual variance in the analgesia produced by morphine.144–146) Since a single nucleotide polymorphism (SNP) in the UGT2B7 promoter significantly alters its promoter activity,147) this SNP is also expected to contribute to inter-individual differences in the effect of morphine. However, polymorphisms of the UGT2B7 gene do not seem to fully explain the differences in the analgesic effect of morphine. Our previous study has shown that the functional interaction between CYP3A4 and UGT2B7 alters not only the efficiency but also the regio-selectivity of UGT2B7-catalyzed morphine glucuronidation.48) In addition to this, our more recent study suggests that there is modulation of human morphine UGT by fatty acyl-CoAs.110) The profile of the activation (15 mM) and inhibition (À50 mM) by oleoyl-CoA was comparable with that seen in 4-MU glucuronidation catalyzed by rat liver microsomes. Further evidence has suggested that such modification in morphine UGT is also true for UGTs expressed in human liver microsomes.

Perspective We have provided evidence for the altered function of UGT caused by endogenous compounds such as adeninerelated nucleotides and fatty acyl-CoAs. However, the mechanisms underlying the changes in UGT function by these endogenous substances will not be fully understood until more data from cell biological and membrane biological analyses are obtained. Hence, the modulation of the concentration of adenine nucleotides in the lumen of the ER is of great interest. Further, the target site of fatty acyl-CoA-dependent activation of UGT needs to be inves-

Modulation of UDP-Glucuronosyltransferase Activity by Endogenous Compounds

tigated. The modulation of UGT by endogenous compounds may be one of the major mechanisms explaining inter-/intra-individual differences in drug sensitivity which cannot be understood by SNP analysis. It is assumed that dietary components and cellular metabolomes can explain the individual differences at least in part. Thus, we will have to pay more attention to lifestyle-related factors affecting the catalytic function and expression of drug metabolizing enzymes.

Acknowledgments: This review was written to commemarate the Young Investigator Award 2008 of the Japanese Society for the Study of Xenobiotics (recipient, Y.I.). The authors would like to express sincere gratitude to emeritus professors Drs. Hidetoshi Yoshimura and the late Kazuta Oguri for their valuable advice throughout our research. We also thank graduate students of the Graduate School of Pharmaceutical Sciences, Kyushu University, for their participation in the studies described in this review. The authors are also grateful to collaborators Dr. Peter I. Mackenzie (Flinders University of South Australia), Dr. Yasushi Yamazoe (Tohoku University), Dr. Kiyoshi Nagata (Tohoku Pharmaceutical University), Dr. Shin'ichi Ikushiro (Toyama Prefectual University), Dr. Satoru Ohgiya (National Institute of Advanced Industrial Science and Technology), and Drs. Yoshihiko Maehara and Akinobu Taketomi (Kyushu University). Finally, we would like to express sincere thanks to Dr. Kan Chiba, Editor-in-Chief, for giving us an opportunity to write this review. References 1)

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