Regulation of Hepatobiliary Transporters During Liver Injury☆

2.09 Regulation of Hepatobiliary Transporters During Liver Injuryq JE Manautou, University of Connecticut, Storrs, CT, United States CI Ghanem, Univ...

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2.09

Regulation of Hepatobiliary Transporters During Liver Injuryq

JE Manautou, University of Connecticut, Storrs, CT, United States CI Ghanem, Universidad de Buenos Aires, Buenos Aires, Argentina © 2018 Elsevier Ltd. All rights reserved.

2.09.1 2.09.2 2.09.2.1 2.09.2.1.1 2.09.2.1.2 2.09.2.1.3 2.09.2.1.4 2.09.2.1.5 2.09.2.2 2.09.2.2.1 2.09.2.2.2 2.09.2.2.3 2.09.2.2.4 2.09.2.2.5 2.09.2.2.6 2.09.2.2.7 2.09.2.2.8 2.09.3 2.09.3.1 2.09.3.2 2.09.3.3 2.09.3.3.1 2.09.3.3.2 2.09.3.3.3 2.09.3.3.4 2.09.3.3.5 2.09.3.3.6 2.09.3.4 2.09.3.5 2.09.3.5.1 2.09.3.5.2 2.09.3.5.3 2.09.3.5.4 2.09.3.5.5 2.09.3.5.6 2.09.3.6 2.09.3.7 2.09.3.8 2.09.3.9 2.09.3.10 2.09.4 2.09.4.1 2.09.4.2 2.09.4.3 2.09.4.4 2.09.4.5 2.09.5 References Further Reading

Introduction Liver Transporters: Classes, Localization, and Function Uptake Solute Carriers Oatp/OATP Ntcp/NTCP Asbt/ASBT Oct/OCT Oat/OAT Efﬂux Pumps and Transporters Mrps/MRPs Mdr/MDR Bsep/BSEP Bcrp/BCRP ABCG5/ABCG8 Abca1/ABCA1 Mate/MATE Osta-Ostb/OSTa-OSTb Adaptive Changes in Transporters During Liver Injury Cholestasis Extrahepatic Cholestasis Intrahepatic Cholestasis Estrogen induced Endotoxin induced cholestasis Bile acid accumulation Alpha-naphthylisothiocyanate PBC Sclerosing cholangitis Obesity, Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Chemical-Induced Hepatocellular Injury APAP Carbon tetrachloride Troglitazone Sulindac Bromobenzene Phalloidin Hepatocellular Carcinoma (HCC) Ischemia–Reperfusion Injury Hepatitis B Virus Infection Hepatitis C Virus Infection Liver Regeneration Signaling Pathways Underlying Transporter Expression During Liver Injury Transcriptional Regulation via Nuclear Hormone Receptors Transcriptional Regulation via Transcription Factors Mechanisms of Regulation of ABC Transporters by Cytokines and the Interplay With Nuclear Receptors, Transcription Factors and Epigenetic Regulation Epigenetic Regulation Interplay Between Epigenetics and Nuclear Receptor or Transcription Factors Concluding Remarks

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q

Change History: February 2017. CI Ghanem and JE Manautou updated the text in all sections. This is an update of JE Manautou, SN Campion, LM Aleksunes, Regulation of Hepatobiliary Transporters during Liver Injury, Comprehensive Toxicology, Second Edition, edited by Charlene A. McQueen, Elsevier, Oxford, 2010, Volume 9, Pages 175–220.

215

216

Regulation of Hepatobiliary Transporters During Liver Injury

Abbreviations ABC ATP-binding cassette ANIT Alpha-naphthylisothiocyanate APAP Acetaminophen ARE Antioxidant response element ASBT Apical sodium-dependent bile acid transporter AZT Azidodeoxythymidine BCRP Breast cancer resistance protein BSEP Bile salt export pump BSP Bromosulfophthalein C/EBP CCAAT/enhancer binding protein CAR Constitutive androstane receptor CV Central vein CYP Cytochrome P450 ddC 20 ,30 -Dideoxycytidine, Zalcitabine DHEAS Dehydroepiandrosterone 3-sulfate DNP-SG 2,4-Dinitrophenyl-S-glutathione EE 17a-Ethinylestradiol FXR Farnesoid X receptor GSH Glutathione GSSG Oxidized GSH HCC Hepatocellular carcinoma HCV Hepatitis C virus HIV Human Inmunodeﬁciency virus HNF1a Hepatocyte nuclear factor 1a ICP Intrahepatic cholestasis of pregnancy ISBT/IBAT Ileal Naþ/bile acid cotransporter LPS Lipopolysaccharide LTC4 Leukotriene C4 MATE Multidrug and toxin extrusion MCD Methionine- and choline-deﬁcient MDR Multidrug resistance protein MPP 1-Methyl-4-phenylpyridinium MRP Multidrug resistance associated protein MTX Methotrexate NAPQI N-Acetyl-p-benzo-quinoneimine NLT Novel liver-speciﬁc transport protein Nrf2 Nuclear factor E2-related factor 2 NSAID Nonsteroidal anti-inﬂammatory drug NTCP Naþ-dependent taurocholate cotransporting polypeptide OAT Organic anion transporter OATP Organic anion-transporting polypeptide OCT1 Organic cation transporter 1 OST Organic solute transporter PAH p-Amminohippurate PBC Primary biliary cirrhosis PFIC Progressive familial intrahepatic cholestasis PG Prostaglandin Pgp P-Glycoprotein PMEA 90 -(20 -Phosphonylmethoxyethyl) adenine PSC Primary sclerosing cholangitis PV Portal vein PXR Pregnane X receptor

Regulation of Hepatobiliary Transporters During Liver Injury

217

SNPs Single nucleotide polymorphisms TEA Tetraethylammonium VEGF Vascular endothelial growth factor

2.09.1

Introduction

Drug transporters gained notoriety when it was determined that their overexpression in multiple forms of cancer conferred protection against conventional chemotherapy regimens. Research efforts were taken to examine the ability of these transport proteins to afford resistance to tumor cells by enhancing removal of cytotoxic drugs. These “multi-drug resistance” transporters are also expressed ubiquitously in normal, noncancerous organs. The collective work of multiple investigators has led to the understanding that drug transporters play an important role in the pharmacokinetics and disposition of pharmaceuticals, environmental contaminants, and endogenous compounds. Over the last two decades, considerable interest has centered on studying the expression and regulation of drug transporters and on how different chemicals and disease states alter their expression. Both induction and repression of transporter expression have been documented with exposure to classical drug metabolizing enzyme inducers, treatment with target organ toxicants, and under a variety of pathological conditions. More recently, epigenetic regulation of drug metabolizing enzymes and transporters has gained considerable attention. Along with these studies equal and signiﬁcant efforts were made to understand the pharmacological and toxicological consequences of changes in drug transporter function. In the liver, the main organ responsible for biotransformation and disposition, drug transporters are important for the uptake and excretion of many chemicals. Therefore, drug transporters are now considered an integral part of the hepatic biotransformation and disposition machinery. Changes in the expression of transporters and/or interference with their function have emerged as an important mechanism of drug-induced liver injury. On the other hand, less is known about the afﬁnity of environmental toxicants for transporters and their ability to regulate transporter expression and function. This chapter summarizes the major ﬁndings from studies examining the expression and regulation of drug and bile acid transporters in hepatic disease states. We have included an overview of the various classes of uptake and efﬂux transporters and their localization and function, with an emphasis on substrate speciﬁcity. This information is also summarized in Table 1. Genetic disorders and human polymorphisms for transporters and their phenotypes are also discussed. The availability of genetic knockout animals has been instrumental in unveiling some of the physiological functions of drug transporters. Several of these animal models have no apparent phenotype, which illustrates redundancies and overlapping substrate speciﬁcities of certain transporters. The relevant ﬁndings with knockout mice and rats with spontaneous mutations in transporters are also presented in this review. Then, the expression and regulation of drug transporters in different models of liver disease are discussed. These include drug-induced liver injury, cholestatic liver disease, fatty liver disease, and hepatocellular carcinoma. This information is summarized in Table 2. The importance and relevance of changes in transporter expression to liver pathology will be discussed, as well as the signaling pathways contributing to altered transporter expression during liver disease.

2.09.2

Liver Transporters: Classes, Localization, and Function

The localization of hepatobiliary transporters is depicted in Fig. 1. This schematic diagram shows two adjacent hepatocytes. The apical membranes of adjacent hepatocytes form a tubular space known as the bile canaliculus. Transporters present in the apical membrane of hepatocytes mediate biliary excretion of chemicals, while transporters present in the basolateral membrane are involved in the uptake or efﬂux of substances into hepatocytes or from hepatocytes into sinusoidal blood, respectively. The combined function of these transporters mediates the vectorial transport of substances from the blood into the bile. In this section, the localization, function, and substrate speciﬁcity of the different classes of canalicular and basolateral transporters are discussed.

2.09.2.1 2.09.2.1.1

Uptake Solute Carriers Oatp/OATP

The organic anion-transporting polypeptides (rodents: Oatps, humans: OATPs) form a superfamily containing 11 members in humans (Hagenbuch and Stieger, 2013). These transport proteins have 12 putative membrane spanning domains with a wide spectrum of amphipathic substrates. Substrates include bile acids, steroid conjugates, thyroid hormones, numerous pharmaceuticals, and other xenobiotics (Hagenbuch and Meier, 2004). Oatp/OATP transporters are classiﬁed as members of the Slco (rodents)/ SLCO (humans) gene family (Hagenbuch and Meier, 2004). Transport by Oatps/OATPs is sodium independent, occurring via an anion exchange transport mechanism. The cellular uptake of organic compounds by Oatps has been shown to be coupled with the efﬂux of bicarbonate or glutathione (GSH) (Hagenbuch and Meier, 2004; Li et al., 1998, 2000; Satlin et al., 1997; Jacquemin et al., 1994). Transport by Oatps/OATPs may also be bi-directional (Li et al., 2000; Mahagita et al., 2007; Shi et al., 1995).

Localization, function and substrates of hepatobiliary transporters

218

Table 1

Gene symbol

Species

Localization/function a

Substrates

References

OATP1B1

SLCO1B1

Human

Basolateral uptake

Bile salts, bilirubin (conjugated and unconjugated), BSP, steroid conjugates, thyroid hormones, eicosanoids, cyclic peptides, microcystin, phalloidin, methotrexate, benzylpenicillin, pravastatin, rifampicin statins, angiotensin II receptor blockers, inhibitors of angiotensin converting enzyme, oral anti-diabetes drugs.

OATP1B3

SLCO1B3

Human

Basolateral uptake

Oatp1a1

Slco1a1

Rodent

Basolateral uptake

Oatp1a4

Slco1a4

Rodent

Basolateral uptake

Oatp1b2

Slco1b2

Rodent

Basolateral uptake

OATP2B1

SLCO2B1

Human

Basolateral uptake

NTCP/Ntcp

SLC10A1/Slc10a1

Human/rodent Basolateral uptake

Bile salts, monoglucuronosyl bilirubin, BSP, steroid conjugates, thyroid hormones, LTC4, linear and cyclic peptides, digoxin, ouabain, methotrexate, rifampicin, microcystin, phalloidin Bile salts, steroid hormones and conjugates, BSP, monoglucuronosyl bilirubin, ochratoxin A, leukotriene C4, dexamethasone, enalapril, fexofenadine, ouabain, pravastatin Bile salts, hormones and their conjugates, digoxin, fexofenadine, ouabain, pravastatin Bile salts, steroid conjugates, BSP, thyroid hormones, LTC4, microcystin, phalloidin BSP, estrone-3-sulfate, DHEAS, benzylpenicillin, atorvastatin Bile salts (conjugated and unconjugated), estrone-3sulfate, DHEAS, BSP, chlorambucil-taurocholate, Statins (Rosuvastatin, atorvastatin, pitavastatin).

ASBT/Asbt

SLC10A2/Slc10a2

OCT1/Oct1

SLC22A1/Slc22a1

Human/rodent Apical membrane of cholangiocytes – uptake from bile duct lumen into cholangiocyte Human/rodent Basolateral uptake

Abe et al. (1999, 2001); Cui et al. (2001a,b); Fischer et al. (2005); Hagenbuch and Meier (2003); Hsiang et al. (1999); Nakai et al. (2001); Tamai et al. (2000); Vavricka et al. (2002) Niemi (2010); Yamada et al. (2007); Ishiguro et al. (2006); Abu-Zahra et al. (2000), Kalliokoski and Niemi (2009); Choi et al. (2011a) Abe et al. (2001) Cui et al. (2001a,b),Fischer et al. (2005), Hagenbuch and Meier (2003), König et al. (2000a), Kullak-Ublick et al. (2001), and Vavricka et al. (2002) Bossuyt et al. (1996), Hagenbuch and Meier (2003), Jacquemin et al. (1994), Kullak-Ublick et al. (1994), Li et al. (1998), and Shi et al. (1995) Hagenbuch and Meier (2003) and Reichel et al. (1999) Cattori et al. (2000, 2001) and Hagenbuch and Meier (2003, 2004) Grube et al. (2006), Kullak-Ublick et al. (2001), and Tamai et al. (2000) Boyer et al. (1994), Craddock et al. (1998), Hagenbuch and Meier (1994), Hata et al. (2003), Kullak-Ublick et al. (1997, 2000a), Schroeder et al. (1998), Ho et al. (2004), and (2006), Choi et al. (2011a) Craddock et al. (1998); Geyer et al. (2006); Kramer et al. (1999); Schroeder et al. (1998)

OCT3/Oct

SLC22A3/Slc22a3

Human/rodent Basolateral uptake

Conjugated and unconjugated bile acids

MPP, TEA, TPrA, TBuA, N-methylquinine and N-(4.4-azo- Breidert et al. (1998), Busch et al. (1996), Gorboulev et al. (1997), Grundemann et al. n-pentyl)-21-deoxyajmalinium, ipratropium; choline, (1994), Jonker and Schinkel (2004), Kimura acetylcholine, dopamine, norepinephrine, creatinine, et al. (2002), Koepsell et al. (2003),Wang et al. agmatine, serotonin, PGE2, PGF2a, quinidine, quinine, (2003a), Thomas et al. (2004), Zhang et al. amantadine, aciclovir, ganciclovir, metformin, (2006), White et al. (2006), Yonezawa et al. oxaliplatin, imatinib, (2006), Jung et al. (2008), Minuesa et al. Cisplatin, (2009), More et al. (2010), Tzvetkov et al. Lamivudine Picoplatin, (2013), Andreev et al. (2016), and Chen et al. Morphine (2017) daunorubicin MPP, TEA Tyramine, Dopamine, epinephrine, Yonezawa et al., (2006), Nies et al. (2009), Chen norepinephrine serotonin, histamine, lidocaine, et al. (2010), Koepsell et al. (2013), and Koepsell et al. (2015)

Regulation of Hepatobiliary Transporters During Liver Injury

Protein name

SLC22A7/Slc22a7

Human/rodent Basolateral uptake

OAT7 MRP1/Mrp1

SLC22A9 ABCC1/Abcc1

Human Human/rodent Basolateral efﬂux

MRP2/Mrp2

ABCC2/Abcc2

Human/rodent Canalicular efﬂux

MRP3/Mrp3

ABCC3/Abcc3

Human/rodent Basolateral efﬂux (hepatocytes and cholangiocytes)

219

(Continued)

Regulation of Hepatobiliary Transporters During Liver Injury

OAT2/Oat2

quinidine, agmatine, cyclo(His-Pro), salsolinol oxaliplatin, metformin, cAMP, cGMP, 2- deoxyguanosine, L-ascorbate, glutamate, Sekine et al. (1998), Morita et al. (2001), Sun et al. (2001), Babu et al. (2002), Enomoto et al. prostaglandin E2 prostaglandin, F2a, urate, (2002), Kimura et al. (2002), Takeda et al., p-amminohippurate (PAH), bumetanide, ethacrynate, (2002), Khamdang et al. (2002), Khamdang furosemide, chlorothiazide, cyclothiazide, et al. (2003), Hasannejad et al. (2004), Tahara hydrochlorothiazide, cefamandole, ceftriaxone, et al. (2005), Kimura et al. (2007), Kobayashi erythromycin, tetracycline, chloramphenicol, et al. (2005a), Kobayashi et al. (2005b), Cropp doxycycline, minocycline, oxytetracyclinesalicylate, et al. (2008), Cropp et al. (2008), Minematsu diclofenac, indomethacin, mefenamate, piroxicam, et al. (2008), Sato et al. (2010), Cheng et al. ibuprofen, ketoprofen, naproxen, sulindac, acyclovir, (2012), and Zhang et al. (2016a,b,c) ganciclovir, penciclovir, zidovudine azidodeoxythymidine, 6-ﬂuorouracil, taxol, methotrexate, paclitaxel, cimetidine and ranitidine. Estrone sulfate; dehydroepiandrosterone sulfate. Burckhardt (2012) and Shin et al. (2007) GSH, GSSG, GSH conjugates, glucuronide conjugates, Lee et al. (2010), Videmann et al. (2009), sulfate conjugates, E217bG, GSH-LT (C4, D4, E4), Nieuwenhuis et al. (2009), Falcao et al. (2007), Bakos and Homolya (2007), Okada et al. sulfated bile acids, GSH-prostaglandin A, 4-HNE, (2007), Xiao et al. (2005), Haimeur et al. unconjugated bilirubin, estrone 3 sulfated, DHEA, (2004), Michot et al. (2004), Laochariyakul vincristine, vinblastine, daunorubicin, etoposide, et al. (2003), Tribull et al. (2003), Grzywacz methotrexate, ﬂutamide, ritonavir. Saquinavir and et al. (2003), Lorico et al. (2002), Olson et al. indinavir, FK228 and apicidin, ciproﬂoxacin, diﬂoxacin, (2002), Loe et al. (2000), Qian et al. (2001), pirarubicincalcein, calcein-AM, aﬂatoxin B, Bakos et al. (2000), Hooijberg et al. (1999), methoxychlor, chloropropharm, sodium arsenite, Srinivas et al. (1998), Essodaigui et al. (1998), arsenate, potassium antimonite, zearalenone, Barnouin et al. (1998), Keppler et al. (1998), citalopram Evers et al. (1997), Jedlitschky et al. (1997), Jedlitschky et al. (1996), Loe et al. (1996),Ishikawa et al. (1996), Grant et al. (1994), and Cole et al. (1994) GSH conjugates, glucuronide conjugates, sulfate Chen et al. (1999), Cui et al. (1999), Borst et al. conjugates, divalent bile acids, bilirubin conjugates, (2000), Cui et al. (2001), Gerk and Vore GSH, cholecystokinin peptide (CCK-8), leucotrieno C4, (2002), Potschka et al. (2003), Wright and Dickinson et al. (2004), Haimeur et al. (2004), cholecystokinin peptide (CCK-8), leucotrieno C4, statins Sugie et al. (2004), Letschert et al. (2005), pravastatin, ﬂuvastatin, lovastatin, rosuvastatin, Huisman et al. (2005), Liu et al. (2006), Nies methotrexate, docetaxel, doxorubicin, epirubicin, and Keppler (2007), Vlaming et al. (2009), etopoxide, irinotecan, amoxicilin, ampicillin, Franke et al. (2011), Green and Bain (2013), ceftriaxone, erythromycin, azithromycin, rifampicin Fujiwara et al. (2012), and Ellis et al. (2013) carbamazepine temocaprilat E217bG, dehydroepiandrosterone-3-sulfate, folic acid, de Waart et al. (2012), Lagas et al. (2010), Kitamura et al. (2010), Vlaming et al. (2008), LTC4, dinitrophenyl S-glutathione, glucuronide conjugates, glutathione conjugates, monovalent bile Borst et al. (2007, 2000), Plasschaert et al. (2005), Haimeur et al. (2004), Lee et al. salts, methotrexate, etoposide, leucovorin, teniposide, fenofenadin, morphine-3-glucuronide, acetaminophen(2004), Zeng et al. (2001), Kool et al. (1999a), glucuronide, 4-methylumbelliferone glucuronide, Manautou et al. (2005), and Zelcer et al. bisphenol A glucuronide, harmol glucuronide, (2001, 2005)

220

Localization, function and substrates of hepatobiliary transportersdcont'd

Protein name

Gene symbol

Species

Localization/function a

MRP4/Mrp4

ABCC4/Abcc4

Human/rodent Basolateral efﬂux

MRP5/Mrp5

ABCC5/Abcc5

Human/rodent Basolateral efﬂux

MRP6/Mrp6

ABCC6/Abcc6

Human/rodent Basolateral efﬂux

MRP7/Mrp7

ABCC10/Abcc10

Human/rodent Basolateral efﬂux?

MRP8

ABCC11

Human

MRP9/ABC12 MDR1/Mdr1a/ 1b

Mrp9/Abcc12 ABCB1/Abcb1a/1b

Human/rodent ? Human/rodent Canalicular efﬂux

?

Substrates

References

resveratrol, glucuronide enterodiol glucuronide, genistein glucuronide, APAP sulfate, harmol sulfate, 4methylumbelliferone sulfate Sun et al., (2015), Roggenbeck et al. (2015), cAMP, cGMP, GSH, folate, PGE1, PGE2, leukotrienes, Nornberg et al., (2015), Ferslew et al. (2014), sulfated steroids, bile acids, uric acid, 6Banerjee et al. (2014), Fukuda et al. (2013), de mercaptopurine, 6-thioguanine, nucleotide and Waart et al. (2012), Hasegawa et al. (2007), nucleoside analogs, nesperetin sulfates, methyl Adachi et al. (2002), Chen et al. (2002), Lee parathion, enalaprilat, cefadroxil, furosemide, et al. (2000b), Leggas et al. (2004), Reid et al. hydrochlorothiazide,dimethylarsinic acid, diglutathione (2003), Rius et al. (2003, 2005, 2008), conjugate monomethylarsonous acid, nelﬁnavir, Schuetz et al. (1999), Van Aubel et al. (2005), methotrexate Wielinga et al. (2003), and Zelcer et al. (2003) cAMP, cGMP, GSH conjugates, nucleotide analogs, Jansen et al. (2015), Jedlitschky et al. (2000), folates, methotrexate Glutamato derivates, PMA, Wielinga et al. (2003, 2005), and Wijnholds stavudine et al. (2000) BQ123, GSH conjugates such as LTC4, N-ethylmaleimide Belinsky et al. (2002), Ilias et al. (2002), and S-glutathione, and dinitrophenol glutathione Madon et al. (2000) E217bG, LTC4 docetaxel, paclitaxel, vincristine, vinblastine Chen et al. (2005), Hopper-Borge et al. (2004), AraC, gemcitabine, ddC, PMEA, epothilone B Naramoto et al. (2007), and Hopper-Borge et al. (2009) E217bG, LTC4, DHEAS, AMPc, GMPc, cholylglycine, Chen et al. (2005), Jedlitschky et al. (2000), Guo methotrexate folate, PMEA dipivoxil, ddC 5-FU et al. (2003a), and Oguri et al. (2007) ? ? Chen et al. (2016), Nornberg et al. (2015), Pohl Anthracyclines, vinca alkaloids, epipodophyllotoxins, et al. (2002), Uhr et al. (2002), Gottesman taxanes, entanyl, morphine; amiodarone, digoxin, et al. (1996), and Ford and Hait (1990) quinidine; ceftriaxone, clarithromycin, rifampicin, cimetidine, ranitidine, lovastatin, simvastatin, diltiazem, nifedipine; indinavir, saquinavir, ritonavir; cyclosporin A, sirolimus, tracolimus; chlorpromazine, phenothiazide. Curcuminoids, ﬂavonoids. Methyl parathion, paraquat phospholipids, steroid hormones corticosterone, cortisol, aldosterone, progesterone

Regulation of Hepatobiliary Transporters During Liver Injury

Table 1

ABCB4/Abcb4 ABCB11/Abcb11

Human/rodent Canalicular efﬂux Human/rodent Canalicular efﬂux

BCRP/Bcrp

ABCG2/Abcg2

Human/rodent Canalicular efﬂux

ABCG5/8/ Abcg5/8 ABCA1/Abca1

ABCG5/8/Abcg5/8

Human/rodent Canalicular efﬂux

ABCA1/Abca1

Human/rodent Basolateral efﬂux, also expressed in Kupffer Phospholipids, cholesterol, a-tocopherol, APO E. cells

MATE1/Mate1

SLC47A1/Slc47a1

Human/rodent Canalicular efﬂux

OSTa-OSTb/ Osta-Ostb

OSTa-OSTb/OstaOstb

Human/rodent Basolateral membrane of cholangiocytes – efﬂux into hepatocytes

a

Unless otherwise stated, localization indicates location on hepatocyte plasma membrane.

Phospholipids (e.g., phosphatidylcholine) Bile salts, taxol, vinblastine, pravastatin

Ruetz and Gros (1994) and Smith et al. (1994) Childs et al. (1998), Gerloff et al. (1998), Hirano et al. (2005), Lecureur et al. (2000), and Trauner and Boyer (2003) Mitoxantrone, doxorubicin, daunorubicin, topotecan, Polgar et al. (2008), Kis et al. (2008), Mao and methotrexate, nucleoside reverse transcriptase Unadkat (2005), Janvilisri et al. (2005), Imai inhibitors, genistein, leﬂunomide, prazosin, conjugated et al. (2004), Suzuki et al. (2003), Volk and organic anions, E217bG, DNP-SG, bile acid and other Schneider (2003), Wang et al. (2003c), Litman sulfate conjugates et al. (2000), Allen et al. (1999), Chen et al. (2003), and Doyle et al. (1998) Cholesterol, phyto- and shellﬁsh sterols Graf et al. (2003), Yu et al. (2002b, 2004) Lawn et al. (1999), Wang et al. (2001), Von Eckardstein et al. (2001), and Oram and Heinecke (2005) TEA, MPP, ipratropium, cimetidine, quinidine, verapamil, Otsuka et al. (2005), Tanihara et al. (2007), Yonezawa et al. (2006), Yokoo et al. (2007), rhodamine-123, nicotine, choline, serotonin, Tanihara et al. (2007), and Chen et al. (2017) metformin, creatinine, guanidine, procainamide, thiamine, topotecan, estrone sulfate, corticosterone, acyclovir, ganciclovir, cisplatin, oxaliplatin, cephalexin, cephradine, ﬂuoroquinolone Ballatori et al. (2005) and Seward et al. (2003) Bile acids, estrone sulfate, DHEAS, digoxin, PGE2

Regulation of Hepatobiliary Transporters During Liver Injury

MDR3/Mdr2 BSEP/Bsep

221

Table 2

Regulation of hepatobiliary transporters during liver injury

Toxicant/model

Basolateral Ntcp

Intrahepatic cholestasis

17a-Ethinyl estradiol

Y Ntcp (G, P)

Basolateral Oatp, Basolateral Mrp1, 3, 4, 5, 6, Oat, Oct Osta,b

Canalicular Mrp2, Bsep, Bcrp, Mdr/Pgp

Y Oatp1a1 (G, [ Mrp3 (G, P) P) Y Oatp1a4 (G, P) Y or 4 Oatp1b2 (G) Y Oatp1b2 (P)

4 Bsep (G)

Y Oct1 (G,P)

Estradiol-17b-D-glucuronide

Lipopolysaccharide

Bile acids

Y Ntcp (G, P)

Cholic acid: Y Ntcp (P) 4 Ntcp (G)

UDCA: 4 Ntcp (G, P)

Y Oatp1a1 (G)

[ or 4 Mrp1 (G)

Y Oatp1a4 (G)

[ Mrp1 (P)

Y [ [ Y Y

[ or Y Mrp3 (G) 4 Mrp4 (G) 4 Mrp5 (G)

Oatp1b2 (G) Oatp1a6 (G) Oatp3a1 (G) OATP2 (G) Oat2 (G) mouse Y Oat3 (G) rat Y Oct1 (G) Cholic acid: Y Oatp1a1 (G, P) [ Oatp1a4 (P) Y Oatp1b2 (P)

UDCA: Y Oatp1a1 (G, P)

Y Mrp6(G)

Y or 4 Bsep (P) Y Mrp2 (P) 4 Mrp2 (G) Y (slight) or 4 Pgp (P)

Meng et al. (2015a,b), Cermanova et al. (2015), Ruiz et al. (2013), Zhou et al. (2011), Jin et al. (2009), Ruiz et al. (2007), Yamamoto et al. (2006), Kamisako and Ogawa (2005), Fiorucci et al. (2005), Geier et al. (2003a), Micheline et al. (2002), Crocenzi et al. (2001), Lee et al. (2000a), Koopen et al. (1998),Accatino et al. (1996), and Simon et al. (1996) Crocenzi et al. (2003), Mottino et al. (2002), Accatino et al. (1998),

Y Abcg5 (G) Y Abcg8 (G) Y Bsep (P) Y Mrp2 (P) Mrp2 and Bsep proteins are internalized Y Bsep (P), 4 or Y Bsep Arab et al. (2009), Donner et al. (GP) (2007), Lee et al. (2000a), Lickteig Y Mrp2 (G, P) and protein et al. (2007b), Bolder et al. (2006), retrival Cherrington et al. (2004), Elferink Y or 4 Mdr1a (G) et al. (2004), Geier et al. (2003b), Mdr1b (G) Bolder et al. (2002), Hojo et al. 4 or Y Mdr2 (G) (2003), Hartmann et al. (2002), Lee et al. (2000a), Trauner et al. (1998), Vos et al. (1998), and Green et al. Y or 4 Pgp (P) (1996)

Cholic acid: 4 Mrp3 (G)

Cholic acid: [ Bsep (G, P)

[ Mrp3 (P)

[ Mrp2 (G, P) [ Mdr1a (G) [ Mdr1b (G) [ Pgp (P) UDCA: [ Bsep (P)

UDCA: [ Mrp3 (G, P)

References

4 Bsep (G) [ Mrp2 (G, P) [ Mdr1a (G) 4 Mdr1b (G) [ Pgp (P)

Beilke et al. (2008), Fickert et al. (2001, 2006), Gupta et al. (2000), Miyata et al. (2005), Rost et al. (2003), Wolters et al. (2002), and Zollner et al. (2002, 2003a)

Regulation of Hepatobiliary Transporters During Liver Injury

Liver injury

Efflux transporters

222

Uptake transporters

Taurocholate: Y Ntcp (P)

Taurocholate: Y Oatp1a1 (G, P)

Taurocholate: [ Bsep (G, P)

4 Ntcp (G) LCA: Y or 4 Ntcp (G) Y Ntcp (P)

a-Napthylisothiocyanate

Cholestyramine: 4 Ntcp (G, P)

Cholestyramine: Y Oatp1a1 (G) 4 Oatp1a1 (P)

Y Ntcp (G, P)

Y Oatp1a1 (G)

Y Y Y

Primary sclerosing cholangitis

2,4,6-Trinitro-benzenesulfonic acid

Y

LCA: [ Mrp1 (G, P) 4 Mrp3 (G) [ or 4 Mrp3 (P) [ Mrp4 (G) 4 Mrp5 (G) [ Mrp5 (P) 4 Mrp6 (G, P)

[ Mrp3 (G, P)

4 Oatp1a4 (G) 4 [ Mrp4 (G) Y Oatp1b2 (G) [ Ostb (G) [ Oatp 1(G) NTCP (G,P) or [ NTCP (G) [ MRP1 (G, P) or 4 OATP1B1 (G, P) [ or 4 MRP3 (G, P) dependig depending the stage the stage of PBC or 4 OATP1B3 (G,P) [ or 4 MRP4 (G) depending the stage [ MRP4 (P) [ MRP5 (G, P) 4 MRP6 (G, P) [ OSTa (G, P) [ OSTb (G, P) Ntcp (G, P) Y Oatp1a1 (G, P) Y Oatp1a4 (G, P) Y Oatp1b2 (G) 4 Oatp1b2 (P)

4 Bsep (G, P) 4 Mrp2 (G, P)

Cholestyramine: 4 Bsep (G, P) 4 Mrp2 (G) 4 Mdr2 (G) [ Bsep (G, P)

Zhang et al. (2016), Tan et al. (2016), Ding et al. (2014), Yang et al. (2013a,b), Tanaka et al. (2009), Cui et al. (2009), Liu et al. (2005), Ogawa et al. (2000), Tanaka et al. (2009)

[ Mrp2 (G, P) [ Mdr2 (G) [ BCRP (G, P) [ or 4 BSEP (G) [ BSEP (P) [ or 4MRP2 (G, P) [ or 4 MDR1 (G) [ or 4 MDR3 (G) [ Pgp (P) Y Bsep (G, P)

Takeyama et al. (2010); Takeyama et al. (2009); Gradhand et al. (2008); Zollner et al. (2007); Barnes et al. (2007); Boyer et al. (2006); Zollner et al. (2003b); Kojima et al. (2003); Ros et al. (2003a); Zollner et al. (2001))

Geier et al. (2002a)

Y Mrp2 (G, P)

(Continued)

Regulation of Hepatobiliary Transporters During Liver Injury

Primary biliary cirrhosis Note: transporter changes are typically observed in advanced PBC cases.

LCA: Y Oatp1a1 (G, P) 4 Oatp1a4 (G) Y Oatp1b2 (G)

4 Mrp2 (G) 4 Mdr2 (G) LCA: 4 Bcrp (G)

223

Table 2

Regulation of hepatobiliary transporters during liver injurydcont'd

Liver injury

Efflux transporters

Basolateral Ntcp

Basolateral Oatp, Basolateral Mrp1, 3, 4, 5, 6, Oat, Oct Osta,b

Canalicular Mrp2, Bsep, Bcrp, Mdr/Pgp

3,5-Diethoxycarbonyl-1,4dihydrocollidine

Y Ntcp (G, P)

Y Oatp1b2 (G) [ Mrp3 (G, P)

4 Bsep (G)

[ Mrp4 (G, P) 4 Mrp2 (G)

[ Mdr1a (G)

Nonalcoholic fatty liver disease

Y OATP2 (G)

NASH and NAFLD

Y Ntcp (G)

Obesity and fatty liver

Obese-Zucker rat

Ob/Ob mice

4 Ntcp (G, P)

Y Ntcp (G) \ Y Ntcp (P) \, _

Methionine- and choline-deﬁcient diet Y Ntcp (G)

[ Bsep (P) 4 OSTa (G) [ Ostb (G)

Y Mrp2 (P)

Patients

Kurzawski et al. (2012); Fickert et al. (2007)

[ [ MRP3 (G, P) Y [ MRP4 (G, P) Y Y Y Oatp1a1 (G, P) Y Oatp1a4 (G) Y Oatp1b2 (G) Y OAT2 (G) Y OAT3 (G) 4 Oatp1a1 (P) Y Oatp1a4 (G, P)

Y Oatp1a1 (G, P) \, _ Y Oatp1a4 (G) \, _ [ Oatp1a4 (P) \, _ Y Oatp1b2 (G) \ [ Oatp1b2 (P) \ Y Oatp1b2 (P) _ Y Oatp1a1 (G, P) Y Oatp1a4 (G) 4 Oatp1a4 (P) Y Oatp1b2 (G, P) Y Oatp2b1 (G) Y Oat2, Oat3 (G)

4 Mdr1b (G) Mdr2 (G) MRP2 (G) BCRP (G) ABCA1 (G, P)

Oswald et al., (2001) and Kurzawski et al. (2012) Canet et al. (2015); Lake et al. (2011); Hardwick et al. (2011); Yang et al. (2010); Fisher et al. (2009)

[ MRP1 (G, P) [ MRP3 (P) [ MRP4 (G, P) [ MRP5 (G, P) [ MRP6 (P) 4 Mrp3 (P) 4 Mrp4 (P)

[ MRP2 (P) with delocalization [ PGP (G, P) [ BCRP (G, P) 4 Bcrp (P) Y or 4Bsep (G)

Geier et al. (2005a,b); Pizarro et al. (2004)

Y Mrp1 (G, P) \

4 Bsep (P) 4 Mrp2 (G) Y Mrp2 (P) [ Bcrp (G) \

Cheng et al. (2008)

[ Mrp3 (G, P) _

[ Bcrp (P) \

[ Mrp4 (G, P) \, _

Y Bsep (G) \

[ Mrp5 (G, P) _ Y Mrp6 (G, P) \ 4 Mrp1 (G)

4 Mrp2 (G) \, _ [ Mrp2 (P) \, _ [ Mdr2 (G) _ [ Bcrp (G, P)

[ Mrp3 (G, P) [ Mrp4 (G, P) 4 Mrp5 (G)

Y Bsep (G) 4 Mrp2 (G) [ Mrp2 (P)

Y Mrp6 (G)

Lickteig et al. (2007a) Fisher et al. (2009)

Regulation of Hepatobiliary Transporters During Liver Injury

Toxicant/model

References

224

Uptake transporters

Extrahepatic cholestasis

Hepatocellular necrosis

Bile duct ligation

Acetaminophen

Y Ntcp (G, P)

Y Ntcp (G, P)

Bromobenzene

Troglitazone

Y Ntcp (G, P)

Y Oatp1a1 (G, P) [ Oatp1a4 (G) Y Oatp1b2 (G, P)

[ Mrp1 (G, P)

4 or [ Bsep (G, P)

[ Mrp3 (G, P) [ Mrp4 (G, P) [ Mrp5 (G, P) 4 Mrp6 (G, P) 4 Mrp7 (G) 4 Mrp9 (G) [ Osta (P) [ Ostb (G) [ Asbt (G, P)

[, Y or 4 Mrp2 (G) Y or [ Mrp2 (P) [ Mdr1b (G) [ Pgp (P) [ Mdr2 (G) Y Abcg5 (G) Y Abcg8 (G)

[ MRP1 (G)

[ BCRP (P)

[ Mrp3 (G, P) [ Mrp4 (G, P)

[ Mrp2 (G, P) [ Pgp (P)

[ MRP4 (G, P) [ MRP5 (P) [ Mrp1 (G) [ Mrp3 (G) [ Mrp1 (G, P)

Y or 4 Oatp1a1 (G) Y or [ Oatp1a4 [ Mrp4 (G, P) (G) Y Oatp1b2 (G, Y Mrp3 (P) P) Y Oat3 (G) Y Mrp6 (G) [ Abcg1 (G)

4 Bsep (P) 4 Bcrp (P) Y or [ Mrp2 (G, P)

[ Mdr1a (G) [ Mdr1b (G) [ Mdr2 (G) [ Pgp (P) [ Mrp1 (G) [ Bcrp (G) Y Mrp2 (G) Y Bsep (G) Aditionally inhibit the transport activity of OATP1B1; OATP1B3; MRP3; MRP4; BSEP and BCRP

Boyer et al. (2006); Denk et al. (2004a,b); Donner and Keppler (2001); Donner et al. (2007); Dumont et al. (1997); Gartung et al. (1996); Hyogo et al. (2001); Kagawa et al. (1998); Kamisako and Ogawa (2005); Lee et al. (2000a, 2001); Lickteig et al. (2007b); Ogawa et al. (2000); Slitt et al. (2007); Soroka et al. (2001); Trauner et al. (1997); Wagner et al. (2003); Zollner et al. (2002) Aleksunes et al. (2008); Campion et al. (2008); Barnes et al. (2007); Aleksunes et al. (2007, 2006, 2005); Ghanem et al. (2004);

Tanaka et al. (2007); Heijne et al. (2004); Lagadec et al. (2015); Meng et al. (2015a,b); Okumura et al. (2007); Yokooji et al. (2006); Aleksunes et al. (2005, 2006); Geier et al. (2003b); Song et al. (2003); Nakatsukasa et al. (1993)

Foster et al. (2012); Weiss et al. (2009); He et al. (2015), Morgan et al. (2013), Marion et al. (2011), Enokizono et al. (2007), and Nozawa et al. (2004)

Sulindac Inhibit the transport activity of OATPs, NTCP; OAT1; OAT3; OCT1; OCT3, MRP1; MRP2;; MRP4; BSEP and BCRP

Lee et al. (2010a), El-Sheikh et al., (2007), O’Connor et al. (2004), Wang et al. (2003a), Rius et al. (2003), Khamdang et al. (2002), and Bolder et al. (1999)

Regulation of Hepatobiliary Transporters During Liver Injury

Carbon tetrachloride

Y Oatp1a1 (G, P) [ Oatp1a4 (G) Y Oatp1a5 (G) Y Oatp1b2 (G) [ Oatp3a1 (G) 4 Oatp2b1 (G) 4 Oatp4a1 (G) 4 Oatp1c1 (G) Y Oct1 (G, P)

(Continued)

225

226

Regulation of hepatobiliary transporters during liver injurydcont'd Uptake transporters

Liver injury

Toxicant/model

Basolateral Ntcp

Hepatocellular carcinoma

Hypoxia

Ischemia–reperfusion

Hepatitis

Hepatitis virus C infection

Liver regeneration

Partial hepatectomy

Y Ntcp (G, P)

Efflux transporters

Basolateral Oatp, Basolateral Mrp1, 3, 4, 5, 6, Oat, Oct Osta,b

Canalicular Mrp2, Bsep, Bcrp, Mdr/Pgp

Y OATP1B1 (G, P) Y OATP1B3 (G, P) Y NTCP (G) Y OCT1 (G,P) [ OCT3 (G,P)

[ Mdr1a (G)

Y Oatp1a1 (G) 4 Mrp1 (G) Y Oatp1a4 (G) 4 Mrp3 (G) Y Oatp1b2 (G) [ or 4 Mrp4 (G)

[ Mrp1 (G)

Y Bsep (G, P) Yor [ Mrp2 (G) Y Mrp2 (P) internalized [ or 4 Mdr1b (G) Yor [ Pgp (P) 4 BSEP (G) Y or 4 MRP2 (G, P) [ MDR1 (G) 4 MDR3 (G) Y BCRP (G) Y MATE1 (G) [ or 4 Bsep (G, P)

[ Mrp3 (G, P)

Y, [ or 4 Mrp2 (G, P)

[ Mrp4 (G) Y Mrp6 (G)

[ Mdr1b (G) 4 Mdr1a (G) [ or 4 Mdr2 (G) [ Pgp (P) [ BCRP (G)

[ or 4 MDR1 (G, P) [ MRP1 (G) [ MRP2 (G, P)

Y OCT1 (G) [ MRP3 (G) Y OATP1B1 (G) [ or 4 MRP1 (G) [ MRP4 (G, P)

Y or 4 Ntcp (G, P)

Y or 4 Oatp1a1 (G, P) Y Oatp1a4 (G, P) [ Oatp1a6 (G) Y Oatp1b2 (G) Y OATP1 (G) Y OATP2 (G) Y OATP4 (G)

G, gene expression; P, protein expression; Y, downregulation; [, upregulation; 4, no change in expression.

References

Heise et al. (2012), Martinez-Becerra et al. (2012), Schaeffeler et al. (2011), Chang et al. (2009), Park et al. (2006), Zollner et al. (2005b), Cui et al. (2003), Kinoshita and Miyata (2002), Bonin et al. (2002), Grude et al. (2002), Okabe et al. (2001), Kato et al. (2001), Chenivesse et al. (1993), Teeter et al. (1990) Miah et al. (2014); Donner et al. (2013); Ban et al. (2009); Tanaka et al. (2008); Fouassier et al. (2007); Tanaka et al. (2006); Kudo et al. (2004) Kurzanki et al. (2012), Ogasawara et al. (2010), Ros et al. (2003a), Hinoshita et al. (2001), and Dumoulin et al. (1997)

Kimura et al. (2012), Miura et al. (2011), Csanaky et al. (2009), Dransfeld et al. (2005); Chang et al. (2004), Ros et al. (2003b), Gerloff et al. (1999), Vos et al. (1998), and Green et al. (1997)

Regulation of Hepatobiliary Transporters During Liver Injury

Table 2

Regulation of Hepatobiliary Transporters During Liver Injury

MRP1

MRP3

MRP4

MRP5

MRP6

MRP7

MRP8

227

MRP9

OCT1

Tight junction

OCT3

Basolateral/Sinusoidal Membrane

Pg

OATP1B3

P

E1 AT M

OATP1B1

MD

R3

GS

ABC

Bile Canaliculus

Hepatocyte

OATP2B1

MRP

ABC

2

G8

BS

EP

OATP1A2 OAT2

BC

RP

Apical/Canalicular Membrane

OAT7 NTCP

PGT ENT1

ENT2

Fig. 1 Hepatobiliary transport systems in the liver. Uptake transporters present in the basolateral membrane extract chemicals from sinusoidal blood, while canalicular transporters mediate the movement of chemicals into the lumen of the bile canaliculus. Basolateral efﬂux transporters participate in the excretion of solutes from hepatocytes into sinusoidal blood. For simplicity purposes, not all hepatobiliary transporters discussed in this chapter are shown in this diagram. Abbreviations: ABCG, ATP-binding cassette transporters faminly G, BCRP, breast cancer resistance protein; BSEP, bile-salt export pump; ENT, equilibrative nucleoside transporter; MATE, multidrug and toxin extrusion protein; MDR3, phosphatydylcholine translocase; MRP, multidrug-resistance-associated protein; NTCP, Naþ-dependent taurocholate cotransporting polypeptide; OAT2, organic anion transporter 2; OATP, organic anion transporting protein; OCT1, organic cation transporter 1; Pgp, P-glycoprotein.

Members of the Oatp/OATP family are expressed in multiple tissues, including the liver, kidney, small intestine, and blood– brain barrier (Cheng et al., 2005; Tamai et al., 2000; Jacquemin et al., 1994). Hepatic Oatps/OATPs are all expressed at the basolateral/sinusoidal plasma membrane of hepatocytes. Oatps/OATPs mediate the uptake of substrates from sinusoidal blood into the hepatocytes, which is the ﬁrst step in the biliary elimination of a wide variety of compounds. Members of the Oatp/OATP family found in rat liver are Oatp1a1/Slco1a1, Oatp1a4/Slco1a4, and Oatp1b2/Slco1b2, whereas OATP2B1/SLCO2B1, OATP1B1/ SLCO1B1, and OATP1B3/SLCO1B3 are present in human liver. OATP1B1 is expressed exclusively in liver tissue (König et al., 2000b) and it is the most abundant isoform. While the expression of OATP1B3 and OATP2B1 is lower than OATP1B1, expression levels are similar between these two OATPs (Badée et al., 2015). OATP1B1 transports a wide spectrum of structurally-unrelated substrates including bile acids (cholate, glycocholate, and taurocholate), conjugated and unconjugated bilirubin, bromosulfophthalein (BSP), steroid conjugates, thyroid hormones, eicosanoids, cyclic peptides, and the toxins microcystin and phalloidin. It also transports numerous clinically important drugs, including methotrexate (MTX), benzylpenicillin, rifampicin, hydroxymethylglutaryl (HMG)-CoA reductase inhibitors such as pravastatin, members of the angiotensin II receptor blockers known as sartans, inhibitors of angiotensin converting enzyme, and glinides class of oral anti-diabetes agents drugs (Choi et al., 2011a; Niemi, 2010; Kalliokoski and Niemi, 2009; Yamada et al., 2007; Ishiguro et al., 2006; Fischer et al., 2005; Hagenbuch and Meier, 2003; Vavricka et al., 2002; Abe et al., 2001; Cui et al., 2001a; Nakai et al., 2001; Abu-Zahra et al., 2000, Tamai et al., 2000; Hsiang et al., 1999; Abe et al., 1999). OATP1B3 shares 80% amino acid identity with OATP1B1 (Hagenbuch and Meier, 2003), and its expression is also restricted to the basolateral membrane, principally in perivenous hepatocytes (König et al., 2000a). OATP1B3 has broad and similar substrate speciﬁcity to OATP1B1, transporting bile acids (glycocholate and taurocholate), monoglucuronosyl bilirubin, BSP, steroid conjugates (17-b-D-estradiol-glucuronide (E217bG), dehydroepiandrosterone sulfate (DHEAS)), thyroid hormones, leukotriene C4 (LTC4), linear and cyclic peptides such as the natural toxins microcystin and phalloidin, and numerous drugs, including digoxin, ouabain, MTX, rifampicin (Fischer et al., 2005; Hagenbuch and Meier, 2003; Vavricka et al., 2002; Kullak-Ublick et al., 2001; Abe et al., 2001; Cui et al., 2001a; König et al., 2000b). Recently, it has been reported that the complete loss of function in both OATP1B1 and OATP1B3 genes results in a rare form of hereditary hyperbilirubinemia so-called Rotor syndrome (van de Steeg et al., 2012). In the rat and mouse, a single ortholog (Oatp1b2) has been identiﬁed for the two human OATP1B proteins (Cattori et al., 2000; Ogura et al., 2000). Oatp1b2 is functionally similar to human OATP1B1 and OATP1B3. It transports bile acids (taurocholate), steroid conjugates (E217bG, DHEAS), BSP, thyroid hormones, LCTC4, microcystin, and phalloidin (Hagenbuch and Meier, 2003, 2004; Cattori et al., 2000, 2001). Oatp1b2 knockout mice exhibit normal development and no apparent phenotype.

228

Regulation of Hepatobiliary Transporters During Liver Injury

However, they are resistant to phalloidin- and microcystin-induced hepatotoxicity due to decreased hepatocyte uptake of these toxins (Lu et al., 2008). The third OATP expressed in human liver is OATP2B1. Unlike OATP1B1 and OATP1B3, OATP2B1 is also expressed in extrahepatic tissues (Kullak-Ublick et al., 2001; Tamai et al., 2000). OATP2B1 has a very narrow substrate speciﬁcity, transporting BSP, estrone-3-sulfate and DHEAS, benzylpenicillin, and atorvastatin (Grube et al., 2006; Kullak-Ublick et al., 2001; Tamai et al., 2000). Rodent Oatp1a1 and Oatp1a4 are homologs of the human subfamily OATP1A. Substrates of Oatp1a1 include bile acids (cholate, glycocholate, and taurocholate), steroid hormones and their conjugates (aldosterone, cortisol, E217bG, DHEAS, and thyroid hormones), BSP, monoglucuronosyl bilirubin, ochratoxin A, LCT C4, and numerous drugs such as dexamethasone, enalapril, fexofenadine, ouabain, and pravastatin (Hagenbuch and Meier, 2003; Li et al., 1998; Bossuyt et al., 1996; Shi et al., 1995; Jacquemin et al., 1994; Kullak-Ublick et al., 1994). Oatp1a4, which is expressed in the liver, blood–brain barrier, choroid plexus, and retina, transports bile acids, hormones and their conjugates (E217bG, DHEAS, and thyroid hormones), digoxin, fexofenadine, ouabain, and pravastatin (Hagenbuch and Meier, 2003; Reichel et al., 1999). As described here, hepatic Oatps/OATPs are multispeciﬁc transport proteins withbroad and overlapping substrate speciﬁcity. Due to the numerous drugs that they transport, Oatps/OATPs can play an important role in hepatic ﬁrst-pass clearance of drugs. Several polymorphisms have been identiﬁed in human OATP1B1 and OATP2B1 (Nozawa et al., 2002; Tirona et al., 2001). Among them, two major genetic polymorphisms in OATP1B1, 388A > G (130NASN130 / ASP) and 521T> C (VAL174 /ALA), and their effects on pharmacokinetics, pharmacodynamics and drug adverse effects have been extensively studied (Gong and Kim, 2013; Maeda and Sugiyama, 2008). While these polymorphisms alter OATP function/substrate transport (Michalski et al., 2002), there is no evidence that impaired OATP function causes any known human disease (Hagenbuch and Meier, 2003; Nozawa et al., 2002; Tirona et al., 2001). The overlapping substrate speciﬁcity of OATP family members is most likely responsible for this. However, polymorphisms in OATP genes clearly contribute to interindividual variability in drug pharmacokinetics (Seithel et al., 2008). The inﬂuence of OATP1B1 and OATP1B3 on clinical pharmacokinetics of their drug substrate is reviewed in Maeda (2015).

2.09.2.1.2

Ntcp/NTCP

Naþ-dependent taurocholate cotransporting polypeptide (NTCP) is a member of the sodium bile salt cotransport family, SLC10. NTCP/SLC10A1 (humans) and Ntcp/Slc10a1 (rodents) are localized on the basolateral/sinusoidal domain of hepatocytes and their main function is the extraction of bile acids from portal blood, ultimately leading to their biliary excretion (Fig. 2) (Hagenbuch and Meier, 1994; Stieger et al., 1994; Hagenbuch et al., 1991). The inwardly directed Naþ-gradient maintained by the Naþ, Kþ-ATPase, and the negative intracellular potential provides the driving force for NTCP-mediated bile acid uptake (Meier, 1995). Speciﬁcally, Ntcp/NTCP mediates the uptake of conjugated and unconjugated bile acids, such as taurocholate, glycocholate, taurochenodeoxycholate, and tauroursodeoxycholate, with high afﬁnity for conjugated bile acids (Schroeder et al., 1998; Boyer et al., 1994; Hagenbuch and Meier, 1994). While Ntcp/NTCP primarily transports bile acids, thyrods hormones, the steroid sulfates estrone-3-sulfate and DHEAS, along with BSP, statins and chlorambucil-taurocholate, are non-bile acid substrates for this protein (Anwer and Stieger, 2014; Choi et al., 2011a; Ho et al., 2006; Craddock et al., 1998; Hata et al., 2003; Kullak-Ublick et al., 2000a; Schroeder et al., 1998; Kullak-Ublick et al., 1997). Several compounds also have been described as inhibitors of NTCP; among them antifungal, antihyperlipidemic, immunosuppressant, antihypertensive, anti-inﬂammatory, and glucocorticoid drugs (Anwer and Stieger, 2014; Dong et al., 2013; McRae et al., 2006; Kim et al., 1999). Some speciﬁc examples of these drug inhibitors are propranolol, nifedipine, simvastatin, cyclosporin A, progesterone, ketoconazole and ritonavir. Interestingly, rosuvastatin is transported by hNTCP, but not by rNtcp (Ho et al., 2006). This particular example demonstrates that despite of the large substrate overlap between rat, mouse and human NTCP (Stieger, 2011), actual transport data must be extrapolated with caution across different species. NTCP represents the predominant bile acid uptake system in hepatocytes, accounting for most, if not all, hepatic Naþ-dependent bile acid transport (Kullak-Ublick et al., 2000b; St-Pierre et al., 2001; Trauner and Boyer, 2003). Four nonsynonymous single nucleotide polymorphisms (SNPs) have been reported for NTCP in populations of European, African, Chinese, and Hispanic Americans. These polymorphic forms are associated with signiﬁcant loss of transport function (Ho et al., 2004). Two other polymorphisms have been demonstrated in Korean, Chinese and Vietnamese populations (Pan et al., 2011). Among them, Ser267 / Phe and Ile223 / Thr may be more clinically relevant, as demonstrated in in vitro experiments, while a Ile279 / Thr or Lys314 / Glu polymorphism was detected only once in a total of 370 DNA samples tested (Ho et al., 2004). The T668C (Ile223 / Thr), a variant only seen in African Americans, is associated with decreased plasma membrane protein expression. Interestingly, the C800T (Ser267 / Phe) variant, seen only in Chinese Americans, exhibits a near complete loss of function for bile acid uptake, yet it possesses fully normal transport function for the non-bile acid substrate estrone sulfate, suggesting that the region where this substitution resides is critical for the speciﬁc recognition of bile acid, but not for other substrates (Ho et al., 2004). Furthermore, NTCP has been identiﬁed as a strong candidate receptor for hepatitis B virus (HBV) because of its documented interaction with the N-terminus domain of the HBV large envelope protein (Yan et al., 2012). Additionally, some NTCP polymorphisms have been associated to different HBV susceptibility. This subject is addressed in greater detail in the HBV “Hepatitis B Virus Infection” section. Vaz et al. (2015) reported the ﬁrst case of a patient with NTCP deﬁciency produced by nonsynonymous point mutation (Arg252 /Hys) that affects the trafﬁcking of the immature protein from the endoplasmic reticulum its normal plasma membrane localization. This patient, a 39-week-old woman from a consanguineous family, was clinically characterized as having mild

Regulation of Hepatobiliary Transporters During Liver Injury

229

Fig. 2 Immunoﬂuorescent subcellular localization of Bcrp and Ntcp in normal mouse liver. Indirect immunoﬂuorescence was performed on liver cryosections from normal mice. Double labeling of Bcrp (green) and Ntcp (red) demonstrates canalicular and sinusoidal hepatocyte membrane staining, respectively. No colocalization of Ntcp and Bcrp is observed. Nuclei are stained in blue. Modiﬁed from Fig. 4 of Aleksunes, L. M.; Scheffer, G. L.; Jakowski, A. B.; Pruimboom-Brees, I. M.; Manautou, J. E. Toxicol. Sci. 2006, 89(2), 370–379.

hypotonia, growth retardation, and delayed motor skills. Her total plasma bile salts levels were extremely elevated, but there were no clinical signs of cholestatic jaundice, pruritis, or liver dysfunction. A complete review for this transporter is found in Döring et al. (2012).

2.09.2.1.3

Asbt/ASBT

Apical sodium-dependent bile acid transporter (rodents: Asbt/Slc10a2, humans: ASBT/SLC10A2) is also a member of the sodium bile salt cotransport family SLC10. This protein is also called ileal Naþ/bile acid cotransporter (ISBT/IBAT), as it was ﬁrst identiﬁed in the small intestine. ASBT is expressed in the apical brush border membrane of enterocytes in the terminal ileum, where it is responsible for bile acid uptake from the lumen into the enterocytes (Craddock et al., 1998; Shneider et al., 1995; Wong et al., 1994). It was later found to be present in cholangiocytes also (Alpini et al., 1997; Lazaridis et al., 1997). ASBT is involved in apical to basolateral vectorial transport of bile acids within cholangiocytes by mediating bile acid uptake from the bile duct lumen into cholangiocytes. Transport of bile acids by ASBT has been demonstrated to be Naþ dependent (Lazaridis et al., 1997). ASBT has a very narrow substrate speciﬁcity, transporting only conjugated (taurine and glycine conjugates) and unconjugated bile acids (Craddock et al., 1998). ASBT has a higher afﬁnity for the taurine and glycine conjugates over unconjugated forms. In addition, it has higher afﬁnity for dihydroxy bile acids (e.g., chenodoexycholate) over trihydroxy bile acids (e.g., cholate, taurocholate, and glycocholate) (Geyer et al., 2006; Kramer et al., 1999; Schroeder et al., 1998; Craddock et al., 1998). Bile acids absorbed by cholangiocytes are recycled back to hepatocytes where they are resecreted into the bile. This circulation of bile acids is known as cholehepatic shunting (Xia et al., 2006; Trauner and Boyer, 2003; Hofmann, 1989) and contributes to enterohepatic circulation and conservation of bile acids. In contrast to NTCP, ASBT does not appear to play any role in the transport xenobiotics or steroid sulfates (Lionarons et al., 2012; Ho et al., 2006; Craddock et al., 1998). However, a recent study identiﬁed two nonsteroidal small molecules with afﬁnity to ASBT (Kolhatkar et al., 2012). These are the ﬁrst two non-bile acids ASBT substrates identiﬁed. In addition to the native rat Asbt, a truncated form (t-Asbt) has been identiﬁed in ileum, kidney, and cholangiocytes (Lazaridis et al., 2000). This short protein is produced by alternative splicing of exon 2. The expression of this shorter variant is greater than the

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native one in the ileum and cholangiocytes. Interestingly, expression of t-Asbt on X. laevis oocytes results in bile salts efﬂux instead of uptake (Lazaridis et al., 2000). The physiological signiﬁcance of t-Asbt function is not completely understood. It is postulated that the coordinated function of both the native and truncated Asbt mediates an alternative cholehepatic shunt pathway for conjugated bile acids (Alpini et al., 2005). Expansion of the bile salt pool size by taurocholate feeding decreases both ASBT and t-ASBT mRNA and protein expression in cholangiocytes, while bile salt depletion with cholestyramine increases the expression on both transporters (Kip et al., 2004). The contrary effect was observed in ileocytes suggesting that the expression of ASBT and t-ASBT in cholangiocytes is regulated by a negative feedback loop while the expression of these transporters in terminal ileum is altered through a positive feedback mechanism (Kip et al., 2004). Asbt knockout mice exhibit greatly reduced intestinal bile acid absorption, increased cytochrome P450 (CYP) 7A1 expression, and elevated hepatic bile acid synthesis, which results in decreased hepatic cholesterol content in response to interruption of the enterohepatic circulation of bile acids (Dawson et al., 2003). Livers of HNF-1a knockout mice (also known as Tcf1 / mice) have decreased expression of ASBT, which leads to impaired portal bile acid uptake and elevated plasma bile acids concentrations (Shih et al., 2001). This is indicative of a prominent role for this transcription factor in ASBT expression and function. It has been suggested that the physiological role of ASBT is to help regulate bile formation by hepatocytes and cholangiocytes or to activate cellular signaling pathways within cholangiocytes (e.g., protein kinase C, cyclic adenosine monophosphate (cAMP)) to regulate secretion and proliferation/survival in response to biliary contents (Alpini et al., 2001, 2002; Lazaridis et al., 1997). Several ASBT mutations and polymorphisms have been identiﬁed, with implications to various diseases (Ho et al., 2011; Pan et al., 2011, Renner et al., 2009a; Montagnani et al., 2006, Love et al., 2001; Oelkers et al., 1997; Wong et al., 1995). A sustitution at donor-splice site of exon 3, which produces an alternative mRNA and the amino acid sustitution leu243 /Pro and Thr262 / Met, are associated with reduced bile acid transport function in intestine (Oelkers et al., 1997). In a patient with Crohn’s disease, ASBT function was decreased by the mutation Pro290 /Ser (Wong et al., 1995). This functional deﬁcit in ASBT transport results in primary bile acid malabsorption, which is an idiopathic intestinal disorder characterized by interruption of the enterohepatic circulation of bile acids and increased plasma cholesterol levels (Oelkers et al., 1997; Wong et al., 1995). Also, a frame-shift mutation variant (646insG) is associated with abolished bile acid transport activity. This was detected in a patient with familial hypertriglyceridemia (Love et al., 2001). Some nonsynonymous mutations are also asssociated with decreased ABST mRNA and protein expression and function (e.g., Val159 /Ile, Val98 / Ile, Cys144 /Tyr, Met264 /Val) (Ho et al., 2011; Renner et al., 2009b). Another mutation of high frequency (Ala171 /Ser) does not affect ABST activity (Pan et al., 2011; Renner et al., 2009b; Oelkers et al., 1997). ASBT expression is also diminished in non-obese patients with gallstone (Renner et al., 2008; Bergheim et al., 2006). Most importajntly, an association between the SNP rs9514089 (an intron SNP) with gallstone formation was observed in two distinct human Caucasian populations (Renner et al., 2009a). However, this relationship could not be conﬁrmed in a meta-analysis and case-control study (Tönjes et al., 2011). These conﬂicting results underscore the importance of performing further studies to completely understand the impact on aberrant ABST expression and function in speciﬁc disorders. A complete review of this transporter funcitons and charasteristics is found in Döring et al. (2012).

2.09.2.1.4

Oct/OCT

Two isoforms of the organic cation transporter (OCT), a member of the Slc (rodents)/SLC22 (humans) gene family, are expressed in liver. The type 1, is liver-speciﬁc and much more abundant than type 3, which has a much broader tissue distribution (Nishimura and Naito, 2005). OCT1 (humans: OCT1/SLC22A1, rodents: Oct1/Slc22a1), a member of the Slc (rodents)/SLC22 (humans) gene family, is localized to the basolateral hepatocyte membrane (Nishimura and Naito, 2005; Koepsell and Endou, 2004; MeyerWentrup et al., 1998; Zhang et al., 1997; Gorboulev et al., 1997; Grundemann et al., 1994) and is highly expressed in human and rodent liver (Alnouti et al., 2006; Zhang et al., 1997). OCT1 operates independently of sodium, mediating the electrogenic transport of organic cations across the hepatocyte membrane (Koepsell and Endou, 2004; Busch et al., 1996). Transport by OCT1 is bidirectional and substrates may be translocated in either direction because the driving force for transport is the electrochemical gradient of the transported organic cation (Koepsell and Endou, 2004). Through uptake of substrates across the sinusoidal hepatocyte membrane, OCT1 mediates the ﬁrst step in the hepatic excretion of many cationic drugs and xenobiotics (Koepsell and Endou, 2004). OCT1 substrates are primarily organic cations; however, some weak bases, non charged compounds, and anions can also be transported by OCT1 (Koepsell and Endou, 2004). Substrates of OCT1 include the model cations 1-methyl4-phenylpyridinium (MPP), tetraethylammonium (TEA), tetrapropylammonium, ipratropium, tetrabutylammonium, Nmethylquinine, and N-(4,4-azo-n-pentyl)-21-deoxyajmalinium, the endogenous compounds choline, acetylcholine, dopamine, norepinephrine, creatinine, agmatine, serotonin, prostaglandin (PG) E2 and PGF2a, and the drugs quinidine, quinine, amantadine, aciclovir, ganciclovir, cisplatin, oxaliplatin, picoplatin, imatinib, morphine, lamivudine, metformin and daunorubicin (Chen et al., 2017; Andreev et al., 2016; Tzvetkov et al., 2013; More et al., 2010; Minuesa et al., 2009, Jung et al., 2008; Yonezawa et al., 2006; White et al., 2006; Zhang et al., 2006; Thomas et al., 2004; Jonker and Schinkel, 2004; Koepsell et al., 2003; Wang et al., 2003a; Kimura et al., 2002; Breidert et al., 1998; Gorboulev et al., 1997; Busch et al., 1996; Grundemann et al., 1994). Ahlin et al. (2008) performed a robust high-throughput assay that screened almost 200 compounds as inhibitors of OCT1. Fourty-seven novel inhibitors were identiﬁed. This list includes several tricyclic antidepressants (e.g. chlorpromazine, ﬂuphenazine, ﬂupentixol), all of which contain a phenothiazin moiety, resulting in OCT1 activity inhibition of greater than 70% (Ahlin et al., 2008). Another study comﬁrmed that psychotropic drugs such as amisulpride and sulpiride are also transported by OCT1 and that polymorphisms signiﬁcantly reduced uptake of both drugs (Dos Santos Pereira et al., 2014). Lamivudine is a novel substrate for hOCTs and its

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transport is inhibited by low concentrations of abacavir and azidothymidine, which could have implications for the pharmacokinetics of lamivudine (Minuesa et al., 2009). Oct1 knockout mice are viable, healthy, and fertile with no obvious physiological defects or phenotypic abnormalities. Jonker et al. (2001) reported that Oct1 knockout mice exhibited a decrease in hepatic accumulation of TEA and MPP in comparison with wild-type mice, conﬁrming the importance of OCT1 in the hepatic uptake and distribution of organic cations. OCT1 is highly polymorphic. Five of the six common OCT1 alleles, Arg61 / Cys, Cys88 / Arg, Gly401 / Ser, Gly465 /Arg, and the Met420 / deletion, are known to impair the biliary excretion of hydrophobic cationic drugs (Sakata et al., 2004; Kerb et al., 2002) and absent transport activity in close to 9% of Caucasians (Shu et al., 2003; Kerb et al., 2002). Two other OCT1 mutations associated with decreased activity while conservating its membrane localization and level of expression are the Pro283 / Leu and Arg287 / Gly (Takaeuchi et al., 2003). These mutations have been demonstrated to decrease OCT1-mediated uptake of amisulpride and sulpiride (Dos Santos Pereira et al., 2014), morphine (Tzvetkov et al., 2013), tropisetron and ondansetron (Tzvetkov et al., 2012), the tramadol metabolite o-desmethyltramadol (Tzvetkov et al., 2011) and picoplatin (More et al., 2010). While these mutations in human OCT1 and their resultant altered pharmacokinetic parameters for certain drugs are well documented, the biomedical consequences of such mutations deserve further scrutiny. A complete review of this transporter is found in Wagner et al. (2016) and Koepsell (2015). OCT3 (humans: OCT3/SLC22A3 rodents: Oct3/Slc22a3) is most strongly expressed in skeletal muscle, but also present in liver, salivary glands, prostate, uterus, placenta, adrenal gland and trachea (Nies et al., 2009; Nishimura and Naito, 2005). Somewhat lower expression of hOCT3 is observed in numerous other tissues, including brain (Koepsell, 2013; Nishimura and Naito, 2005). In liver, OCT3 is localized to the sinusoidal membrane of hepatocytes and its mRNA expression is on average oneﬁfteenth that of OCT1 (Nies et al., 2009). OCT3 transport afﬁnity has been demonstrated for MPP, TEA tyramine, dopamine, epinephrine, norepinephrine serotonin, histamine, lidocaine, quinidine, agmatine, cyclo(HisePro), salsolinol and metformin (Koepsell, 2015; Koepsell, 2013; Chen et al., 2010; Nies et al., 2009). Particularly, metformin as substrate has similar afﬁnity for OCT3 and OCT1, however OCT3 has a two-fold higher maximal transport rate compared to OCT1 (Nies et al., 2009). Additionally, OCT3 is a weak transporter of oxaliplatin (Yokoo et al., 2008; Yonezawa et al., 2006). Several genetic polymorphisms in coding and non coding regions of OCT3 have been described (Chen et al., 2013a; Chen et al., 2010; Nies et al., 2009; Lazar et al., 2008; Lazar et al., 2003). The genetic variant Thr400 /Ile (rs8187725) has been associated with impaired transport function in vitro (Chen et al., 2010; Nies et al., 2009). Additionally, the Thr400 / Ile and Val423 / Phe mutants do not appreciably affect OCT3 expression or its subcellular localization, suggesting that impairment in metformin and catecholamines transport may result from a disruption in the structure of OCT3 (Chen et al., 2010). The promoter region variant g.-2G > A (rs555754), found in all ethnic groups at high allele frequencies of greater than 32%, enhances liver OCT3 transcription (Chen et al., 2013a), while the intronic SNP variant (rs518295) is associated with low expression (Schadt et al., 2008). In addition to the aforementioned polymorphic forms, epigenetic regulation of OCT3 by promoter hypermethylation has been described as a negative modulation of gene expression (Chen et al., 2013a). Due to its widespread expression and functions, mutations in OCT3 have been linked to increased risk of HCC, prostate cancer, colorectal cancer, as well as for other diseases, such as coronary artery disease and obsessive-compulsive disorders (Heise et al., 2012; Cui et al., 2011; Trégouët et al., 2009; Lazar et al., 2008; Tomlins et al., 2007; True et al., 2006). Phenotypically, the Oct3 KO mouse (Zwart et al., 2001) presents behavioral alterations with increased locomotor activity and altered neurochemical responses to psychostimulants (Zhu et al., 2010; Cui et al., 2009; Wultsch et al., 2009).

2.09.2.1.5

Oat/OAT

The organic anion transporters (humans: OATs, rodents: Oats) are members of the SLC22 gene family. The OAT/SLC22A family of multispeciﬁc transporters is actually composed of a group of 10 transmembrane proteins (Nigam et al., 2015). These are responsible for the transcellular movement of numerous small hydrophilic organic anions in comparison with OATPs, that typically transport larger and more lipophilic organic anions. OATs do not directly utilize ATP as driving force for substrate translocation. OATs operate as anion exchangers, coupling the uptake of an organic anion to the release of another organic anion from within the cell (Rizwan and Burckhardt, 2007). All OAT family members are expressed in almost all barrier epithelia including kidney, intestine, brain placenta and testis, where they play key roles in renal organic anion secretion. In human liver, OAT2 (SLC22A7) and OAT7 (SLC22A9) are the only OAT family members that are highly expressed (Sun et al., 2001; Sekine et al., 1998, 2000, OAT2 was originally cloned and identiﬁed as a novel liver-speciﬁc transport protein (NLT) in the rat (Simonson et al., 1994). It was named NLT and later renamed OAT2 when it was demonstrated to have sequence homology and functional similarities to renal OAT1 (Sekine et al., 1998). It is localized to the basolateral membrane of hepatocytes where it mediates sodium-independent uptake of organic anions (Kobayashi et al., 2005a; Sekine et al., 1998). OAT2 has a very broad substrate speciﬁcity, transporting endogenous compounds such as nucleobases, nucleosides and nucleotides (cAMP, cGMP and 2- deoxyguanosine), L-ascorbate, ES, glutamate, PGs E2 and F2a, and urate (Cheng et al., 2012; Sato et al., 2010; Cropp et al., 2008; Kobayashi et al., 2005a; Kimura et al., 2002; Enomoto et al., 2002; Sun et al., 2001). More globally, the substrates transported by OATs include anionic drugs such as p-aminohippurate (PAH), loop diuretics (bumetanide, ethacrynate, and furosemide) and thiazide diuretics (chlorothiazide, cyclothiazide, hydrochlorothiazide), antibiotics (cefamandole, ceftriaxone, erythromycin, tetracycline, chloramphenicol, doxycycline, minocycline and oxytetracycline, nonsteroidal anti-inﬂammatory drugs (NSAID) (salicylate, diclofenac, indomethacin, mefenamate, piroxicam, ibuprofen, ketoprofen, naproxen, and sulindac), antiviral nucleoside analogs (acyclovir, ganciclovir, penciclovir zidovudine azidodeoxythymidine (AZT)), antitumor

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drugs (6-Fluorouracil, taxol, MTX, paclitaxel), and H2 receptor antagonists (cimetidine and ranitidine) (Zhang et al., 2016a; Cheng et al., 2012; Cropp et al., 2008; Minematsu et al., 2008; Kimura et al., 2007; Kobayashi et al., 2005a; Kobayashi et al., 2005b; Tahara et al., 2005; Hasannejad et al., 2004; Khamdang et al., 2003; Khamdang et al., 2002; Babu et al., 2002; Takeda et al., 2002; Morita et al., 2001; Sun et al., 2001; Sekine et al., 1998). Polymorphisms in human OAT2 have been identiﬁed; however, functional investigations to assess their effects have not been performed (Xu et al., 2005). SLC22A9/OAT7, previously known as UST3 or OAT4 (Sun et al., 2001), is found in humans, with an ortholog present in primates, but not in rodents. Although not well studied so far, human OAT7 can mediate the uptake of some classical organic anions, such as estrone sulfate and DHEAS. Remarkably, neither PAH nor probenecid has been shown to effectively interact with OAT7 (Burckhardt, 2012; Shin et al., 2007). A complete review of OAT transporters can be found in Nigam et al. (2015) and Burckhardt and Burckhardt (2011).

2.09.2.2 2.09.2.2.1

Efﬂux Pumps and Transporters Mrps/MRPs

The ATP-binding cassette (ABC) superfamily consists of a large number of functionally diverse transmembrane proteins. The multidrug resistance-associated proteins (rodents: Mrp, humans: MRP) includes nine members, Mrp1–9, and belong to a sub-family of the ABC transporter, named ABCC in humans or Abcc in rodents. This ABCC/Abcc sub-family is composed of 13 members (He et al., 2011). Among them the binding and hydrolysis of ATP by the nucleotide-binding domains of ABC transporters supplies the energy for the transport of substances against concentration gradients (Borst et al., 1999). Mrps proteins are expressed in multiple polarized ephitelia, including liver. With the exception of MRP2, all other hepatic MRP proteins are localized to the basolateral membrane of hepatocytes where they efﬂux substrates from within the hepatocyte into the blood. The ﬁrst member of the MRP/ABCC family, MRP1/ABCC1, can transport GSH, oxidized GSH (GSSG), and a number of GSH, glucuronate, and sulfate conjugates of exogenous and endogenous compounds (Bakos and Homolya, 2007; Haimeur et al., 2004). Speciﬁc and additional endogenous substrates of MRP1 include several glucuronides, such as bilirubin-glucuronide and E217bG; GSH-conjugated, such as LTC4, D4 and E4, PGs A and 4-hydroxynonenal; sulfated bile acids, estrone 3 sulfated, DHEA, unconjugated bilirubin and sphingosine 1-phosphate (Nieuwenhuis et al., 2009; Falcão et al., 2007; Bakos and Homolya, 2007; Haimeur et al., 2004; Loe et al., 2000; Qian et al., 2001; Bakos et al., 2000; Barnouin et al., 1998; Keppler et al., 1998; Evers et al., 1997; Jedlitschky et al., 1997; Jedlitschky et al., 1996; Loe et al., 1996). Antineoplasic agents (vincristine, vinblastine, daunorubicin, etoposide, MTX, ﬂutamide), HIV (Human Inmunodeﬁciency virus) protease inhibitors (ritonavir. Saquinavir and indinavir), histone deacetylase inhibitors (FK228 and apicidin), antibiotics (ciproﬂoxacin, diﬂoxacin, pirarubicin), ﬂuorescent probes (calcein, calcein-AM), toxicans (aﬂatoxin B, methoxychlor, chloropropharm), metalloids (sodium arsenite and arsenate, potassium antimonite), zearalenone and citalopram are among other drug substrates of MRP1 (Lee et al., 2010a; Videmann et al., 2009; Bakos and Homolya, 2007; Okada et al., 2007; Xiao et al., 2005; Haimeur et al., 2004; Michot et al., 2004; Laochariyakul et al., 2003; Tribull et al., 2003; Grzywacz et al., 2003; Lorico et al., 2002; Olson et al., 2002; Hooijberg et al., 1999; Srinivas et al., 1998; Essodaigui et al., 1998; Ishikawa et al., 1996; Grant et al., 1994; Cole et al., 1994). GSH has been shown to stimulate MRP1-mediated transport of some substrates. Cotransport of substrates with GSH by MRP1 has also been demonstrated (Cole and Deeley, 2006; Loe et al., 1998, 2000). Mrp1 knockout mice exhibit an impaired inﬂammatory response and increased sensitivity to anticancer agents, supporting its role in the immune response and in the multidrug resistance of tumor cells (Wijnholds et al., 1997). Mutations in MRP1/ABCC1 are not associated with any genetic diseases (He et al., 2011). Up until now, more than than 2300 SNPs have been identiﬁed for MRP1/ABCC1 and roughly 1.0% of them are non-synonymous (He et al., 2011). Many of these non-synonymous SNPs can be correctly predicted to result in changes in protein function using the algorithms SIFT and PolyPhen (Wang et al., 2011). One of such predicted SNPs was shown to reduce MRP1 transport acitivity (Conseil et al., 2005; Letourneau et al., 2005). However, the pathophysiological consequenes of most SNPs, if any, is unknown. MRP2/ABCC2 is the only MRP localized to the canalicular membrane of hepatocytes. Mrp2/MRP2 is the major ABC transporter responsible for transport of conjugated drugs into the bile (Nies and Keppler, 2007; Keppler and Kartenbeck, 1996). MRP2 and MRP1 have similar substrate speciﬁcities, both transporting GSH, glucuronide, and sulfate conjugates (Haimeur et al., 2004; Borst et al., 2000). The cotransport of MRP2 substrates with GSH is similar to that observed for MRP1 (Bakos et al., 2000; Cui et al., 1999; Evers et al., 2000). The substrate proﬁle of MRP2 includes endogenous compounds such as divalent bile acids, cholecystokinin (CCK-8), LTC4 and GSH. It also transports several glucuronide (i.e., bilirubin, estradiol, acetaminophen and valproic acid) and sulfate conjugates (i.e., taurolithocholate, estrone, moxiﬂoxacin) of endogenous and exogenous compounds. In addition to conjugated metabolites, parent drugs such as statins (pravastatin, ﬂuvastatin, lovastatin, rosuvastatin), various anti-cancer drugs (MTX, docetaxel, doxorubicin, epirubicin, etoposide, irinotecan), antibiotics (amoxicilin, ampicillin, ceftriaxone, erythromycin, azithromycin, rifampicin) psychostimulants (carbamazepine), and angiotensin converting enzyme (temocaprilat, enalapril, fosinopril) are transported by MRP2 (Ellis et al., 2013; Fujiwara et al., 2012; Franke et al., 2011; Green and Bain, 2013; Vlaming et al., 2009; Nies and Keppler, 2007; Liu et al., 2006; Huisman et al., 2005; Letschert et al., 2005; Wright and Dickinson, 2004; Haimeur et al., 2004; Sugie et al., 2004; Potschka et al., 2003; Gerk and Vore, 2002; Cui et al., 1999, 2001b; Borst et al., 2000; Chen et al., 1999). Mutations in MRP2 lead to Dubin–Johnson syndrome, a condition characterized by chronic conjugated hyperbilirubinemia (Paulusma et al., 1997; Kartenbeck et al., 1996). Transport-deﬁcient or Groningen yellow Wistar and Eisai hyperbilirubinemic Sprague–Dawley are rat strains with a spontaneous mutation in Mrp2. These rats exhibit a similar phenotype to that observed in

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their Dubin–Johnson human counterparts (Ito et al., 1997; Buchler et al., 1996; Paulusma et al., 1996; Hosokawa et al., 1992; Jansen et al., 1985). Several polymorphic forms have been reported in both the coding and non-coding regions of MRP2, with implications to the response to various drug treatments, as well as drug-induced toxicity (van der Schoor et al., 2015). The most frequent genetic variants are SNPs -24C> T, 1249G > A and 3972C > T. The -24C > T SNP, resulting in decreased MRP2 expression (Haenisch et al., 2007). All three are associated with altered pharmacokinetics of various pharmaceuticals including mycophenolic acid, telmisartan, diclofenac, antiepileptic drugs, simvastatin and MTX (Liu et al., 2014; Becker et al., 2013; Qu et al., 2012; Miura et al., 2009; Naesens et al., 2006). MRP3/ABCC3 is localized to the basolateral membrane of hepatocytes and cholangiocytes (Fig. 3) (Kool et al., 1999a). MRP3 transports E217bG, LTC4, DHEAS, folic acid, dinitrophenyl GSH, glucuronide conjugates, GSH conjugates, and monovalent bile acids (e.g., cholate, glycocholate, and taurocholate) (Kitamura et al., 2010; Borst et al., 2007; Haimeur et al., 2004; Lee et al., 2004; Zeng et al., 2001; Borst et al., 2000). Unlike MRP1 and MRP2, MRP3 has a higher afﬁnity for glucuronide than GSH conjugates (Zelcer et al., 2001; Zeng et al., 2000; Hirohashi et al., 1999). Drug substrates of MRP3 include anti cancer drugs (MTX, etoposide, leucovorin, teniposide), antiallergic drugs (fenofenadine) several glucuronides, such as those of morphine, acetaminophen (APAP), 4-methylumbelliferone, bisphenol A, harmol, resveratrol, enterodiol, genistein; and sulfate conjugates, like APAP, harmol and 4-methylumbelliferone sulfate (de Waart et al., 2012; Lagas et al., 2010; Vlaming et al., 2008; Plasschaert et al., 2005; Manautou et al., 2005; Zelcer et al., 2005; Zeng et al., 2001; Zelcer et al., 2001; Kool et al., 1999a). In cholangiocytes, MRP3 is responsible for bile acid efﬂux from the basolateral membrane into the blood (Fig. 4) (Xia et al., 2006; Trauner and Boyer, 2003;). Mrp3 knockout mice exhibit only increased levels of liver bile acids and lower serum levels of bilirubin glucuronide after bile duct ligation, supporting the function of Mrp3 as a bile acid and glucuronide conjugate export pump (Belinsky et al., 2005). Additionally, Mrp3 knockout mice exhibit changes in pharmacokinetics for glucuronide-conjugates of several drugs and other xenobiotics including APAP, morphine, bisphenol A, MTX, resveratrol, gemﬁbrozil, troglitazone, 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridymethyl) benzothiazole (E3040), 4-methylumbelliferon, dietary phytoestrogens and the ﬂuorescent bile salt derivative cholyl-L-lysylﬂuorescein (van de Wetering et al., 2007; van de Wetering et al., 2009a; van de Wetering et al., 2009b; Hirouchi et al., 2009; Kitamura et al., 2008; Manautou et al., 2005; Zelcer et al., 2005). Polymorphisms in MRP3 have been shown to decrease MRP3 mRNA levels; however, no differences in transport activity have been observed (Lang et al., 2004; Lee et al., 2004). Several polymorphism have been described in humans (Sasaki et al., 2011). The most studied MRP3 SNP is -211C> T,this change in the 50 promoter region of the gene is associated with an increased response to clopidogrel (Zou et al. 2013), decreased response to chemoterapy treatment for small cell lung cancer (Müller et al., 2009) and acute myeloid leukemia (Müller et al., 2008), and an increased response to MTX in patients with juvenile idiopathic arthritis (de Rotte et al., 2012). However, the synonymous polymorphism 3039C > T in exon 22 is associated with shorter survival in patients undegoing MTX chemotherapy for osteosarcoma (Yang et al., 2013a; Caronia et al., 2011). Another polymorphic form linked to shorter disease free survival in adult acute myeloid leukemia with cytarabine, etoposide and busulfan is the intronic SNP rs4148405 (Yee et al., 2013). MRP4/ABCC4 is localized to the basolateral hepatocyte membrane and its expression in the liver under normal conditions is very low (Maher et al., 2005b; Rius et al., 2003; Lee et al., 1998). Substrates of MRP4 include cyclic nucleotides (cAMP and cyclic guanosine monophosphate (cGMP)), GSH, folate, PGs (E1 and E2), leukotrienes, sulfated steroids, bile acids, uric acid, and

Fig. 3 Zonal localization of Mrp3 in normal mouse liver. Indirect immunoﬂuorescence was performed on liver cryosections from normal mice. Mrp3 (green) is expressed in hepatocytes around the central vein (CV). Nuclei are stained in blue. The arrow depicts a bile duct around a portal vein (PV). Modiﬁed from supplementary Fig. 1 of Aleksunes, L. M.; Scheffer, G. L.; Jakowski, A. B.; Pruimboom-Brees, I. M.; Manautou, J. E. Toxicol. Sci. 2006, 89(2), 370–379.

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Regulation of Hepatobiliary Transporters During Liver Injury

Fig. 4 Immunoﬂuorescent localization of Mrp3 in normal rat cholangiocytes. Indirect immunoﬂuorescence was performed on sections of liver from normal Sprague–Dawley rats. Mrp3 (red) is also seen on the basolateral membrane of rat cholangiocytes and does not colocalize with zona occludins-1 (ZO-1) (green). Modiﬁed from Fig. 1 of Soroka, C. J.; Lee, J. M.; Azzaroli, F.; Boyer, J. L. Hepatology 2001, 33(4), 783–791.

several drugs including 6-mercaptopurine, 6-thioguanine, sulfated hesperetin, methyl parathion, enalaprilat (the active metabolite of enalapril); antibiotics (cefadroxil), diuretics (furosemide and hydrochlorothiazide), arsenic metabolites (dimethylarsinic acid and diGSH conjugate of the highly toxic monomethylarsonous acid), protease inhibitors (nelﬁnavir); antineoplasics (MTX), nucleotide analogs such as 90 -(20 - phosphonylmethoxyethyl) adenine (PMEA), and nucleoside analogs such as ganciclovir (Sun et al., 2015; Roggenbeck et al., 2015; Nornberg et al., 2015; Ferslew et al., 2014; Banerjee et al., 2014: Fukuda et al., 2013; de Waart et al., 2012; Rius et al., 2008; Hasegawa et al., 2007; Rius et al., 2005; Van Aubel et al., 2005; Leggas et al., 2004; Adachi et al., 2002; Chen et al., 2002; Lee et al., 2000b; Reid et al., 2003; Rius et al., 2003; Schuetz et al., 1999; Wielinga et al., 2003; Zelcer et al., 2003). Studies in Mrp4 knockout mice have demonstrated its role in drug disposition and its protective role against bile acid accumulation in liver during cholestasis (Kruh et al., 2007; Mennone et al., 2006; Zamek-Gliszczynski et al., 2006a; Leggas et al., 2004). MRP5/ABCC5 is structurally similar to MRP4 and has a similar substrate proﬁle. MRP5 transports the cyclic nucleotides cAMP and cGMP, GSH conjugates, glutamate derivates (conjugates and analogs), nucleotide analogs, PMA, folates, stavudine and MTX (Jansen et al., 2015; Wielinga et al., 2005; Wielinga et al., 2003; Jedlitschky et al., 2000; Wijnholds et al., 2000). Mrp5 knockout mice have been generated and they are viable, with no apparent phenotype (Wijnholds et al., 2000). The strong overlapping substrate speciﬁcities between MRP5/ABCC5 and MRP4/ABCC4 (and possibly MRP8/ABCC11 and MRP9/ABCC12) is must likely the reason why the absence of Mrp5/Abcc5 does not result in any pathophysiological abnormalities. MRP6/ABCC6 is highly expressed in the liver and is localized to the basolateral membrane of hepatocytes (Matsuzaki et al., 2005; Scheffer et al., 2002; Madon et al., 2000; Kool et al., 1999b). Rat Mrp6 is able to transport the endothelin-1 receptor antagonist BQ123 (Madon et al., 2000). Human MRP6 transports GSH conjugates such as LTC4, N-ethylmaleimide GSH, and dinitrophenol GSH (Belinsky et al., 2002; Ilias et al., 2002). Mutations or deletions in MRP6 result in pseudoxanthoma elasticum, a connective tissue disorder characterized by ectopic mineralization of connective tissues (Chassaing et al., 2007; Schulz et al., 2005; Le Saux et al., 2001; Ringpfeil et al., 2001), reportedly due to an under-carboxylation of matrix gla protein, which renders it suceptible to ectopic mineralization (Li et al., 2007a). In mice, Abcc6 has also been identiﬁed as the causal gene within the Dyscalc1 locus that predisposes certain strains (C3H/HeJ and DBA/2J) to dystrophic cardiac calcinosis and other ectopic soft tissue calciﬁcations (Meng et al., 2007; Korff et al., 2006). Mrp6 knockout mice recapitulate the features of the human disease (Klement et al., 2005). MRP7 (ABCC10) is expressed at the mRNA level in pancreas, liver, placenta, lung, kidney, brain, ovary, lymph node spleen and colon (Takayanagi et al., 2004; Hopper et al., 2001). Studies on its protein expression have not yet appeared in the literature. MRP7 is a lipophilic transporter that mediates the transport of a number of physiological substrates including E217bG and LTC4, as determined using membrane vesicles from HEK293 cells expressing recombinant MRP7 (Chen et al., 2005). However, its physiological role is still unknown. MRP7 confers high levels of resistance to natural anticancer drugs (docetaxel, paclitaxel, vincristine and vinblastine) in HEK293 over expressing cells clones (Hopper-Borge et al., 2004) and head and neck cancer cell lines (Naramoto et al., 2007). Also to nucleoside-based agents (AraC and gemcitabine), antiviral agents (ddC and PMEA) and to the microtubule stabilizing agent epothilone B (Hopper-Borge et al., 2009), suggesting that all these anticancer agents are Mrp7 substrates as well. Substances such as the herbal extract cepharanthine (Zhou et al., 2009) and the tyrosine kinase inhibitor lapatinib (Kuang et al., 2010), have been described as inhibitors of resistance to cancer chemotherapy mediated by MRP7.

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235

MRP8/ABCC11 has been cloned from a cDNA library of human adult liver (Yabuuchi et al., 2002; Tammur et al., 2001; Bera et al., 2001). However, no mouse gene ortholog was found. MRP8 is expressed at high levels in liver, brain and placenta, followed by breast and testis (Bera et al., 2001). It is also expressed in apocrine sweat glands (Martin et al., 2010). Substrates for this transporter include, E217bG, LTC4, DHEAS, cyclic nucleotides (cAMP and cGMP), cholylglycine, MTX and folate (Chen et al., 2005; Jedlitschky et al., 2000). MRP8 confers resistance to PMEA, the active metabolite of the prodrug Adefovir dipivoxil, an acyclic nucleoside phosphonate employed in the treatment of hepatitis B; ddC (20 ,30 -dideoxycytidine, Zalcitabine), an anti-AIDS drug (Guo et al., 2003a); and 5-ﬂuorouracil (5-FU), an antimetabolite used in the treatment of a variety of cancers, including breast and colon (Oguri et al., 2007). Yoshiura et al. (2006) showed that a SNP (538G–A) in MRP8 leading to a Gly180 / Arg substitution, provokes a dry and white earwax phenotype, which is predominant among east Asians (80%–95%) and rare among European and African populations (0%–3%), which normally have a wet and yellow earwax phenotype. This nucleotide polymorphism affects Nlinked glycosylation, resulting in increased proteasomal degradation of the variant protein (Toyoda et al., 2009). Also, MRP8 seems to be crucial for the secretion of odorants and their precursors. The same 538G–A mutation leads to a nearly complete loss of the typical odor components in axillary sweat (Martin et al., 2010). MRP9/ABCC12 and its orthologous Mrp9/Abcc12 (Shimizu et al., 2003; Yabuuchi et al., 2001; Tammur et al., 2001; Bera et al., 2001) are the last members of the family. Its mRNA presence has been reported in several tissues, including liver (Yabuuchi et al., 2001). However, Maher et al. (2005a) did not detect gene expression in liver. Further studies analyzing protein expression are needed to clarify the function of these last three transporters: MRP 7–9. Another disctinct ABC gene, ABCC13, was cloned from a cDNA library of adult human placenta (Yabuuchi et al., 2002). This gene encodes for a truncated protein of unknown proven function and high expression in fetal liver.

2.09.2.2.2

Mdr/MDR

The multidrug resistance proteins (Mdr) or P-glycoprotein (Pgp) was the ﬁrst ABC transporter identiﬁed (Ling et al., 1983). Mdr (rodents: Mdr, humans: MDR) are members of the B subfamily of the ABC transporter superfamily (ABCB). There are two members of the MDR/ABCB family in humans (MDR1/ABCB1 and MDR3/ABCB4) and three members in rodents (Mdr1a/Abcb1a, Mdr1b/ Abcb1b, and Mdr2/Abcb4). Mdr1a/Abcb1a and Mdr1b/Abc1b are the two rodent homologs of MDR1/ABCB1 and MDR3 is the human homolog of Mdr2. The MDR/Mdr proteins are expressed in multiple polarized epithelia of different organs, such as liver, intestine and kidney. MDRs are critical components of highly protective membranes, such as the blood brain barrier, the hematotesticular barrier and placenta, that limit exposure of extremely sensitive organs as to potentially damaging chemicals (Cascorbi, 2011). All MDR/Mdr proteins are expressed in the canalicular membrane of hepatocytes (Thiebaut et al., 1987). However, in rodents, the expression of the isoform Mdr1b is several time higher than Mdr1a, while the latter is expressed more abundantly in intestine and blood brain barrier. MDR1 was named multidrug resistance protein due to the observation that it confers resistance to a large number of chemotherapeutic agents. It was discovered to be a protein overexpressed in certain drug-resistant tumor cell lines (Kartner et al., 1983, 1985). MDR1 reduces the intracellular accumulation of various endogenous and exogenous compounds by mediating their ATPdependent export. MDR1 acts as an efﬂux pump for a broad range of pharmaceutical agents, not only chemotherapeutic drugs, such as anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes but also, analgesic such as entanyl, morphine; the antiarrhythmic drugs amiodarone, digoxin, quinidine; antibiotics such as ceftriaxone, clarithromycin, rifampicin; the antihistamines cimetidine, ranitidine; antilipidemic agents such as lovastatin, simvastatin; calcium channel blockers such as diltiazem, nifedipine; the HIV-protease inhibitor indinavir, saquinavir and, ritonavir; the immunosuppressive agents cyclosporin A, sirolimus, tracolimus; and neuroleptic agents such as chlorpromazine and phenothiazide. Other MDR1 substrates include natural producs such as curcuminoids and ﬂavonoids. Well known toxicants such as methyl parathion and paraquat are also transported by MDR1 (Chen et al., 2016a; Nornberg et al., 2015; Ford and Hait, 1990; Gottesman et al., 1996). Among endogenous substrates that have been identiﬁed are phospholipids and the steroid hormones corticosterone, cortisol, aldosterone, and progesterone (Pohl et al., 2002; Uhr et al., 2002). Mdr1a/Mdr1b knockout mice are viable and fertile, with no apparent phenotype. They have normal biliary phospholipids, cholesterol excretion, and normal bile formation (Schinkel 1997, 1998). However, these mice exhibit delayed clearance of and hypersensitivity to drugs, supporting the important role of Mdr1/MDR1 in overall drug disposition (Schinkel 1998, 1997). No loss-of-function variant of MDR1 is known in humans. However, since the ﬁrst evidence of MDR1 polymorphism reported by Mickley et al. (1998), which described the existence of two naturally occurring SNPs, one in exon 21 (2677G > T) and the other in exon 24 (2995G > T), multiple other polymorphic forms of this gene have been reported. The number of SNPs listed in the NCBI database (version 142) is 8643 (Wolking et al., 2015). Among them the most frequent are 1236C > T, 2677G> T/A and 3435C > T, with differences in frequency depending the ethnic populations examined (mean of 0.5% approximately) (Ieiri, 2012). Some MDR1 polymorphisms have been linked to Crohn’s disease and ulcerative colitis. Mdr1a/ mice develop spontaneous colitis (Wilk et al., 2005; Potocnik et al., 2004). However, regarding the incidence of polymorphisms in MDR1 and their impact on function and expression, inconsistent results have been reported, even when the same drug probe and disease/racial population are studied. A comprehensive review of this can be found in Ieiri (2012), Bruhn and Cascorbi (2014), and Wolking et al. (2015). MDR3/ABCB4 (human) and its mouse ortholog Mdr2/Abcb4 are the major phosphatidylcholine transporters in the canalicular membrane. MDR3 mediates the ATP-dependent translocation of phosphatidylcholine from the inner to the outer leaﬂet of the hepatocyte canalicular membrane and is also called the phospholipid export pump (Ruetz and Gros, 1994; Smith et al., 1994). Once exported by MDR3, the lipids are available to form mixed micelles with bile acids secreted by hepatocytes. Bile salts play

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a crucial role, presumably by extracting phosphatidylcholine from the outer leaﬂet, because it was demonstrated that phosphatidylcholine can be released only when bile salts are added to the medium of ABCB4 overexpressing cells (Morita et al., 2007). A detailed and complete mechanism of phospholipids transport by ABCB4 is described in Morita and Terada (2014). This function protects the biliary epithelium from the detergent action of bile acids. The importance of biliary phospholipid transport by MDR3 was demonstrated in Mdr2 (Abcb4) knockout mice, which develop liver disease characterized by cholangiocyte injury, pericholangitis, periductal ﬁbrosis and, ﬁnally, macroscopic and microscopic features of sclerosing cholangitis (Fickert et al., 2004; Fickert et al., 2002). This pathology is attributed to the toxic effects of nonmicellar bile acids on the biliary epithelium (Trauner et al., 2007; Smit et al., 1993). MDR3 defects or mutations result in a variety of cholestatic syndromes including progressive familial intrahepatic cholestasis (PFIC) in neonates to biliary cirrhosis in adults, cholestasis of pregnancy and drug-induced cholestasis. The role of this transporter in certain liver diseases is discussed below, but a more comprehensive review of this subject can be found in Trauner et al. (2007). Homozygous or compound heterozygous mutations in MDR3, which result in its absence from the canalicular membrane, cause the hereditary disease PFIC type 3 (Oude Elferink and Paulusma, 2007; de Vree et al., 1998; Deleuze et al. 1996). PFIC is a group of inherited disorders characterized by impaired bile ﬂow/defective canalicular bile acid secretion and progressive liver disease (Jacquemin, 1999). PFIC-3 is characterized by reduced biliary phosphatidylcholine levels, resulting in bile duct injury, ductular proliferation, and elevated serum g-glutamyl transpeptidase levels (Jacquemin, 2001a; Jacquemin et al., 2001b). PFIC-3 starts manifesting early in childhood and progresses to cirrhosis and liver failure, which may be lethal in the absence of liver transplantation (Jacquemin et al., 2001a). In heterozygotes, the MDR3 monoallelic defect is associated with a less severe form of the disease, which usually appears in young adults, mainly as intrahepatic cholestasis of pregnancy or low phospholipid-associated cholelithiasis syndrome (Falguières et al., 2014). More than 200 variations of the MDR3 gene have now been identiﬁed, while mutations leading to a change in the reading frame and the introduction of a premature stop codon result in a loss-of-function, the pathophysiological signiﬁcance of point mutations are still uncertain. In theory, a missense mutation can lead to a large spectrum of protein defects, including misfolding, improper targeting, reduced half-life and/or lack of activity (Dietrich and Geier, 2014; Falguières et al., 2014). Mutations in the ABCB4 can also lead to gallstone formation in certain patients (Wendum et al., 2012; Rosmorduc et al., 2003). These ﬁndings are consistent with spontaneous occurrence of gallstones in Mdr2 (Abcb4) KO (Lammert et al., 2004). Also, Mdr2 (Abcb4) KO develops chronic cholangiopathies such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), so the question arises as whether MDR3 defects may also be linked to these diseases in humans.

2.09.2.2.3

Bsep/BSEP

Bile salt export pump (rodents: Bsep/Abcb11, humans: BSEP/ABCB11) belongs to the ABC superfamily of transporters. Originally named sister of Pgp, Bsep/BSEP is exclusively expressed in the liver and is localized to the canalicular hepatocyte membrane (Fig. 2) (Gerloff et al., 1998; Childs et al., 1995). Bsep/BSEP is the primary transporter responsible for excretion of monovalent bile acids into the bile (Trauner and Boyer, 2003; Gerloff et al., 1998). Biliary secretion of bile acids by Bsep/BSEP is the major driving force in the generation of bile ﬂow (Stieger et al., 2007; Meier and Stieger, 2002). In addition to the export of bile acids across the canalicular membrane, rodent Bsep also transports taxol, vinblastine, and pravastatin (Hirano et al., 2005; Lecureur et al., 2000; Childs et al., 1998). PFIC Type 2 is caused by mutations in the BSEP gene, which result in the absence of a functional protein (Jacquemin, 1999; Jansen et al., 1999; Strautnieks et al., 1998). Symptoms develop in early infancy and include severe pruritus, moderate jaundice, cholelithiasis, elevated serum bile acids, and low concentrations of biliary bile acids (Strautnieks et al., 1998; Whitington et al., 1994). The disease rapidly progresses to hepatic failure, often requiring liver transplantation. Otherwise, death from liver failure can occur before adolescence. The reduction of biliary bile acids to less than 1% of normal values supports the concept that the major physiological role of BSEP is to transport bile acids (Jansen et al., 1999). Mice deﬁcient in Bsep develop much milder cholestatic liver injury, with less impaired bile acid secretion than humans with the same mutation. This is attributed to upregulation of Mdr1, which is hypothesized to function as an alternative pathway for bile acid efﬂux (Lam et al., 2005; Wang et al., 2001b). Additionally, bile acids in rodents tend to be less toxic than those in humans (Wang et al., 2001b).

2.09.2.2.4

Bcrp/BCRP

Breast cancer resistance protein; BCRP/ABCG2 in humans (Bcrp/Abcg2 in rodents) is a member of the G subfamily of ABC transporters, which is a family of half transporters. These half transporters/ABCG proteins must dimerize to form a homodimer or heterodimer to be functionally active. ABCG2 may function in the form of a homodimer or homotetramer (Xu et al., 2004; Kage et al., 2002). It is expressed in the canalicular membrane of hepatocytes (Maliepaard et al., 2001). In addition to normal expression in a number of tissues (e.g., liver, small intestine, mammary gland, kidney, blood brain barrier and placenta), ABCG2 is overexpressed in certain tumor cells, contributing to their multidrug resistance phenotype (Han and Zhang, 2004; Diestra et al., 2002; Maliepaard et al., 2001). ABCG2 confers multidrug resistance through cellular efﬂux of anticancer drugs such as mitoxantrone, doxorubicin, daunorubicin, topotecan, and MTX (Volk and Schneider, 2003; Allen et al., 1999; Doyle et al., 1998). In addition to transporting numerous anticancer agents, ABCG2 has a broad substrate speciﬁcity, transporting nucleoside reverse transcriptase inhibitors, genistein, leﬂunomide, prazosin, conjugated organic anions, E217bG, dinitrophenyl-GSH, and sulfate conjugates of steroids and xenobiotics (e.g., DHEAS, estrone-3-sulfate) (Polgar et al., 2008; Kis et al., 2008; Mao and Unadkat, 2005; Imai et al., 2004; Chen et al., 2003; Suzuki et al., 2003; Litman et al., 2000; Wang et al., 2003b). It was also demonstrated that Bcrp transfected P388 vesicles, generated from a mouse lymphoma cell line, transport taurocholic acid and taurolithocholate sulfate (Suzuki et al., 2003).

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Inhibition of [3H] estrone sulfate uptake into BRCP transfected human erythroleukemia cells in the presence of taurolithocholate, taurolithocholate sulfate and to a lesser degree, by taurocholate has been reported (Imai et al., 2003). Similarly, membrane vesicles from BCRP-expressing L. Lantis bacteria are also capable of transporting primary bile acids (Janvilisri et al., 2005). Bcrp/Abcg2 knockout mice exhibit higher plasma concentration of unconjugated bilirubin, accumulation of the heme precursor protoporphyrin IX also in plasma and erythrocytes, and increased sensitivity to pheophorbide a-induced phototoxicity (Jonker et al., 2002). Numerous SNPs in the human ABCG2 gene have been reported, some of which result in reduced protein expression and function (Tamura et al., 2007; Yanase et al., 2006; Kobayashi et al., 2005c; Imai et al., 2002). The Q141K gene variant, which carries a substitution of glutamine with lysine at amino acid 141 in the NBD, has a specially highincidence rate in the general population (between 10 and 30%, depending on ethnicity) (Kobayashi et al., 2005c). This SNP results in decreased transport activity compared to the wildtype form (Morisaki et al., 2005; Mizuarai et al., 2004). Various studies have evaluated the clinical relevance of Q141K in patients undergoing chemotherapy and also in healthy volunteers. The presence of Q141K results in elevated plasma concentrations of geﬁtinib (Li et al., 2007b), diﬂomotecan (Sparreboon et al., 2014) and increased oral bioavailability oftopotecan (Sparreboon et al., 2014). However, these ﬁndings are yet to be conﬁrmed since relatively small group of subjects were included in these studies.

2.09.2.2.5

ABCG5/ABCG8

Like BCRP, ABCG5 and ABCG8 in humans (Abcg5 and Abcg8 in rodents) are also members of the ABCG family of half transporters. The human ABCG5 and ABCG8 genes are adjacent to each other on the same chromosome and are coordinately regulated, resulting in similar expression patterns (Berge et al., 2000). The crystal structure of ABCG5 and ABCG8 that unite to form a functionally active heterodimer sterol transporter was recently described by Lee et al. (2016). Co-expression of both proteins is required for their translocation to the cell membrane and for function (Graf et al. 2002). ABCG5/ABCG8 is strongly expressed in the intestine and canalicular hepatocyte membrane (Graf et al., 2002, 2003). In addition to mediating intestinal sterol absorption, ABCG5/8 plays an important role in hepatobiliary cholesterol transport (Wang et al., 2015; Yu et al., 2002b,c). In addition to cholesterol, ABCG5 and ABCG8 efﬂux phyto- and shellﬁsh sterols into the bile (Yu et al., 2004; Graf et al., 2003; Yu et al., 2002c). Mutations in either ABCG5 or ABCG8, but not in both, cause sitosterolemia, a rare disorder characterized by elevated plasma levels of plant sterols and cholesterol due to increased absorption and decreased biliary excretion. This leads to the development of xanthomas and premature atherosclerosis (Hubacek et al., 2001; Lu et al., 2001; Berge et al., 2000; Bhattacharyya and Connor, 1974). Similar effects are seen in Abcg5/Abcg8 double knockout mice. While these mice do not exhibit any obvious physical abnormalities or phenotypes, they have signiﬁcantly increased plasma phytosterol concentrations (Yu et al., 2002b). Abcg5/Abcg8/ knockout mice also exhibit very low biliary cholesterol concentrations compared to wild-type mice (Yu et al. ,2002b). Also, an increased expression of ABCG5/ABCG8 is associated with increased gallstone formation in both humans (Jiang et al., 2008) and mice (Uppal et al., 2008). Two variants in ABCG5/G8 (ABCG5- R50C and ABCG8-D19H) were identiﬁed not only in Germans and Chileans, but also in Chinese and Indians (von Kampen et al., 2013; Katsika et al., 2010; Rudkowaska et al., 2008; Kuo et al., 2008; Wang et al., 2007; Grünhage et al., 2007). Additionally, studies that employed inbred strains of mice that are susceptible and resistant to cholesterol gallstone formation identiﬁed the nuclear bile salt receptor FXR and ABCG5/ABCG8 as susceptibility loci for the disease (Wittenburg et al., 2003). This is warrants further studies in humans with cholelithiasis. ABCG5/ABCG8 knockout mice fed with a high fat diet show higher increases in liver weight, hepatic lipid content, and plasma alanine aminotransferase values compared to wild types. Consistent with the development of nonalcoholic fatty liver disease, macrophage inﬁltration, the number of TUNEL-positive cells, and the expression of proinﬂammatory cytokines were also increased in the high fat diet G5/G8 knockout mice (Su et al., 2012).

2.09.2.2.6

Abca1/ABCA1

Abca1(rodents)/ABCA1(humans) is a member of the A subfamily of ABC transporters involved in the handling of cellular lipids. ABCA1 is most strongly expressed in the liver, adrenal glands, testis, pregnant uterus, and placenta (Wellington et al., 2002). ABCA1 is also present in tissue macrophages (Langmann et al., 1999). In the liver, ABCA1 is expressed on the basolateral membrane of hepatocytes where is known to play a critical role in the regulation of intracellular cholesterol levels (Brunham et al., 2006). Its expression has also been detected in Kupffer cells (Hoekstra et al., 2003; Neufeld et al., 2002). ABCA1 mediates cellular efﬂux of phospholipids and cholesterol into lipid-free apolipoprotein A-1 (apoA-1) containing lipoproteins (Wang et al., 2001a; Lawn et al., 1999). This is the initial step in the formation of high-density lipoprotein (HDL). Therefore, ABCA1 plays a key role in maintaining cholesterol homeostasis (Wang and Tall, 2003; Wang et al., 2001a). The mechanism(s) underlying ABCA1-mediated lipid efﬂux is still unknown (Cavelier et al., 2006). Mutations in ABCA1 are responsible for Tangier disease, a lipid metabolism disorder (Rust et al., 1999). Tangier disease is characterized by very low plasma HDL and ApoA-1 levels due to impaired cellular efﬂux of phospholipids and cholesterol. This leads to accumulation of cholesterol and cholesteryl esters in macrophage foam cells and many tissues, including the liver and spleen (Oram, 2000; Francis et al., 1995). The consequences of this impaired cholesterol transport include peripheral neuropathy, splenomegaly, thrombocytopenia, and increased incidence of cardiovascular disease (Oram, 2000). Abca1 knockout mice reproduce the human disease, exhibiting HDL deﬁciency, reduced cholesterol efﬂux activity, and foam cell accumulation (McNeish et al., 2000), whereas transgenic mice that overexpress Abca1 exhibit increased plasma HDL levels, increased cholesterol efﬂux from macrophages, and reduced diet-induced atherosclerosis (Joyce et al., 2003).

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Although hepatic Abca1 expression is a rate-limiting factor for plasma HDL production (Aiello et al., 2002), selective inactivation or overexpression of Abca1 in macrophages has little or no effect on plasma HDLconcentration (Haghpassand et al., 2001). However, selective knockout of Abca1 in macrophages of either apoE or LDL receptor-null mice signiﬁcantly enhances the development of atherosclerosis (Aiello et al., 2002). Thus, although Abca1 in macrophages does not inﬂuence plasma HDL, it is an important factor in the prevention of atherosclerosis development.

2.09.2.2.7

Mate/MATE

The multidrug and toxin extrusion protein family (humans: MATE, rodents: Mate), also called the SLC47 family, has three known members: MATE1, MATE2-K, and MATE2-B. MATE1 is strongly expressed in human liver and kidney. It is also expressed in adrenal gland, testis, skeletal muscle (Yonezawa and Inui, 2011; Otsuka et al., 2005), and ﬁrst trimester placenta (Ahmadimoghaddam et al., 2013). Human SLC47A1 and SLC47A2 are located in tandem on chormosome 17p11.2. SLC47A1 encodes for MATE1 and SLC47A2 produces two splice variants of MATE2, known as MATE2-K and MATE2-B. MATE2-K and MATE2-B are preferencially localized in kindney (Komatsu et al., 2011) and placenta (Ahmadimoghaddam et al., 2013) and are also expressed in low levels in the liver (Masuda et al., 2006). MATE1 is expressed on the canalicular membrane of hepatocytes where it mediates biliary excretion of organic cations (Otsuka et al., 2005). In mouse liver, Mate1 is present in biliary membranes of hepatocytes, bile duct epithelial cells, and Ito cells (Hiasa et al., 2006; Otsuka et al., 2005). MATE1 is considered to be a secondary active transporter, because it is an antiporter that mediates Hþ-coupled transport and elimination of organic cations (Otsuka et al., 2005). Human MATE1 transports TEA, MPP, Ipratropium, cimetidine, quinidine, verapamil, rhodamine-123, nicotine, choline, serotonin, metformin, creatinine, guanidine, procainamide, thiamine, topotecan, estrone sulfate, corticosterone, acyclovir, ganciclovir, cisplatin, oxaliplatin, and the antibiotics cephalexin, cephradine and ﬂuoroquinolones (Chen et al., 2017: Yokoo et al., 2007; Tanihara et al., 2007; Yonezawa et al., 2006; Otsuka et al., 2005). MATE1 also mediates cellular ﬂavonoid accumulation in cultured cells, with quercetin aglycone showing the highest accumulation, while Kaempferol, luteolin, and apigenin uptake was moderately enhanced by MATE1 overexpression (Lee et al., 2014). Genetic polymorphisms in MATE proteins have been identiﬁed and characterized. For instance, the SLC47A1 variants 66T> C (rs2252281, allelic frequency 23.1–44.5%) and 130G > A (rs12943590, allelic frequency 43%) are associated with decreased protein expression and better response to metfornin therapy, a typical MATE substrate (Stocker et al., 2013; Tkácc et al., 2012; Becker et al., 2009). In contrast, 130G > A (rs12943590, allelic frequency 22%–28%), a SLC47A2 polymorphism manifests the opposite effect, a reduction in the glucose-lowering activity of metformin (Stocker et al., 2013; Choi et al., 2011b). Mouse Mate1 has a similar substrate speciﬁcity to human MATE1 (Tanihara et al., 2007; Yonezawa et al., 2006; Hiasa et al., 2006). Species differences in MATE1 expression patterns exist, with much wider tissue distribution in rodents, as some expression was also observed in the stomach, spleen, lung, prostate, skeletal muscle, and brain (Hiasa et al., 2006; Ohta et al., 2006; Terada et al., 2006). Differences in tissue distribution also exist between mice and rats, with Mate1 being highly expressed in mouse liver, kidney, and heart whereas in rats the strongest expression of Mate1 is detected in the kidney (Hiasa et al., 2006; Terada et al., 2006). Mate1 KO mice were found to be viable, fertile and of normal body weight. No genotype-related histopathological abnormalities were detected in any of the tissues examined (Tsuda et al., 2009). A complete review of this transporter is found in Wagner et al. (2016).

2.09.2.2.8

Osta-Ostb/OSTa-OSTb

OSTa-OSTb is a basolateral organic solute transporter (OST) composed of two different gene products, OSTa (Slc51A) and OSTb (Slc51B) with speciﬁcity toward bile acids and steroid conjugates. These were initially identiﬁed in the liver of the little skate (Leucoraja erinacea) (Seward et al., 2003; Wang et al., 2001c). Coexpression of both proteins, OSTa and OSTb, is required for transport activity. Furthermore, coexpression is necessary for their membrane delivery and stability (Li et al., 2007c). The precise mechanism by which OSTa and OSTb interact to generate transport activity is not well known (Seward et al., 2003; Wang et al., 2001c). However, it is now recognized that modiﬁcations in the N-terminal region of human OSTa abolishes transport activity and its ability to co-immunoprecipitate with OSTb (Li et al., 2007c). In addition, modiﬁcation of the N-terminal segment of the OSTb subunit, particurlarly a highly conserved acidic dileucine motif ( EL20L21EE) at the extracellular loop of this segment, modiﬁes its association with the a subunit (Xu et al., 2016; Li et al., 2007c). The modiﬁcation of both N-terminal region of subunit a and b, or at least in one, impairs its polarized plasma membrane localization. Recently, Christian et al. (2012) also demostrated that highly the conserved transmembrane domains, particurlarly the TM domain region (Ostb-29–53) and the C-terminal region of human OSTb are necesary for trafﬁking of OSTa and the formation of the active heterodimer. OSTa-OSTb is expressed in high levels in the small intestine, kidney, and liver (Ballatori et al., 2005) and in other steroid rich organs as adrenal gland; testis, mammary gland, uterus, prostate, and thyroid (Lee et al., 2006; Seward et al., 2003). Within the liver, OSTa-OSTb is localized to the basolateral membrane of cholangiocytes and hepatocytes, mediating the efﬂux of substrates from within cholangiocytes into hepatocytes (Ballatori et al., 2005). Transport is ATP and sodium independent, mediating facilitated diffusion of bile acids and sterols. It is bidirectional and therefore follows chemical gradients (Ballatori et al., 2005; Seward et al., 2003). OSTa-OSTb is a multispeciﬁc transporter that can transport bile acids (e.g., taurocholate, glycocholate, tauroursodeoxycholate, glycoursodeoxycholate, and taurodeoxycholate), estrone sulfate, DHEAS, digoxin, and PGE2 (Ballatori et al., 2005; Seward et al., 2003). OSTa-OSTb plays a role in the enterohepatic circulation of bile acids, by allowing bile acid reabsorption across the basolateral membrane of cholangiocytes (Ballatori et al., 2005). In cooperation with ASBT, OSTa-OSTb contributes to the reabsorption of bile acids by mediating their vectorial transport from the bile duct lumen into the hepatocytes (Ballatori et al., 2005).

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Like other hepatobiliary transporters, the OSTa/OSTb heterodimer is positively regulated by FXR (Landrier et al., 2006; Lee et al., 2006). Recently, it was reported that retinoic acid modulates OSTb expression levels via RARa or CAR heterodimerization with RXRa and then by binding to DR5 elements in the promoter region of the gene (Xu et al., 2014). The development of an Osta knockout mouse led to the observations that the absence of this gene protects against cholestatic liver injury produced by BDL (Soroka et al., 2010) or oral bile acid feeding (Soroka et al., 2011). In humans, low illeal OSTa/OSTb expression is associated with gallstone formation in non-obese patients (Renner et al., 2008; Bergheim et al., 2006). Up until now, the absence of OSTa/OSTb has not been directly associated with any speciﬁc disease. However, this transporter complex plays a central role in bile acid homeostasis; therefore functional alterations could contribute to the progression of diseases related to bile acid malabsorption, cholestasis, or cholelithiasis.

2.09.3

Adaptive Changes in Transporters During Liver Injury

2.09.3.1

Cholestasis

Cholestasis is the interruption of bile ﬂow. This can occur at the cellular level in the hepatocyte, at the level of the intrahepatic biliary ductules, or as a result of extrahepatic obstruction of the bile ducts. Impairment of bile ﬂow leads to the accumulation of bile acids and other bile components in the liver, and ultimately to hepatocyte damage. Cholestasis is divided into two categories: intrahepatic and extrahepatic. Extrahepatic cholestasis is observed in patients with gallstones and tumors of the biliary tract and is modeled in rodents by ligating the common bile duct. On the other hand, intrahepatic cholestasis is caused by physiological and pathological factors, including genetic mutations in bile acid synthesis or transport proteins, pregnancy, chemicals or drugs, hepatitis, inﬂammation, ischemia–reperfusion, PBC, and primary sclerosing cholangitis (PCS) (Colombo et al., 2000; de Pagter et al., 1976; Jansen, 2000; Leevy et al., 1997; Lucena et al., 2003). A better understanding of the disruption and/or adaptive changes in hepatobiliary transporters during extrahepatic and intrahepatic cholestasis may be important in the development of new more effective therapies.

2.09.3.2

Extrahepatic Cholestasis

Hepatobiliary transporter expression is well characterized in mice and rats after bile duct ligation (BDL). This is a severe model of extrahepatic cholestasis due to the complete interruption of bile ﬂow. In general, BDL decreases mRNA and protein levels of uptake transporters including Ntcp, Oatp1a1, Oatp1a5, Oatp1b2, and Oct1 (Mennone et al., 2010; Slitt et al., 2007; Denk et al., 2004a; Donner et al., 2007; Lee et al., 2000a; Dumont et al., 1997; Gartung et al., 1996). Downregulation of Ntcp and Oatps likely contributes to the increased serum and urinary bile acid concentrations observed in BDL rodents (Mennone et al., 2010; Kamisako and Ogawa, 2005; Lee et al., 2000a, 2001; Zollner et al., 2002). This compensatory reponse limits further intrahepatic accumulation of toxic bile acids. Apart from these ﬁndings, there are a number of mouse Oatp isoforms (2b1, 4a1, 1c1) for which the mRNA expression does not change during extrahepatic cholestasis (3 days after BDL) (Lickteig et al., 2007b). Two Oatp genes (1a4 and 3a1) are induced in mouse liver 3–7 days following BDL (Lickteig et al., 2007b; Slitt et al., 2007). Collectively, these ﬁndings suggest that although the inﬂux of bile acids into hepatocytes is diminished after BDL, uptake of some organic anions may be enhanced. The functional signiﬁcance of enhanced chemical uptake via Oatp1a4 and 3a1 during BDL is presently unknown. Further studies are needed to determine whether BDL alters the protein levels and function of these Oatp isoforms concurrently with these reported changes in gene expression. Bsep mRNA and protein are unchanged or increased in rodents following BDL (Mennone et al., 2010; Lickteig et al., 2007a; Slitt et al., 2007; Kamisako and Ogawa, 2005; Wagner et al., 2003; Hyogo et al., 2001). However, one report described reductions in Bsep protein and mRNA levels at 3 days post BDL, with partial restoration occuring in the 7 to 14 days after surgery was performed (Lee et al., 2000a). Also, internalization of this transporter to a subapical compartment has been described in rats undergoing BDL (Donner et al., 2007; Paulusma et al., 2000). Donner et al. (2007) also reported that this process is associated with portal inﬂammation mediated by TNFa and IL-1ß. Conﬂicting reports reveal both up and downregulation of canalicular Mrp2 mRNA and protein in rodents after BDL, while Mrp2 mRNA and protein are downregulated in rats after BDL (Mennone et al., 2010; Villanueva et al., 2006; Kamisako and Ogawa, 2005; Dietrich et al., 2004; Denk et al., 2004b; Donner and Keppler, 2001; Hyogo et al., 2001; Lee et al., 2001; Paulusma et al., 2000; Lee et al., 2000a; Kagawa et al., 1998; Trauner et al., 1997), it remains preserved or slightly increased in mouse liver (Slitt et al., 2007; Wagner et al., 2003). The exact nature of the species-speciﬁc Mrp2 regulation by BDL-mediated cholestasis is unclear and warrants further investigation. However, decreased binding of RARa:RXRa nuclear receptor dimer to the promoter region of Mrp2 in BDL rats, due to increased levels of interleukin-1b, is reported to account for this Mrp2 down-regulation (Dietrich et al., 2004; Denson et al., 2002). Additionally, immunoﬂuorescence analysis shows that decreased Mp2 staining by BDL is accompanied by intracellular localization in pericanalicular vesicular structures (Paulusma et al., 2000). The events leading the endocytic internalization remain uncertain, but hepatocyte bile salt overload promotes membrane retrieval of Mrp2. This redistribution of Mrp2 appears to be associated with rearrangement of cytoskeletal actin-binding proteins. Speciﬁcally radixin, which is found exclusively in the plasma membrane under normal conditions, becomes resitributed to intracellular compartments along with actin aggregates and Mrp2 in response to bile salt-induced cholestasis (Rost et al., 2008). This event most likely involves an oxidative stress-mediated mechanism (Borgognone et al., 2005; Sokol et al., 1993). In addition to well documented changes in expression and function of nuclear receptors that regulate drug transporter gene expression during cholestatis, the recruitment of multi-subunit complexes containing coregulator proteins and histone modifying

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enzymes are also involved. The steady-state complex called activating signal cointegrator-2 (ASC-2)-containing complex (ASCOM) is altered in mouse liver during bile duct ligation. This complex contains the transcriptional coactivator nuclear receptor coactivator 6 (NCOA6), histone H3 lysine 4 (H3K4) methyltransferase, mixed lineage leukemia 3 (MLL3) and its paralog MLL4. Ananthanarayanan et al. (2011) described that MLL3, MLL4 and NCOA6 can interact directly with FXR and GR and are involved in regulating the expression of the their target genes BSEP, MRP2, and NTCP in both mice and human liver cell lines. Moreover, BDL in mice impairs the recruitment of the ASCOM complex to FXR responsive elements in the Bsep and Mrp2 promoters and to GRE in NTCP, pointing toward a critical function of this complex in cholestasis. Also, H3K4 trimethylation of histoneH3 surrounding BSEP-FXRE and NTCP-GCRE was also altered. These two phenomena can adversely affect FXR/GR transactivation and signaling, even when their expression is not altered. Expression of the Mdr class of canalicular transporters (namely, Mdr1b and Mdr2) is increased in rodent liver following BDL (Mennone et al., 2010; Hyogo et al., 2001; Kagawa et al., 1998; Accatino et al., 1996). Upregulation of Mdr mRNA corresponds with elevations in Pgp protein. By contrast, gene expression of the sterol half transporters (Abcg5 and Abcg8) is reduced within 1 day after BDL in rats (Kamisako and Ogawa, 2005). Increases in canalicular genes such as Mdr, Mrp2, or Bsep after BDL likely reﬂect a general, unconsequential adaptation to liver injury since enhanced efﬂux transporter function cannot restore bile ﬂow in BDL animals. Induction of basolateral efﬂux transporters after BDL is an alternative mechanism to prevent intracellular accumulation of bile constituents within the hepatocyte. As a result of the complete blockade of biliary excretion, there is a shift in chemical efﬂux from the canalicular to the basolateral membrane. mRNA and protein levels of Mrp1, 3, 4, 5, Osta (protein only), and Ostb (mRNA only) are elevated during a period of 3–14 days after BDL, while expression of Mrp6, 7, and 9 mRNA remains unchanged (Mennone et al., 2010; Slitt et al., 2007; Boyer et al., 2006; Denk et al., 2004b; Donner and Keppler, 2001; Kamisako and Ogawa, 2005; Wagner et al., 2003; Soroka et al., 2001; Lee et al., 2001; Ogawa et al., 2000). Mrp3 is normally expressed in centrilobular hepatocytes (Aleksunes et al., 2006). Following BDL, Mrp3 staining is enhanced in centrilobular hepatocytes and extends to periportal cells (Donner and Keppler, 2001; Soroka et al., 2001). Additionally, Mrp3 staining is increased along the basolateral surface of proliferating cholangiocytes after BDL (Soroka et al., 2001). Although Asbt mRNA and protein levels are increased two- to three-fold in livers from rats 14 days after BDL, the intensity of Asbt staining on proliferating cholangiocytes is reduced (Lee et al., 2001). This discrepancy may be due to dramatic induction of cholangiocyte proliferation (10- to 15-fold), essentially leading to dilution of Asbt protein among a greater number of cells. Coordinated regulation of the efﬂux transporters Mrp3, Mrp4, Asbt, Osta, and Ostb in the hepatocytes and cholangiocytes likely reduces the bile acid burden of the liver during extrahepatic cholestasis. The increased expression of basolateral transportes is associated with increase export of substrates into blood for subsequent elimination in urine, as compensatory mechanims to diminution in bile secretion. This compensatory mechanism has been described in BDL rats for morphine-3-glucuronide (Hasegawa et al., 2009) and APAP-glucuronide (Villanueva et al., 2008). Furthermore, the importance of Mrp4 in protecting the liver against obstructive cholestasis was documented in studies by Mennone et al. (2006) where null mice that underwent BDL developed more severe liver injury than wild types. The same basolateral induction of hepatic MRP3 mRNA and protein expression is seen in patients with obstructive cholestasis caused by gallstone blockage of bile ducts, with induction of MRP3 mRNA expression signiﬁcantly and positively correlated with serum levels of TNF-a, but not IL-1b (Chai et al., 2012).

2.09.3.3 2.09.3.3.1

Intrahepatic Cholestasis Estrogen induced

Estrogens are implicated in the pathogenesis of intrahepatic cholestasis of pregnancy (ICP) and in women prescribed oral contraceptives. Gestational cholestasis occurs during the third trimester. This condition is also known as obstetric cholestasis. It is characterized by pruritus and elevated serum bile, often in the presence of other signs of liver dysfunction. In addition to maternal symptomatology, this condition can be associated with adverse fetal outcomes (Geenes et al., 2014). Exogenous administration of two different species of estrogens recapitulates this clinical syndrome. Chronic administration of 17a-ethinylestradiol (EE) or the acute administration of the estrogen metabolite E217bG, to rats produce a decreased in biliary ﬂux. While EE administration produces a modiﬁcation in the expression of hepatic transporters, E217bG administration produces the delocalization of ABC transporters, as is described in details below. Daily administration of EE to rats for 3–10 days increases serum bile acids and alkaline phosphatase levels and reduces bile ﬂow and biliary GSH excretion (Koopen et al., 1998; Accatino et al., 1996). As early as 12 h following EE exposure, Ntcp mRNA and protein are decreased and remain low throughout the following 5–10 days of treatment (Meng et al., 2015a; Fiorucci et al., 2005; Geier et al., 2003b; Micheline et al., 2002; Lee et al., 2000a; Koopen et al., 1998; Simon et al., 1996). Similarly, decreased Oatp1a1 and 1a4 mRNA are observed within 12 h of EE treatment with subsequent declines in protein levels seen between 3 and 5 days (Fiorucci et al., 2005; Geier et al., 2003a). By contrast, Oatp1b2 mRNA levels are relatively stable following EE exposure. Oatp1b2 protein expression decreases between 3 and 5 days suggesting that its regulation occurs posttranscriptionally (Geier et al., 2003b). EE causes adaptive increases in Mrp3 mRNA and protein (Ruiz et al., 2007; Fiorucci et al., 2005). Furthermore, studies in primary hepatocyte cultures show that EE-mediated induction of Mrp3 is depedent on the estrongen receptor (Ruiz et al., 2013). Taken together, downregulation of Ntcp and Oatp isoforms and increased Mrp3 corresponds with reduced taurocholate inﬂux into cultured hepatocytes isolated 3–5 days after EE treatment (Simon et al., 1996). Expression of canalicular transporters is typically reduced in response to EE treatment. Modest reductions in Pgp and Bsep proteins in livers from EE-treated rats have been observed (Meng et al., 2015a; Cermanova et al., 2015; Zhou et al., 2011; Micheline et al., 2002; Lee et al., 2000a; Stieger et al., 2000; Accatino et al., 1996), with some exceptions. In the studies by Ruiz et al. (2007)

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241

and Fiorucci et al. (2005), Bsep levels were unaffected by EE treatment. Although immunohistochemical analysis conﬁrms lower Bsep protein expression, residual staining is largely localized to the bile canaliculi (Lee et al., 2000a). Mrp2 protein is markedly lower in response to EE and corresponds with decreased biliary GSH output in vivo (Meng et al., 2015a; Cermanova et al., 2015; Zhou et al., 2011; Ruiz et al., 2007; Fiorucci et al., 2005; Micheline et al., 2002; Lee et al., 2000a; Koopen et al., 1998) and in vitro (Crocenzi et al., 2001). Downregulation of Bsep and Mrp2 proteins occurs posttranscriptionally since mRNA levels are unchanged by EE (Lee et al., 2000a). EE induced cholestasis in rats signiﬁcantly reduced hepatic Oct1 mRNA and protein levels (Jin et al., 2009) and mRNA expression of Abcg5/Abcg8 (Yamamoto et al., 2006; Kamisako and Ogawa, 2005). Several FXR activators have been shown to ameloriate EE-induced cholestasis (Meng et al., 2015a; Cermanova et al., 2015; Zhou et al., 2011; Pellicciari et al., 2002). Among them, modiﬁed CDCA with a ethyl group in position 6 (Pellicciari et al., 2002) has been demonstrated to profoundly inhibit Ntcp, and to also increase Bsep, Mrp2 and Mdr2/MDR3 in the EE model of intrahepatic cholestasis of pregnancy (Fiorucci et al., 2005). Recent reports also show that the FXR activator, alisol B 23-acetate, protects against estrogen-induced cholestatic liver injury in mice by increasing the expression of Bsep and Mrp2 and decreasing Ntcp expression (Meng et al., 2015a). Another FXR agonist, colchicine, has the ability to markedly induce hepatic FXR expression and to increase the expression of Bsep and Mrp2 in EE-treated rats (Zhou et al., 2011). Finally, chronic administration of boldine, the major alkaloid from the boldo extract and another reported FXR activator, increases bile ﬂow and bile acids efﬂux in EE cholestatic rats also by increasing Bsep expression (Cermanova et al., 2015). However, Yamamoto et al. (2006) have reported, using mice lacking several different nuclear receptors (Era /, Erb/, Pxr /, Fxr /, and Car /), that ER a, instead of FXR, is the principal nuclear receptor involved in the effects of EE administration on ABC transporter expression. E217bG is an endogenous metabolite of 17b-estradiol and a potent cholestatic agent (Vore et al., 1997; 1983). The reduction in bile ﬂow and bile acid excretion produced by E217bG is dose-dependent, reversible, and evident within 30 min of metabolite administration. Biliary excretion of E217bG is mediated predominantly by Mrp2, as demonstrated in rats lacking this transporter (Morikawa et al., 2000). Mrp2 function is a mechanistic contributor, in part, for the cholestatic effect of E217bG (Huang et al., 2000). Following transport across the canalicular membrane via Mrp2, E217bG trans inhibits Bsep function, thus contributing to its cholestatic potential (Stieger et al., 2000). In addition, membrane deinsertion of hepatobiliary transporters in response to E217bG administration has been demonstrated as the cause of the reported cholestasis. Bile ﬂow is reduced within 10–25 min of intravenous (IV) administration of E217bG and is accompanied by retrieval of Mrp2 and Bsep proteins from its canalicular membrane localization (Crocenzi et al., 2003; Mottino et al., 2002). Mrp2 and Bsep proteins are internalized and redistributed to intracellular compartments in E217bG-treated livers and rat hepatocyte couplets (Fig. 5) (Crocenzi et al., 2003; Mottino et al., 2002). Pretreatment with dibutyryl-cyclic AMP prior to E217bG prevents intracellular accumulation of Mrp2 and Bsep, and partially restores bile ﬂow (Crocenzi et al., 2003; Mottino et al., 2002). It is hypothesized that dibutyryl-cyclic AMP regulates the canalicular transport capacity by stimulating the insertion of subapical vesicles or endosomes into the canalicular membrane (Mottino et al., 2002; Kipp and Arias, 2000). More recent

Fig. 5 In vivo effect of E217bG on Bsep immunoﬂuorescent localization. F-actin staining, which normally displays pericanalicular localization, was used to demarcate the bile canaliculus. Yellow staining indicates colocalization of Bsep (red) and F-actin (green). In solvent-treated rats, Bsep was mainly conﬁned to the canaliculus (control; A), whereas E217bG disrupted the normal canalicular localization of Bsep, visualized as an increment in the red staining outside the limits of the canaliculus (arrows) and in intracellular, vesicle-like structures (E217bG; B; arrowheads). Modiﬁed from Fig. 2 of Crocenzi, F. A.; Mottino, A. D.; Cao, J.; Veggi, L. M.; Pozzi, E. J.; Vore, M.; Coleman, R.; Roma, M. G. Am. J. Physiol. Gastrointest. Liver Physiol. 2003, 285(2), G449–G459.

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evidence also shows the involvement of ERa in transporter localization, which additionally involves other intermediate signaling proteins via activation of EGFR, PKC, and p38-MAPK responsible for the initial endocytic internalization of canalicular transporters (Barosso et al., 2016; Barosso et al., 2012; Boaglio et al., 2012; Crocenzi et al., 2008). Pathways initiated in the action of E217bG on its receptor G-protein-coupled receptor 30 (GPR30) activates either adenylyl cyclase-PKA or PI3KAkt-ERK1/2. This latter pathway is responsible for keeping transporters in the subapical space (Zucchetti et al., 2014; Boaglio et al., 2012; Zucchetti et al., 2011; Boaglio et al., 2010). A complete review describing details of this signaling event can be found in Crocenzi et al. (2012). Physiological changes in hepatobiliary transporter expression during pregnancy correspond with some of the ﬁndings obtained from the EE and E217bG models of intrahepatic cholestasis. Bile ﬂow is reduced during late gestation in pregnant rats (Cao et al., 2002). Despite unaltered mRNA levels, Mrp2 protein is reduced during late gestation (Arrese et al., 2003; Cao et al., 2001, 2002). Contrary to estrogen-induced cholestasis, subcellular localization of Mrp2 to the canaliculus is not affected by pregnancy (Cao et al., 2002). Hepatic Bsep levels are unchanged during pregnancy (Arrese et al., 2003; Cao et al., 2001). On the sinusoidal membrane, Mrp3, Mrp6, Ntcp, and Oatp1a4 proteins are decreased during pregnancy (Arrese et al., 2003; Cao et al., 2002).

2.09.3.3.2

Endotoxin induced cholestasis

Intrahepatic cholestasis is a complication of extrahepatic bacterial infections. Lipopolysaccharide (LPS), also termed endotoxin, is a component of the outer cell wall of Gram-negative bacteria that enters the liver via circulating portal blood. LPS inhibits bile ﬂow and biliary excretion of organic anions and can ultimately result in cholestatic liver injury. Reductions in bile ﬂow occur within 6– 12 h after exposure of rodents to a single dose of LPS. Because of the rapid decline of bile ﬂow after LPS, one plausible explanation is that LPS exposure leads to altered regulation of transporters involved in bile salt-dependent (Ntcp, Bsep) and bile salt-independent (Mrp2) bile ﬂow. Precipitous decreases in the expression and/or function of these transporters could explain LPS-induced cholestasis. Ntcp is reduced in the basolateral plasma membrane vesicles isolated from LPS-treated rats suggesting impaired bile acid uptake function (Arab et al., 2009; Donner et al., 2007; Lee et al., 2000a; Bolder et al., 1997; Moseley et al., 1996). Expression of Ntcp mRNA begins to decrease in rat liver within 2 h of LPS exposure (Green et al., 1996) and by 16 h, both Ntcp mRNA and protein levels decline to 10% of control rats (Cherrington et al., 2004; Geier et al., 2003b; Lee et al., 2000a; Trauner et al., 1998). A similar reduction in Ntcp mRNA is observed in mice after LPS treatment (Lickteig et al., 2007b). Furthermore, in vitro incubation of human liver slices with LPS decreases NTCP protein (Elferink et al., 2004). In addition to impaired basolateral bile acid transport, efﬂux of taurocholate and taurochenodeoxycholate from canalicular plasma membrane vesicles is reduced in endotoxemic livers (Bolder et al., 1997; Moseley et al., 1996). Downregulation of Bsep mRNA and protein is the likely reason for lower biliary excretion of taurocholate after LPS treatment (Arab et al., 2009; Donner et al., 2007; Cherrington et al., 2004; Hojo et al., 2003; Lee et al., 2000a; Lickteig et al., 2007b; Vos et al., 1998). LPS-treated human liver slices exhibit similarly reduced BSEP protein in the absence of changes in mRNA expression, suggesting that its downregulation occurs posttranscriptionally in humans (Elferink et al. 2004). LPS treatment markedly decreases the biliary excretion of not only bile acids, but also nonbile acid organic anions. Reduced expression of Mrp2 mRNA and protein in livers of LPS-treated rodents are reﬂected in declines in the biliary excretion of the Mrp2 substrates, BSP, and sulfolithocholyltaurine (Arab et al., 2009; Lickteig et al., 2007b; Cherrington et al., 2004; Geier et al., 2003b; Hojo et al., 2003; Lee et al., 2000a; Vos et al., 1998; Bolder et al., 1997). A time course study by Kubitz et al. (1999) demonstrated that biliary BSP excretion is impaired as early as 3 h after LPS in Wistar rats. This functional deﬁcit preceeds the decline in Mrp2 mRNA seen at 12 h. Discordance between mRNA and transport function is due to a rapid retrieval of Mrp2 protein from the canalicular membrane to subapical vesicles shortly after LPS treatment. Although the majority of Mrp2 protein colocalizes with the canalicular tight junction protein zona occludins-1, staining of Mrp2 is fuzzy and broad and by 6 h appears as dots (Kubitz et al., 1999; Zinchuk et al., 2005). Redistribution of some Mrp2 proteins to the basolateral surface can occur 48 h after LPS (Zinchuk et al., 2005). Subapical staining of Mrp2 protein following LPS is also observed in rat liver slices (Elferink et al., 2004). MRP2 staining in human liver slices is also reduced in response to LPS but remains localized to the canaliculus with no observable redistribution to other membrane sites. This suggests that there are species-related differences in protein regulation and trafﬁcking in response to LPS. Additionally, the administration of dimerumic acid, an antioxidant prior to induction of cholestasis by LPS treatment counteracts Mrp2 subcellular distribution, decreased bile ﬂow rate and biliary GSH excretion (Yano et al., 2010). This study suggests that LPSinduced short-term rapid retrieval of Mrp2 from the canalicular surface results from LPS-induced oxidative stress, while the longterm transcriptional regulation of Mrp2 by LPS does not appear to be dependant on intracellular redox status (Yano et al., 2010). The same antioxidant, dimerumic acid, also abolishes Mrp2 retreival in human liver slices incubated with LPS (Sekine et al., 2010). Radixin is the dominant protein from the ezrin–radixin–moesin, a family of proteins crosslinking cytoskeletal actin ﬁlaments (Factin) with integral membrane proteins. This function is regulated by the C terminal phosphorylation status of radixin, via the transition between active (C-terminal phosphorylated) and inactive (C-terminal dephosphorylated) forms (Ishikawa et al., 2001). Mice lacking radixin develop conjugated hyperbilirubinemia due to impaired localization of Mrp2 to the canalicular surface of hepatocytes (Kikuchi et al., 2002). In parallel, radixin canalicular localization also decreases after LPS treatment. Speciﬁcally, the total amount of active radixin (its phosphorylated form) and the proportion that co-immunoprecipitates with Mrp2 decreases during cholestasis by LPS (Saeki et al., 2011). This has been proposed as a posttranscriptional regulatory mechanism for Mrp2 function during cholestasis. Decreased biliary excretion of organic anions during endotoxemia may also result from impaired uptake at the basolateral surface. Uptake of BSP into basolateral plasma membrane vesicles from LPS-treated rats is reduced (Bolder et al., 1997). BSP is a substrate of mouse Oatp 1a4 and human OATP1B1/1B3 (Seithel et al., 2007; van Montfoort et al., 2002). As expected, LPS

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treatment lowers mRNA expression of mouse and rat Oatp1a1, 1a4, and 1b2 (Donner et al., 2007; Lickteig et al., 2007b; Li and Klaassen, 2004; Cherrington et al., 2004; Geier et al., 2003b; Hartmann et al., 2002). Similarly, mouse Oat2 and rat Oat3 are decreased after LPS (Lickteig et al., 2007b; Cherrington et al., 2004). Similarly, decreases in NTCP, BSEP OATP2 mRNA and protein and a decrease only in MRP2 protein, with unaffected mRNA expression in liver biopsies from inﬂammation-induced icteric cholestatic patients, have been reported (Zollner et al., 2001). Additionally, no changes in the expression of MRP3, MDR1, MDR3 were reported in these patients. LPS activates macrophages by binding toll-like receptor 4 and CD14, resulting in the release of inﬂammatory mediators that stimulate various responses in hepatocytes. A crucial role for inﬂammation in mediating the regulation of hepatobiliary transporters after LPS exposure was ascertained from studies in which dexamethasone was given to LPS-treated rats. Dexamethasone is a potent anti-inﬂammatory and immunosuppressive agent that blocks the release of cytokines. Dexamethasone restores expression of Oatp1a1, Oatp1a4, Ntcp, Bsep, and Mrp2 mRNA in endotoxemic rat livers (Cherrington et al., 2004; Kubitz et al., 1999). Administration of IL-6 decreases mRNA levels of Ntcp, Oatp1,Mrp2, MRP3 and Bsep in rat livers (Siewert et al., 2004). The same authors showed that these changes in mRNA expression are not observed in IL-6 KO mice. These ﬁndings provide initial clues into the signaling pathways governing LPS-mediated regulation of uptake and efﬂux transporters. Recently, studies using lymphocyte T, B or T/B knockout mice demonstrated that LPS treatment inhibits liver Bsep and Oct1 mRNA expression, and that this reduction in gene expression was abrogated by loss of T, but not B cells (Bodeman et al., 2013). In addition, these same authors described that the absence of T cells increases Mrp2 mRNA expression, whereas B cell deﬁciency attenuates decreased Oatp1a4 mRNA expression in LPS-treated mice. Oatp1a1, Oatp1b2, Ntcp, and Mrp3 were largely unaffected by T or B cell deﬁciency. Regarding inﬂammatory mediators in these mouse models, lymphocyte deﬁciency alters basal and inﬂammatory IL-6, but not TNF-a or IL-1b mRNA expression (Bodeman et al., 2013). Hyperthermia is being evaluated as a potential intervention for the treatment of intrahepatic cholestasis. Bolder et al. (2006, 2002), reported that warming of mice for 2 h prior to LPS injection prevents decline in bile ﬂow and biliary excretion of bile acids. Also, higher body temperatures partially restore BSP excretion (Bolder et al. 2006, 2002). Heat stress either partially or completely suppresses declines in Bsep, Ntcp, and Mrp2 proteins caused by LPS. The reduction in Mrp2 mRNA levels is also prevented by heat stress. By contrast, heat stress does not protect against reductions in Ntcp and Bsep mRNA. Maintenance of Ntcp and Bsep protein expression is likely related to induction of heat shock proteins 25 and 70. Speciﬁcally, Bsep and heat shock protein 70 were coimmunoprecipitated from livers of LPS-treated rats, suggesting that a chaperone protein-mediated protection of Bsep is responsible for preventing its downregulation (Bolder et al., 2006). The expression and function of liver Pgp is reduced during acute LPS administration, with signiﬁcant decreases in Mdr1a, Mdr1b, Mdr2 and Spgp reported (Hartmann et al., 2005, 2001). The same authors also demonstrated that the administration of IL-6 or IL1b decreases the expression of all these transporters, while TNF-a administration produces a slightly increase in Mdr1b mRNA and downregulation in Mdr1a, Mdr2 and Spgp mRNA expression (Hartmann et al., 2001). Decreased Pgp expression by LPS was associated to functional deﬁcits, as evidenced by lowered biliary excretion of doxorubicin (Hartmann et al., 2005) and Rhodamine 123 (Tomita et al., 2010), two typical substrates for this transporter.

2.09.3.3.3

Bile acid accumulation

An important role for bile acids in the pathogenesis of intrahepatic cholestasis was established by feeding or injecting rodents with exogenous bile acids. Bile acids including cholic acid, its taurine conjugate (taurocholate), and lithocholic acid cause cholestasis and hepatocellular damage. Additionally, diet supplementation with lithocholic acid results in PSC in some mouse strains (Fickert et al., 2006). This injury is accompanied by alterations in the expression of hepatobiliary transporters. Diet supplementation with cholic acid or taurocholate reduces rodent Ntcp and Oatp1a1 expression (Rost et al., 2003; Wolters et al., 2002). Similarly, cholic acid decreases Oatp1b2 and increases Oatp1a4 proteins (Rost et al., 2003). The mRNA levels of efﬂux transporters (Bsep, Mrp2, Mdr1a, Mdr1b) are also elevated by cholic acid (Miyata et al., 2005; Fickert et al., 2001). Parallel increases in protein expression of Bsep, Mrp2, Mrp3, and Pgp are observed with cholic acid feeding (Miyata et al., 2005; Zollner et al., 2003a; Gupta et al., 2000). Lithocholic acid is a 7-a-dehydroxylated derivative of cholic acid and is highly toxic when administered to rodents. Addition of lithocholic acid to mouse feed or daily intraperitoneal (i.p.) injections increases Mrp1, Mrp3, and Mrp4 mRNA while decreasing Ntcp, Oatp1a1, and Oatp1b2 mRNA (Beilke et al., 2008; Fickert et al., 2006). Notably also, levels of Bcrp, Bsep, and Mrp2 mRNA are unchanged by lithocholic acid (Beilke et al., 2008; Fickert et al., 2006). Administration of lithocholic acid caused an initial increase in bile ﬂow on day 1, followed by a decrease in bile ﬂow and biliary secretion of bile acids on day 4 (Fickert et al., 2006). Hepatic transporters are also regulated by ursodeoxycholic acid. This hydrophilic dihydroxy bile acid is used therapeutically to reduce cholesterol absorption and to dissolve cholesterol gallstones in patients who do not wish to undergo cholecystectomy. Ursodeoxycholic acid is also a chemopreventive agent. One potential mechanism for the hepatoprotective action of ursodeoxycholic acid is enhanced bile ﬂow, or choleresis. This increase in bile ﬂow may result from elevated Bsep, Mrp2, and Pgp protein expression (Zollner et al., 2003a; Fickert et al., 2001). Ursodeoxycholic acid also increases basolateral Mrp3 mRNA and protein expression, which may help protect hepatocytes from accumulation of bile constituents (Zollner et al., 2003a) Cholestyramine is a sequestrant that limits the intestinal absorption of bile acids. Treatment of rodents with a diet containing cholestyramine allowed researchers to determine whether transporter expression is inﬂuenced by reductions in bile acids. Cholestyramine in the diet of mice had little effect on hepatic expression of Ntcp, Bsep, Mrp2, and Mdr2 despite the reduced biliary secretion of bile acids (Wolters et al., 2002). By contrast, Oatp1a1 mRNA levels decreased in mice treated with cholestyramine, suggesting that bile acids in the enterohepatic circulation participate in the basal expression of this uptake carrier (Wolters et al., 2002)

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2.09.3.3.4

Alpha-naphthylisothiocyanate

Alpha-naphthylisothiocyanate (ANIT) damages bile ducts and causes intrahepatic cholestasis in rodents. ANIT is metabolized by CYP enzymes and is subjected to GSH conjugation. The ANIT–GSH conjugate is transported into the canalicular domain of hepatocytes via Mrp2 where it rapidly dissociates. Released ANIT injures bile duct epithelial cells leading to reduced bile ﬂow, hepatic accumulation of bile acids, and hepatocyte apoptosis and/or necrosis. Cholestastic liver injury by ANIT is associated with oxidative stress, inﬂammation, and more recently with endoplasmic reticulum stress. Yao et al. (2016) demonstrated that ANIT administration can induce the upregulation of gene expression of the ER stress markers (GRP78, PERK,ATF6, IRE1 and eIF2). ER stress is sensed and the unfolded protein response is activated by three ER transmembrane proteins, PERK, ATF6, and IRE1 (Kim et al., 2015; Zhang and Kaufman, 2008). Aditionally, oxidative stress activates the transcription factor nuclear factor E2-related factor 2 (Nrf2), which is a well-known regulator of various ABC drug transporters. The role of Nrf2 in ANIT toxicity via transporter function and expression was examined in Nrf2 knockout mice. The similar susceptibility of the null mice to ANIT hepatotoxicity was unexpected due to the capacity of ANIT to induce expression of Nrf2-dependent transporters and cytoprotectant genes (Tanaka et al., 2009). To add complexity to the relationship between ANIT, Nrf2 signaling and transporter expression and fuction, the same study found that treatment with the classical Nrf2 activator oltipraz afford protection against ANIT toxicity. For in-depth discussion of ANIT hepatotoxicity. As stated previously, biliary transport of ANIT–GSH is mediated primarily by Mrp2 (Dietrich et al., 2001). In fact, rats lacking Mrp2 are protected from ANIT-induced cholestasis. Interestingly, expression of Mrp2 is upregulated in mice by ANIT (Cui et al., 2009). In addition to Mrp2, canalicular Mdr2 and Bsep and basolateral Mrp3, Mrp4 and Ostb are induced in response to ANIT (Zhang et al., 2016b; Tan et al., 2016; Ding et al., 2014;Tanaka et al., 2009; Cui et al., 2009; Liu et al., 2005; Ogawa et al., 2000). By contrast, Ntcp, Oatp1a1, and Oatp1b2 mRNA are downregulated in livers from ANIT-treated mice and rats (Zhang et al., 2016b; Ding et al., 2014; Cui et al., 2009; Ogawa et al., 2000). Ding et al. (2014) also demonstrated decreased protein expression of Oatp1 and Ntcp in ANIT treated rats. This decrease in Ntcp was conﬁrmed by Tan et al. (2016); but in contrast, these authors reported decreased Oatp 2 and a signiﬁcant increase in Oatp1 mRNA expression in ANIT treated mice. Additionally, Tanaka et al., 2009 showed that Mdr2, Mrp3 and Bsep induction by ANIT treatment is mediated by Nrf2 activation. The same authors also reported that mRNA expression of Mrp2 was unchanged 48 h after ANIT treatment, but they reported an increment in protein expression in wild type mice, but not in mice lacking Nrf2. This, suggests that Mrp2 is potentially regulated by posttranscriptional/post-translational mechanisms via Nrf2 after ANIT (Tanaka et al., 2009). ANIT is a widely used chemical to mimic human intrahepatic cholestasis in rodents (Pollheimer et al., 2011a) and also is used as a chemical model of PCS see next section.

2.09.3.3.5

PBC

PBC is an organ-speciﬁc chronic autoimmune condition characterized by progressive destruction of small bile ducts and subsequent intrahepatic liver disease. This disorder is typically observed in women between the ages of 40 and 60. It is usually characterized by the presence of disease-speciﬁc autoantibodies such as antimitochondrial antibodies (AMA) and anti-p210 antibodies, and also by the presence of autoantigen-speciﬁc T cells (Carey et al., 2015). Histological examination of PBC biopsies demonstrates four stages. Stage I is characterized by inﬁltration of mononuclear inﬂammatory cells in the vicinity of small bile ducts, stage II by proliferation of small bile ducts, stage III by ﬁbrosis and scarring, and in stage V patients often exhibit cirrhosis (Ludwig et al., 1978). Progression from stages I to IV typically takes years. A number of studies using specimens from PBC patients identiﬁed adaptive changes in transporter expression that are consistent with an attempt by the liver to relieve the bile acid burden. Expression of NTCP, OATP1B1, and OATP1B3 mRNA and protein are reduced in stages III and IV, with little to no change in stages I and II (Kojima et al., 2003; Zollner et al., 2003b, 2001). Immunostaining of NTCP in PBC stage IV specimens is reduced in ballooned hepatocytes at the periphery of cirrhotic nodules (Fig. 6) (Zollner et al., 2003b). On the contrary, Takeyama et al. (2010) more recently reported induced expression of NCTP during all stages of PBC in untreated patients. Basolateral efﬂux transporters are upregulated during advanced stages of PBC, likely providing alternative elimination routes for bile acids and biliary constituents during cholestasis. mRNA and protein expression of the heterodimeric transporters OSTa and OSTb are induced in livers from stage III and IV in PBC patients (Boyer et al., 2006). In the case of MRP3, there are conﬂicting reports regarding its gene and protein expression in livers from PBC patients. Some reports documented little changes in MRP3 mRNA and protein from patients in stages I and II (Kojima et al., 2003; Takeyama et al., 2009), while in more advanced cases, MRP3 protein induction is observed with pronounced staining in proliferating interlobular bile ducts and hepatocytes at the periphery of cirrhotic nodules (Fig. 6) (Barnes et al., 2007; Ros et al., 2003a; Zollner et al., 2003b). However, Takeyama et al., (2009) reported that MRP3 expression returns to basal levels in late stages of untreated PBC patients. Barnes et al. (2007) found unchanged MRP3 mRNA, while Ros et al. (2003a) observed a three-fold elevation in mRNA. These discrepancies on patterns of MRP3 expression in PBC livers can be due, at least in part, to the human liver specimens used in the studies by Zollner et al. (2007, 2003b), which were obtained during tissue transplantation in patients that had received UDCA treatment, which did not accurately reﬂect PBC stages III and IV, whereas the Takeyama et al. (2009) study used liver specimens from untreated PBC patients. Regarding the effects of UDCA on hepatobiliary transporters, Marschall et al. showed that hepatic expression of MRP4 and BSEP is upregulated in gallstone patients who received UDCA (Marschall et al., 2005). In mice, UDCA feeding is known to induce hepatic expression of Mrp4, Mrp2 and Mrp3 (Zollner et al., 2003a). In addition to MRP3, sinusoidal MRP1, MRP4, and MRP5 mRNA and protein are elevated in advanced PBC stages (Barnes et al., 2007; Zollner et al., 2007; Kojima et al., 2003; Ros et al., 2003a) Takeyama et al. (2009) reported similar induction patterns not only

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Fig. 6 Reciprocal changes in NTCP and MRP3 tissue localization in PBC. Immunohistochemistry for NTCP A and MRP3 B was performed on serial sections from a PBC stage IV liver. A reduced staining pattern of basolateral NCTP in the peripheral layers of hepatocytes (indicated by black arrows) of cirrhotic nodules representing the zone of cholate stasis. B By contrast, MRP3 staining is induced in hepatocytes of this zone (arrows). These ﬁndings indicate reciprocal changes in NTCP/MRP3 tissue localization. Original magniﬁcation 20. Modiﬁed from Fig. 4 of Zollner, G.; Fickert, P.; Silbert, D.; Fuchsbichler, A.; Marschall, H. U.; Zatloukal, K.; Denk, H.; Trauner, M. J. Hepatol. 2003, 38(6), 717–727.

in the later stages, but also in early stages of PBC. Zollner et al. reported elevated MRP4 protein in stages III and IV, in the absence of altered mRNA levels (Zollner et al., 2007). In a similar report of patients with cholestasis of unidentiﬁed etiologies, both MRP4 mRNA and protein expression were two- to three-fold greater than in normal livers (Gradhand et al., 2008). MRP6 mRNA and protein were unchanged in PBC at all stages, indicating isoform-speciﬁc regulation of MRP transporters (Barnes et al., 2007; Kojima et al., 2003). Some authors describe that livers from PBC patients in stages I and II have stable expression of BSEP, MDR1, MDR3, and MRP2 mRNA and relatively normal canalicular protein staining (Kojima et al., 2003; Zollner et al., 2001; Dumoulin et al. ,1997). However, Enjoji et al. (2009) showed a marked increase in MDR3 expression at both the mRNA and protein levels in newly diagnosed PBC patients (stage I or II), where the impact of factors such as liver insufﬁciency, changes in hepatic lipid homeostasis and medication use on MRP3 expression is signiﬁcantly less. The inconsistencies between Zollner et al. (2003b and 2001) and Enjoji et al. (2009) which previously reported upregulation of hepatic MDR3 at the mRNA level in advanced cases of treated PBC patients, but not in cases of early stages, can also be due to methodological differences (e.g., smaller number of liver specimens analyzed, PCR procedures and antibodies used for immunodetection). For Pgp, the increased in protein levels observed in patients with advanced stages of PBC corresponded well with elevated MDR1 and MDR3 mRNA values (Barnes et al., 2007; Ros et al., 2003a). Pgp staining localizes to the apical membrane of hepatocytes and interlobular bile ducts (Fig. 7) (Ros et al., 2003a; Zollner et al., 2003b).

Fig. 7 Immunohistochemical localization of Pgp and PCNA. Double immunochemical staining of canalicular Pgp (brown) and nuclear PCNA (purple) was performed on parafﬁn sections from control, APAP, and PBC liver specimens. Tissues were counterstained with methyl green. Images of all groups were taken at 20 and 40 magniﬁcation. Modiﬁed from Fig. 5 of Barnes, S. N.; Aleksunes, L. M.; Augustine, L.; Scheffer, G. L.; Goedken, M. J.; Jakowski, A. B.; Pruimboom- Brees, I. M.; Cherrington, N. J.; Manautou, J. E. Drug Metab. Dispos. 2007, 35(10), 1963–1969.

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Interestingly, strong Pgp staining colocalizes with proliferating cell nuclear antigen, a marker of proliferation, in hepatocytes at the periphery of cirrhotic nodules (Barnes et al., 2007). Similar to Pgp, canalicular BSEP and BCRP proteins are elevated during later stages of PBC (Barnes et al., 2007; Ros et al., 2003a; Zollner et al., 2003b). On the contrary, MRP2 mRNA and protein expression are unchanged or minimally increased in PBC livers (Barnes et al., 2007; Ros et al., 2003a; Zollner et al., 2003b). However, Takeyama et al. (2009) reported that MRP2 and MRP3 expression is enhanced in patients with early stage disease, which then decreases as the disease progresses. It is important to note that MRP2 immunostaining is changed in advanced PBC. In stage III, MRP2 protein staining is broad and irregular and extends beyond the hepatocyte canaliculi as evidenced by costaining of MRP2 and the tight junction protein zona occludins-1 (Fig. 8) (Kojima et al., 2003). This staining pattern suggests that MRP2 is redistributed into intracellular structures within hepatocytes. By the end stage of PBC, there is downregulation of MRP2 in scattered hepatocytes containing Mallory bodies at areas of extreme cholate stasis (Ros et al., 2003a). Collectively, these reports suggest differential expression of canalicular transporters in patients with PBC. Furthermore, these transporter changes correlate with the clinical manifestation of PBC since its precirrhotic stage is characterized by anicteric cholestasis, indicating that the modulation of transporters could be a rather late event in PBC, secondary to loss of interlobular bile ducts with progressive cholestasis and resulting liver damage (Zollner et al., 2001). Several clinic studies demonstrate that obeticholic acid (6alpha-ethyl-chenodeoxycholic acid), a farnesoid X receptor (FXR; NR1H4) activator, is beneﬁcial in the treatment of PCB (Hirschﬁeld et al., 2015; Nevens et al., 2014; Kowdley et al., 2011). The activation of FXR increases bile ﬂow in cholestatic conditions, thus protecting the hepatocytes from accumulation of cytotoxic bile acids (Pellicciari et al., 2002). This process is mediated by inhibition of intestinal uptake of bile acids via repression of

Fig. 8 MRP2 staining in PBC Stage III. Confocal laser scanning micrographs of cryosections from control and PBC III livers double-stained for MRP2 (green in A, D) and ZO-1 tight junctions (red in B, E). In control livers, MRP2 is localized mainly to the canalicular space bordered by the ZO-1 staining (A–C). In PBC III, a redistribution of MRP2 into intracellular structures, represented by an irregular staining inside the cytoplasm of hepatocytes, was observed (D–F). Modiﬁed from Fig. 4 of Kojima, H.; Nies, A. T.; Konig, J.; Hagmann, W.; Spring, H.; Uemura, M.; Fukui, H.; Keppler, D. J. Hepatol. 2003, 39(5), 693–702.

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ASBT and by simultaneous induction of hepatic basolateral OSTs, repression of NTCP, and induction of BSEP, MRP2 and MDR3 (Willson et al., 2001). Furthermore, FXR activator also inhibits CYP7A1 in hepatocytes, which results in decreased bile acid synthesis (Goodwin et al., 2000). The role of phosphatidylcholine (PC) in PBC has also been addressed. PC secretion into bile is mediated by MDR3 in the canalicular membrane. Biliary PC prevents bile acid-mediated toxicity by forming micelles with bile acids (Oude Elferink Paulussma 2007 Oude Elferink et al., 1995; Ali and Zakim, 1993; Smit et al., 1993). Furthrmore, OCT1 also plays an important role in PC homeostasis, since it transports choline, which is needed for the synthesis of PC in hepatocytes (Sinclair et al., 2000; Zeisel et al., 1991). Kohjima et al. (2015) proposed a pathophysiological mechanism for PBC that focused on choline and phospholipid metabolism. Several polymorphisms in MDR3 and OCTs that negatively inﬂuence their activity, are associated with progression of PBC. Particularly, polymorphisms at rs31658 C > T, rs31672 T> C, and rs1149222 T > G in MDR3 are associated with severe PBC progression (Ohishi et al., 2008). Similarly, polymorphisms at rs683369 C > G and rs622342 A > C in OCT1 are also correlated with PBC in patients who underwent liver transplantation (Kohjima et al., 2015; Ohhishi et al., 2014).

2.09.3.3.6

Sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that is characterized by inﬂammation and destruction of intra- and extrahepatic bile ducts. PSC can progress over a 10- to 15-year period to biliary cirrhosis and often requires transplantation. In addition to liver disease, inﬂammatory bowel diseases manifest in approximately 75% of patients with PSC, with nearly 80– 90% of these cases diagnosed as ulcerative colitis (Yimam and Bowlus, 2014). Novel rodent models of PSC have been developed in order to elucidate the pathological events contributing to the human disease (Vierling, 2001). Instillation of the hapten reagent 2,4,6-trinitrobenzenesulfonic acid into the bile duct 2 weeks after surgically inducing mild stenosis stimulates histological (bile duct irregularities, moderate ﬁbrosis, mononuclear cell inﬁltration of the portal tract, extrahepatic cholangitis, and bile duct proliferation) and biochemical (antineutrophil cytoplasmic antibody production) features of PSC (Geier et al., 2002a; Orth et al., 2000). Expression of Ntcp, Oatp1a1, Oatp1a4, Oatp1b2, Mrp2, and Bsep mRNA is downregulated by 1 week after 2,4,6-trinitrobenzenesulfonic acid and remains low through 4 weeks (Geier et al., 2002a). By 12 weeks, Oatp1a1, Oatp1a4, and Bsep mRNA return to normal while Ntcp, Oatp1b2, and Mrp2 levels remain decreased. Similar declines in transporter protein expression are observed in 2,4,6-trinitrobenzenesulfonic acid-treated rats, with the exception of Oatp1b2 protein, which does not change. More recently, a second model of PSC was developed in mice (Fickert et al., 2007). Mice fed 0.1% 3,5-diethoxycarbonyl-1,4dihydrocollidine exhibit a cholestatic phenotype including pericholangitis and a ductular reaction resulting in onion skin-like periductal disease (Fickert et al., 2007). These histological changes are accompanied by reductions in Ntcp and Oatp4 mRNA, increases in Mrp3, Mrp4, Mdr1a, Mdr2, and Ostb and no change in Bsep, Mrp2, Mdr1b, and Osta mRNA. At the protein level, Ntcp and Mrp2 are reduced while Bsep, Mrp3, and Mrp4 are increased. Downregulation of Mrp2 is reﬂected in a decline in biliary GSH excretion in mice fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (Kurzawski et al., 2012).

2.09.3.4

Obesity, Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

The high prevalence of chronic liver disease is related to consumption of high fat-containing diets and subsequent accumulation of lipids in adipocytes, muscle, and liver. Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the United States and many other industrialized nations (Lomonaco et al., 2013; Wieckowska and Feldstein, 2008). Fatty liver disease encompasses a wide range of clinical pathologies from simple steatosis to nonalcoholic steatohepatitis (NASH), which may progress toward advanced ﬁbrosis and cirrhosis (Starley et al., 2010; Lomonaco et al., 2013). Although most cases of NAFLD are largely benign, manifesting as simple steatosis, progression to NASH signiﬁcantly increases the risk for hepatic morbidity and mortality. The prevalence of NAFLD is estimated to be 6%–30% worldwide, whereas NASH is reported to affect up to 12.2% of the general population (Lomonaco et al., 2013; Rahimi and Landaverde, 2013). ABCA1, as previously introduced, is an ABC transporter located in the basolateral membrane of hepatocytes that mediates the transport of cellular cholesterol and phospholipids to apoA-I to generate nascent HDL particles (Oram and Heinecke, 2005). Recently, it has been demonstrated that this transporter can contribute to the pathophysiology of NAFLD and NASH (Jeon et al., 2015; Ma et al., 2014; Musso et al., 2013; Yang et al., 2010). In HepG2 cells, over-expression of ABCA1 decreases cellular fatty acids and triglycerides accumulation, while its repression by siRNA increased both cellular fatty acids and triglycerides. Rats with NASH also showed lower ABCA1 protein levels in liver cells, compared to control rats (Yang et al., 2010). Deletion of ABCA1 leads to impairment in hepatic cholesterol efﬂux, followed by intracellular accumulation of free cholesterol in hepatocytes (Musso et al., 2013). The same authors described that accumulation of free cholesterol can promote NASH development by inducing ER stress. Furthremore, overexpression of apoA-I or Abca1 can reduce steatosis by decreasing lipid storage, modifying hepatocyte lipid transport and inhibiting fatty acid synthesis through decreasing 27-hydroxycholesterol levels (Ma et al., 2014). Also, in vivo and in vitro induction of Abca1 by cilostazol, a selective inhibitor of phosphodiesterase 3, leads to reduction in hepatic steatosis (Jeon et al., 2015). In morbidly obese subjects with NASH, ABCA1 protein expression is signiﬁcantly reduced and miR-33a and miR144 (miR-33a/144) levels are inversely correlated with ABCA1 protein expression. This interplay between miR-33a/144 and their gene target ABCA1 has been proposed to contribute to the pathogenesis of NASH (Vega-Badillo et al., 2016). These results are supported by other studies documenting that over-expression of miR-33a/144 acts as a suppressor of hepatic Abca1 expression, thus contributing to hepatic cholesterol metabolism and plasma HDL lipoprotein levels (de Aguiar Vallim et al., 2013; Ramirez et al.,

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2013; Rayner et al., 2011; Najaﬁ-Shoushtari et al., 2010; Rayner et al., 2010;). Additionally, the absence on ABCG5/ABCG8, the sterol transporter, in mice is known to contribute to the development of NAFLD (Su et al., 2012). Increasing trends in mRNA and protein expression of various ABC transporters (e.g., ABCC1, ABCC4–5, ABCB1, ABCG2) are associated with NAFLD progression in humans, whereas immunohistochemical analysis demonstrated a shift in cellular localization of Mrp2 from the canalicular membrane to intracellular compartmentalization (Hardwick et al., 2011). Similar observations were obtained in studies performed with liver samples from pediatric patients with NASH. The expression and functional activity of MRP3 in these patiens were increased, and although total MRP2 expression was also increased, its reduced membrane localization resulted in decreased function (Canet et al., 2015). As was previously demonstrated in rodents (Fisher et al., 2009), the global expression of uptake transporters is also reduced during pathological development of human NASH (Lake et al., 2011). Both genetic (obese Zucker rats, ob/ob mice) and dietary (methionine- and choline-deﬁcient diet or MCD) animal models are commonly utilized to study the pathogenic mechanisms of fatty liver disease. Ob/ob mice and obese Zucker rats are genetically obese rodents with deﬁciencies in leptin signaling, resulting in markedly increased food intake and decreased energy expenditure. The cumulative effects of these genetic abnormalities are weight gain, increased liver weight, elevated blood glucose, insulin resistance, and microvesicular steatosis (Cheng et al., 2008; Pizarro et al., 2004). Despite similarities in pathology, recent work suggests differential regulation of hepatobiliary transporters between these two animal models. Ob/ob mice have reduced mRNA and protein expression of Ntcp and Oatp isoforms (Cheng et al., 2008). There are similar declines in Mrp1 and Mrp6 mRNA and protein in female ob/ob mice. On the contrary, gene and protein levels of Bcrp (females only), Mrp2 (protein only), Mrp3 (males only), Mrp4, and Mrp5 (males only) are elevated in livers of ob/ob mice (Cheng et al., 2008). These ﬁndings are opposite of those in obese Zucker rats where Mrp2 protein expression is reduced and Bcrp, Mrp3, and Mrp4 levels are unchanged (Geier et al., 2005a; Pizarro et al., 2004). Decreased Mrp2 results in functional declines in biliary GSH and BSP excretion in obese Zucker rats. Interestingly, infusion of leptin to Zucker rats using osmotic pumps restores Mrp2 protein expression (Pizarro et al., 2004). Feeding a MCD diet to rats for 8 weeks causes hepatocyte ballooning, hepatic steatosis, lobular inﬂammation, and perisinusoidal ﬁbrosis (Lickteig et al., 2007a). MCD diet induces expression of Mrp3, Mrp4, and Bcrp mRNA and downregulates Mrp6 and Bsep mRNA. Protein expression of hepatic Mrp2, Mrp3, Mrp4, and Bcrp is induced in MCD-fed rats. The upregulation of Mrp3 was accompanied by a shift in excretion of APAP-glucuronide from bile into urine (Lickteig et al., 2007a). In the same model, decreased mRNA expression of the uptake transporters Oatp1a1, Oatp1a4, Oatp1b2 and Oatp2b1 (Fisher et al., 2009) was also reported. This decreased expression had functional implications since hepatic uptake of bromosulfophtalein was similarly reduced in MCD-fed animals. Recognizing the increasing incidence of metabolic X syndrome and obesity within the Western society, additional work is necessary to further characterize hepatobiliary transporter expression during fatty liver disease. Altered expression of transporters could dramatically inﬂuence the pharmacokinetics and pharmacodynamics of drugs to treat hypercholesterolemia, obesity, and insulin resistance. It can also lead to changes in the pharmacokenetic properties of many eviromentally-relevant chemicals.

2.09.3.5 2.09.3.5.1

Chemical-Induced Hepatocellular Injury APAP

APAP has been used as a model hepatotoxicant to study the effects of chemical-induced liver injury on transporter expression and function. APAP is a commonly used analgesic and antipyretic, which is safe when taken at therapeutic doses. When supratherapeutic doses are ingested, detoxiﬁcation pathways (APAP conjugation with sulfate or glucuronide) are overwhelmed, and there is increased bioactivation of APAP by CYP enzymes (primarily CYP2E1 and CYP1A2) to its toxic, reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is detoxiﬁed by conjugation with GSH; however, when intracellular GSH stores are depleted, this metabolite reacts with sulfhydryl groups of cellular proteins. The formation of protein covalent adducts, in addition to oxidative stress, and mitochondrial disfunction results in hepatocellular damage in centrilobular regions of the liver, which may ultimately lead to fulminant hepatic failure (for review see Yuan and Kaplowitz, 2013; Larson, 2007). Rodent models have been used extensively to investigate the effects of APAP hepatotoxicity on hepatic transport protein expression. During APAP-induced liver injury Mrp2 and Pgp protein expression increases in rat liver (Ghanem et al., 2004). In a comprehensive analysis of transporter expression in mice, toxic APAP treatment decreased mRNA expression of the basolateral uptake transporters Oatp1a1, Oatp1b2, and Ntcp (Aleksunes et al., 2005). Concomitantly, basolateral (Mrp3, Mrp4) and canalicular (Mrp2) efﬂux transporter mRNA levels were increased (Aleksunes et al., 2005). Similar results were seen at the protein level, with APAP-damaged mouse liver exhibiting reduced Oatp1a1, Oatp1b2, and Ntcp (Campion et al., 2008) and increased Mrp2, Mrp3, and Mrp4 protein expression (Fig. 9) (Aleksunes et al., 2006). Additionally, increased Mrp3 and Mrp4 protein levels were localized to hepatocytes around the central vein (CV), in regions of hepatic damage and compensatory cell proliferation (Aleksunes et al., 2006). Mrp4 induction by APAP was abolished by chemical depletion of Kupffer cells indicating that paracrine signaling from liver macrophages regulate hepatocyte Mrp4 gene expression (Champion et al., 2008). The same study also reported that Kupffer cell depletion prevents the increase in plasma TNF-a and IL-1b produced by APAP. This alteration in liver cytokine production most likely contributes to the differential regulation of Mrp4 and susceptibility to APAP toxicity when Kupffer cell function is abolished. Mrp4 induction is also absent in Nrf2 KO mice receiving APAP (Aleksunes et al., 2008b); additionaly, Mrp3 induction by APAP was also absent in these KO mice. In these studies, minimal changes in transporter expression were seen with nonhepatotoxic APAP doses, suggesting a dependency on hepatic injury for altered transporter levels (Aleksunes et al., 2005). However, subtoxic doses of APAP induce Mrp4 in proliferating hepatocytes in mice (Aleksunes et al., 2008a) and Mrp3 expresion in rats (Ghanem et al.,

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Fig. 9 Immunoﬂuorescent colocalization analysis of Ntcp and Mrp4 expression in livers from APAP- and CCl4-treated mice. Double labeling indirect immunoﬂuorescence against Mrp4 (green) and Ntcp (red) was performed on liver cryosections obtained at 48 h from control (A), APAP: 400 mg k/g (B), CCl4: 10 mL/kg (C), and CCl4: 25 mL/kg (D) treated mice. Modiﬁed from Fig. 6 of Aleksunes, L. M.; Scheffer, G. L.; Jakowski, A. B.; Pruimboom-Brees, I. M.; Manautou, J. E. Toxicol. Sci. 2006, 89(2), 370–379.

2009). Induction in the expression of these two transporters has been linked to an increased resistence to a subsequent toxic APAP treatment, a phenomenon that is now widely known as autoprotection. Although the precise mechanism of this remains unknown, recent studies provide potential mechanistic leads (Eakins et al., 2015; O’Connor et al., 2014; Rudraiah et al., 2014). Emphasis on better deﬁning the role of drug transporters in the development of tolerance to the action of hepatotoxicants continues to be of great importance. Hepatic efﬂux transporter expression has also been investigated in human liver samples obtained during liver transplantation, in patients with fulminant hepatic failure caused by APAP. MRP1 and MRP4 mRNA levels were signiﬁcantly elevated in APAP human liver specimens (Barnes et al., 2007). MRP4, MRP5, BCRP, and Pgp protein, as detected by Western blot, were increased in these patients also. Additionally, sex differences in susceptibility to APAP hepatotoxicity have been well documented in rodents (Mohar et al., 2014; Rohrer et al., 2014; Masubuchi et al., 2011; Dai et al., 2006). Although the molecular mechanism for this gender difference are not fully deﬁned, it seems to be multifactorial and dependent upon differences in GSH concentration, mitochondrial protein arylation and APAP metabolism. The gene and protein expression of various liver drug transporters in both genders have been fully characterized, with the same study showing that Nrf2 expression and function is not responsible for resilience of female mice to APAP hepatotoxicity (Rohrer et al., 2014) Functional consequences of altered transporter expression by APAP have also been investigated. Increased Mrp2 and Pgp expression in rat liver after toxic APAP exposure results in increased biliary elimination of dinitrophenyl-S-glutathione, GSSG, and digoxin (Ghanem et al., 2004). The ﬁrst two are substrates for Mrp2 while the last one is a substrate for Pgp. Rats with increased hepatic Mrp3 expression due to toxic APAP pretreatment exhibit a shift in the elimination of a subsequent dose of APAP in the form of APAP-glucuronide from bile to urine (Ghanem et al., 2005). Similarly, higher urinary excretion of APAP-glucuronide has been observed in rodent models of human diseases where Mrp3 protein is induced, such as nonalcoholic fatty liver disease, LPS treated or bile duct-ligated rats, and with pediatric nonalcoholic steatohepatitis (Canet et al., 2015; Hassany et al., 2011; Villanueva et al., 2008; Lickteig et al., 2007a). APAP-glucuronide is a known substrate for Mrp3 (Manautou et al., 2005; Slitt et al., 2003). Bcrp contributes to the biliary excretion of APAP-sulfate in the perfused mouse liver (Zamek-Gliszczynski et al., 2006b). Similarly, Mrp3 and Mrp4 appear to play a role in the basolateral excretion of APAP-sulfate (Zamek-Gliszczynski et al., 2006a). Gender differences were reported for ABC transporters and APAP disposition. Mrp4 expression is higher in females than males (Rohrer et al., 2014; Masubuchi et al., 2011). Studies using perfused mouse liver showed higher biliary excretion of APAPglucuronide and –sulfate (Lee et al., 2009) in males, which is consistent with male-predominant Bcrp expression in mice (Merino et al., 2005; Tanaka et al., 2005). The impact of altered disposition of APAP metabolites by hepatic transport proteins and its implications to APAP toxicity are not well understood. Changes in transporter expression during APAP hepatotoxicity may be a compensatory response to reduce the chemical burden of stressed hepatocytes through reduced uptake and enhanced efﬂux of substrates,

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including byproducts of cellular injury. Exported substrates may also serve as signaling molecules to adjacent hepatocytes and nonparenchymal cells to aid in facilitating the recovery process and protecting the liver from additional insult.

2.09.3.5.2

Carbon tetrachloride

Carbon tetrachloride (CCl4) is a compound that was previously used as a dry cleaning solvent, a refrigerant, and also in ﬁre extinguishers. Its industrial use has been largely abandoned due to well-documented adverse health effects. Exposure to CCl4 results in centrilobular hepatic necrosis. CCl4 is metabolized by CYP2E1 to the highly reactive trichloromethyl free radical, which causes hepatocellular damage through lipid peroxidation (Manibusan et al., 2007). For more on CCl4 hepatotoxicity, please refer to Chapter 9.20 Inhalation Toxicology Studies. Nakatsukasa et al. (1993) reported increased Mdr1a, Mdr1b, and Mdr2 gene expression in rat liver after toxic CCl4 administration. In another study, CCl4 exposure caused a decrease in Ntcp and Oatp1a1 mRNA levels in rat liver (Geier et al., 2002b). Reduced Ntcp and Oatp1b2 protein expression was also noted. When hepatic efﬂux transporters were examined in liver plasma membrane vesicles from CCl4 intoxicated rats, an increased Pgp and a decreased Mrp2 protein levels were detected, along with corresponding changes in their transport activity (Song et al., 2003). Analysis of multiple transporters in mice revealed that CCl4 decreased mRNA expression of the basolateral uptake transporters Oatp1a1, Oatp1b2, and Ntcp, and simultaneously increased mRNA levels for the efﬂux transporters Mrp1, Mrp2, and Mrp4 (Aleksunes et al., 2005). Western blot analysis demonstrated reduced Ntcp and increased Mrp1, Mrp2, and Mrp4 in these mice (Aleksunes et al., 2006). Meng et al. (2015b) conﬁrmed the CCl4-mediated increased in Mrp2 expression associated with acute liver damage in mice, while also describing induction of Bsep. Similar to the expression pattern seen after APAP administration, upregulation of Mrp4 protein was observed in hepatocytes adjacent to the central vein after CCl4 treatment (Fig. 9) (Aleksunes et al., 2006). Microarray analysis of livers from rats treated with CCl4 conﬁrmed some of the mouse observations. Gene expression of Mdr1a, Mdr1b, Mrp1, and Mrp4 was increased by CCl4, while the expression of Mrp2, Mrp6, Bsep Oct1, and Oat3 was decreased (Okumura et al. 2007). In contrast to what is observed in mice, Mrp2 expression was decreased during acute liver failure induced in CCl4 treated rats (Yokooji et al., 2006). This reduction was associated with lower 2,4-dinitrophenyl-S-glutathione (DNP-SG) biliary excretion. Advanced liver ﬁbrosis produced by chronic administration of CCl4, pharmacokinetic parameter for maximum enhancement, time to peak, mean residence time and hepatic extraction fraction, determined at dynamic gadoxetate-enhanced MR imaging, and were decreased signiﬁcantly relative to those in control rats (Lagadec et al., 2015). These results provide a strong correlation between reduction in the expression of Oatp1a1 and Mrp2 and increased Mrp4 expression.

2.09.3.5.3

Troglitazone

Troglitazone is an antidiabetic agent and a member of the thiazolidinedione class of drugs. Reports of idiosyncratic reactions characterized by cholestasis and in some cases fulminant hepatic failure prompted its removal from the market in the year 2000 (Smith, 2003). Troglitazone-induced intrahepatic cholestasis has been attributed to reduced bile ﬂow through inhibition of canalicular efﬂux transporters. In human hepatocytes, troglitazone uptake is mediated by OATP1B1 and OATP1B3, with OATP1B1 showing greater afﬁnity for transport (Nozawa et al., 2004). Troglitazone and troglitazone sulfate, the main drug metabolite eliminated in the bile, were found to interfere with the hepatobiliary elimination of bile acids by competitive inhibition of Bsep (Funk et al., 2001a,b) in rats. Speciﬁcally, troglizatone produces a differential effect in bile acid accumulation, with higher increments in chenodeoxycholic acid acculuation than for taurocholate in rat hepatocytes (Marion et al., 2011). Human BSEP activity is also inhibited by troglitazone in sandwich-cultured human hepatocytes (Marion et al., 2007). A considerable volume of work provide strong support to the hypothesis that BSEP inhibition is a contributing event in the development of intrahepatic cholestasis in humans treated with troglitazone (Funk et al. 2001a,b). However, not all drugs that inhibit BSEP produce cholestasis or even hepatic failure, suggesting that liver injury is driven by a combination of drug- and patient-speciﬁc factors. Other hypotheses have been proposed to explain troglitazone-induced hepatotoxicity, such as generation and intrahepatic accumulation troglitazone reactive intermediates, oxidative stress, mitochondrial dysfuction and apoptosis (Masubuchi, 2006). In addition to its well documented interference with BSEP function, troglitazone is also a substrate for BCRP in both mice and humans. A greater ﬂux ratio was observed in human BCRP-expressing cells than in cells expressing the mouse form, indicating that human BCRP transports troglitazone more efﬁciently than in the mouse (Enokizono et al., 2007). Troglitazone not only inhibits BCRP, but also Pgp and it induces mRNA expression of BCRP, but not Pgp in different cell lines (Weiss et al., 2009). The role of BCRP as a major transporter mediating biliary excretion of troglitazone was demonstrated in Bcrp / mice, where its biliary excretion was markedly reduced (Enokizono et al., 2007). Previously it was reported that biliary excretion of troglitazone was delayed in TR rats compared with normal rats; however, the amount of troglitazone excreted into the bile was not markedly reduced in TR rats (Kostrubsky et al., 2001). An interesting study using the PXB mouse model with chimeric human/mouse liver demonstrated that troglizatone administration induced a loss of large lipid droplets in human hepatocytes and a decrease in the expression of two bile acid transporters, BSEP and MRP2 (Foster et al., 2012). These speciﬁc changes are produced in the human portion of this chimeric model without any effects detected in murine tissue. The same species differences, decrease in both bile and basolateral excretory pathways of bile acids, were demostrated to be higher in human rat sandwich-cultured hepatocytes than in rats ones. Increassing their accumulation andtoxicity (Yang et al., 2015a). Additionally, troglitazone-sulfate inhibits the hepatic MRP4 (Yang et al., 2015a) and troglizatone itself has been reported to inhibit MRP3 and MRP4 (He et al., 2015; Morgan et al., 2013).

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In summary, transporter inhibition, and more speciﬁcally inhibition of liver bile acids inﬂux and efﬂux is associated with their intrahepatic accumulation, which appears to be an important mechanism for troglitazone hepatotoxicity.

2.09.3.5.4

Sulindac

Sulindac is a nonsteroidal antiinﬂammatory drug (NSAID) used in the treatment of acute and chronic inﬂammation. Sulindac is the most common and consistent NSAID associated with hepatotoxicity (Aithal and Day, 2007). Its use is associated with cholestatic hepatotoxicity, which resolves when the drug is withdrawn (Tarazi et al., 1993). Sulindac-induced cholestatic liver injury has been partially attributed to the drug’s competitive inhibition of canalicular bile acid transport. Sulindac has been shown to follow the cholehepatic shunt pathway, through which unconjugated bile acids are passively absorbed by cholangiocytes, returned to the hepatocyte by the periductular capillary plexus, and then returned to cholangiocytes by hepatocyte secretion (Bolder et al., 1999; Hofmann, 1989). Sulindac is secreted into the bile in the unconjugated form and is reabsorbed by cholangiocytes, inducing hypercholeresis, a greater degree of bile ﬂow relative to the amount of bile acids excreted into the bile, in addition to increased biliary bicarbonate excretion (Bolder et al., 1999). Continuous cycling of sulindac within the cholehepatic shunt pathway may result in prolonged exposure of hepatocytes to sulindac. Sulindac interacts with and inhibits Bsep at the canalicular membrane (Wang et al., 2003a; Bolder et al., 1999) and OAT1 and OAT3 on the basolateral side. Sulindac was shown to be the most potent of all NSAIDs tested for OCT1 and 2 inhibition in stably transfected cells (Khamdang et al., 2002). Sulindac also inhibited [3H] MTX transport in MRP2- and MRP4-overexpressing membrane vesicles (El-Sheikh et al., 2007). In addition, sunlindac sulﬁde, a its more toxic sulfated metabolite (Leite et al., 2006), was shown to be a potent inhibitor of MRP4-mediated LCT B4 and C4 transport in MRP4-overexpressing membrane vesicles (Rius et al., 2008). Simialrly, sulindac and its metabolites inhibits Ntcp/NTCP, Oatps/ OATPs, Bsep, Bcrp, and MRP2 in rat and/or human hepatocytes (Lee et al., 2010b). As in the case of troglitazone, BSEP inhibition has been also proposed as a contributing factor for sulindac-induced cholestasis (Stieger et al., 2000). Additionally, mitochondrial uncoupling and ATP depletion are proposed mechanistic events associated with hepatic toxicity by sulindac sulﬁde, but not sulindac sulfone or sulindac itself (Leite et al., 2006). TNF-alpha has been shown to enhance cytotoxicity by sulindac sulﬁde in primary hepatocytes, HepG2 cells, as well as in vivo (Zou et al., 2009, 2010). Sulindac and sulindac sulphone, an inactive metabolite of this drug, inhibit [3H]-LTC4 transport in inside-out plasma membrane vesicles generated from the MRP-overexpressing cell line HL60/ADR (Duffy et al., 1998). The same study demonstrated that the combination of nontoxic doses of sulindac with certain anthracycline-type chemotherapeutic drugs enhances their cytotoxicity. A similar effect was also observed with teniposide, VP-16 and vincristine in a human cancer cell line. It was subsequently established that co-administration of nontoxic doses of suldinac with doxorubicin signiﬁcantly potentiates tumor growth inhibitory activity in an MRP1-overexpressing human tumor xenograft model (O’Connor et al., 2004). Then, a dose-escalating, single arm prospective open label, nonrandomized phase I clinical trial of epirubicin in combination with escalating oral doses of sulindac in patients with advanced cancer was conducted to select the appropriated concentration of sundilac to perform a phase 2 clinical study (O’Connor et al., 2007). These reports highlight the innovative uses of sulindac in combination cancer chemotherapy by exploiting its afﬁnity and interaction with Mrp1, an important genetic determinant of cancer multidrug resistance.

2.09.3.5.5

Bromobenzene

Bromobenzene, an industrial solvent that is also used as an additive in motor oils, causes hepatotoxicity following biotransformation in the liver by CYP450 enzymes to its reactive, toxic metabolite bromobenzene 3,4-epoxide. Following depletion of GSH, covalent binding of reactive metabolites to cellular macromolecules in addition to oxidative stress and lipid peroxidation ensues, ultimately resulting in centrilobular hepatocyte necrosis (Lau and Monks, 1988). Levels of liver Mrp1 and Mrp3 mRNA are higher in rats treated with bromobenzene (Heijne et al., 2004). Elevated Mrp3 gene expression was also observed in rat liver with repeated bromobenzene treatment. Repeated exposure to bromobenzene also results in the development of tolerance to hepatotoxicity, suggesting that increased Mrp3 may help contribute to this acquired resistance (Tanaka et al., 2007).

2.09.3.5.6

Phalloidin

Phalloidin is a member of the group of phallotoxins produced by the mushroom Amanita phalloides, which binds to F-actin and prevents its depolymerization, resulting in cytotoxicity (Wieland, 1983). This poison causes hepatotoxicity, characterized by cholestasis, because it is selectively taken up by hepatocytes where it is then able to bind to F-actin (Loranger et al., 1996; Munter et al., 1986). The hepatocyte-speciﬁc transporter OATP1B1/SLC21A6 was identiﬁed as the transporter responsible for hepatocyte uptake of phalloidin. MRP2 is responsible for its biliary excretion (Fehrenbach et al., 2003). It was later demonstrated that rat Oatp1b2, human OATP1B1, and OATP1B3 are all capable of transporting phalloidin across the basolateral hepatocyte membrane, with OATP1B1 being the major phalloidin uptake system in human liver (Meier-Abt et al., 2004). The role of Oatp-mediated phalloidin uptake in hepatotoxicity was demonstrated in Oatp1b2-null mice, which were completely resistant to liver injury (Lu et al., 2008). Altered actin ﬁlament organization has also been shown to alter the localization and distribution of canalicular transport proteins. More speciﬁcally, the canalicular localization of Mrp2 is impaired in phalloidin-treated rats (Rost et al., 1999). Consequently, in addition to causing hepatocellular injury by preventing actin depolymerization, loss of Mrp2 from the canalicular domain also contributes to the pathogenesis of acute phalloidin-induced cholestasis (Rost et al., 1999).

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2.09.3.6

Regulation of Hepatobiliary Transporters During Liver Injury

Hepatocellular Carcinoma (HCC)

HCC is the most frequent primary malignancy of the liver and is the sixth most common form of cancer worldwide (Jemal et al., 2011). Resistance to chemotherapeutic drugs such as anthracyclines and vinca alkaloids is a critical problem in treating HCC. One explanation for the low response rate of HCC to chemotherapy may be overexpression of xenobiotic transporters, which can result in a decreased intracellular retention of anticancer drugs by decreased uptake and/or increased efﬂux. Early work performed in rodents revealed Mdr1a overexpression in carcinogen-induced preneoplastic liver nodules (Fairchild et al., 1987; Teeter et al., 1990). Similarly, Mdr1a mRNA was elevated in tumors that developed spontaneously in C3H/H3N mice and in transgenic mice expressing the hepatitis B virus envelope protein (Teeter et al., 1990). Subsequent clinical analysis identiﬁed higher MDR1 mRNA in HCC compared to non-tumorous liver tissue (Bonin et al., 2002; Grude et al., 2002; Kato et al., 2001; Chenivesse et al., 1993). Overexpression of MDR1 correlated with larger tumor size and reduced overall survival rate (Kato et al., 2001). Immunohistochemical analysis demonstrated distinct staining patterns of MDR/Pgp in the various types of HCC. Pgp protein was detected on the cellular surface facing the blood space in the trabecular type of HCC and on the luminal surface in the pseudoglandular type of HCC. By contrast, little staining of Pgp is observed in the compact-type HCC (Itsubo et al., 1994). Similarly, ABCG2 gene expression increases in HCC patients compares to control tissues. Also, ABCG2 expression was greater in poorly differentiated grade than in well-differentiated HCC (Chen et al., 2016b; Sukowati et al., 2012). In contrast to MDR1, MDR3 mRNA expression is unchanged in HCC specimens (Bonin et al., 2002; Nies et al., 2001). Researchers have developed radiopharmaceuticals to estimate the expression of MDR and MRP transporters in HCC tumors prior to and following chemotherapy. Knowledge of MDR and MRP status enables clinicians to design more appropriate and effective treatment regimens. Correlations between the cellular accumulation of the cationic lipophilic agents, 99mTcmethoxyisobutylisonitrile and 99mTc-tetrofsomin, in HCC tumors and expression of MDR and MRP isoforms have been performed (Ding et al., 2003). In studies of patients with HCC, expression of Pgp is inversely correlated with uptake and accumulation of 99m Tc-methoxyisobutylisonitrile in tumors (Wang et al., 2004; Chang et al., 2003). By contrast, no relationship between MRP1 expression and 99mTc-methoxyisobutylisonitrile clearance was observed (Wang et al., 2004; Chang et al., 2003). A similar correlation has been shown for Pgp expression and 99mTc-tetrofsomin accumulation (Ding et al., 2003). There are contradictory studies that demonstrate highly variable transporter expression in normal liver and HCC specimens. No statistical differences are observed in MRP2, MRP3, BSEP, and MDR1 mRNA and protein expression between HCC and nontumorous tissues (Zollner et al., 2005b; Nies et al., 2001). By contrast, Bonin et al. demonstrate increased MRP1 and MRP2 mRNA in HCC specimens (Bonin et al., 2002). Immunohistochemical staining of well-differentiated HCC specimens demonstrates apical MRP2 with irregular staining (Fig. 10). No MRP2 protein is observed in undifferentiated HCC. Due to the molecular heterogeneity of HCC, it is not surprising that inconsistencies in transporters expression and staining patters have been observed. Therefore, additional studies are necessary to correlate transporter expression with clinical outcomes. Due to the difﬁculties associated with the treatment of HCC, novel therapeutic drug delivery systems are being developed. One area of active research inquiry is aimed at targeting cytotoxic drugs to the liver by adding bile acid moieties to conventional chemotherapeutic agents. Efﬁcacy of this type of delivery system is dependent upon normal expression of bile acid uptake carriers in malignant cells. Unfortunately, research suggests that this is not the case. mRNA and protein expression of OATP1B1 and 1B3 is reduced in HCC cases (Zollner et al., 2005b; Cui et al., 2003; Kinoshita and Miyata, 2002). Using immunohistochemical staining, residual expression of OATP1B1 and 1B3 protein in HCC is focal and variable (Cui et al., 2003). Similarly, NTCP levels are reduced in HCC to 41% of nontumorous tissue (Zollner et al., 2005b). Additionally, mRNA expression of OCT1 (SLC22A1) is downregulated in HCC (Heise et al., 2012; Martinez-Becerra et al., 2012; Schaeffeler et al., 2011; Chang et al., 2009; Park et al., 2006; Okabe et al., 2001). This decrease in OCT1 expression has been conﬁrmed immunohistochemically in HCC tissue samples (Schaeffeler et al., 2011). The same authors also demonstrated that low mRNA and protein expression of OCT1 in HCC tissues is due gene promoter hypermethylation, when compared to adjacent non-tumor or normal human liver samples (Schaeffeler et al., 2011). Also, lower OCT1 expression is associated with advanced tumor stages and poorer patient outcomes (Heise et al., 2012). These authors also demonstrated that tumors with low OCT1 expression showed a higher SLC22A3 expression (Heise et al., 2012), which is in contrast to the physiological state of high SLC22A1 and low SLC22A3 expression. Given these reductions in uptake carrier expression proﬁles, the liver-speciﬁc therapeutic strategy of coupling chemotherapeutics to bile acids to treat malignancies such as HCC has become less attractive. More recently, preclinical studies employing novel drug deliverey systems have been carried out (see review by Li et al., 2016; Zhang et al., 2016c). They involve active targeting triggered by ligands that are recognized and internalized into hepatoma cells with high speciﬁcity and efﬁciency. The desired targets are overexpresed genes in HCC cells that play a role in HCC development and/or resistance to coventional treatment. For example, the high expression of MDR and BCRP results in the poor response of HCC to chemotherapy (Sun et al., 2010; Chenivesse et al., 1993). Therefore, new therapeutic approachs to treat HCC cells have been designed using delivery systems that are co-loaded with both siRNAs for MDR1 or BCRP (Huang et al., 2013; Li et al., 2012) and chemotherapeutic agents or multiple complementary chemotherapeutic agents to HCC (Jin et al., 2016). However, this type of targeted drug delivery systems for HCC has yet to be tested in the clinical setting.

2.09.3.7

Ischemia–Reperfusion Injury

Hepatic ischemia followed by tissue reperfusion is a complication of liver resection surgery, transplantation, hypovolemic shock, intra-arterial chemotherapy, and embolization. Two major types hepatic ischemia can be distinguished, the ‘warm’ type, which

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Fig. 10 MRP2 staining in HCC specimens. Immunohistochemical detection of MRP2 in control liver (A) and HCC (B–D). A Control liver: canalicular localization of MRP2. B Well-differentiated HCC: polarized MRP2 expression in most carcinoma cells in a linear, often irregular pattern. C Welldifferentiated HCC: polarized MRP2 expression at the luminal site of carcinoma cells with pronounced pseudoglandular arrangement. D Undifferentiated HCC: complete absence of MRP2; note malignant cells with giant nuclei. Original magniﬁcations: 530 (a,b); 265 (c,d). Modiﬁed from Fig. 1 of Nies, A. T.; Konig, J.; Pfannschmidt, M.; Klar, E.; Hofmann, W. J.; Keppler, D. Int. J. Cancer 2001, 94 (4), 492–499.

is initiated by hepatocellular damage, develops in situ during liver transplantation surgery or during various forms of shock or trauma, and might lead to liver or even multi-organ failure. The ‘cold’ type, which is initiated by damage to hepatic sinusoidal endothelial cells and disruption of microcirculation, occurs during ex vivo tissue preservation and is usually coupled with warm hepatic ischemia during liver transplantation surgery (Zhai et al., 2013). Although initial cellular targets of the two hepatic ischemia types might be different, they do share a common mechanism in the disease etiology; that is, local innate immune system activation. Prominent features of ischemia-mediated injury include hypoxia (as indicated by elevated vascular endothelial growth factor, VEGF), Kupffer cell activation, and cholestasis. Warm and cold hepatic ischemia can be mimicked surgically in rodents (Zhai et al., 2013; Mendes-Braz et al., 2012) to study different parameters, including the expression and function of ABC transporters. Within 6–24 h following hepatic ischemia in rats (with or without reperfusion), hepatic VEGF mRNA and serum TNF-a, IL-1b, and IL-6 are elevated (Fouassier et al., 2007; Tanaka et al., 2006). Biomarkers of cholestasis, such as serum transaminases, bilirubin, and bile acids are similarly increased. There are parallel declines in bile ﬂow and biliary bile acid output in ischemic rats, which is indicative of abnormal liver function. With regard to transporters, ischemia reduces levels of Ntcp, Oatp1a1, Oatp1a4, Oatp1b2, Bsep, and Mrp2 mRNA in rats (Tanaka et al., 2008; Fouassier et al., 2007; Tanaka et al., 2006). Similarly, exposure of cultured hepatocytes to hypoxic conditions reduces mRNA and protein expression of Ntcp, Bsep, and Mrp2 (Fouassier et al., 2007). Additionally, Mrp2 becomes internalized from its normal canalicular localization during hepatic ischemic injury (Donner et al., 2013; Ban et al., 2009; Kudo et al., 2004). Also, coordinated zonal downregulation of Bsep and Ntcp in pericentral hepatocytes has been described as another potential mechanism for hepatocellular cholestasis in the post-cold ischemic rat liver (Donner et al., 2013). Warm hepatic ischemia reperfusion injury leads to a signiﬁcant decrease in the hepatobiliary disposition of rhodamine-123, a maker of Pgp function, and its glucuronidated metabolite, which is excreted into the bile via Mrp2, at 24 h after reperfusion in the isolated liver (Parasrampuria et al., 2012). In the same model of ischemia-reperfusion, a decrease in Pgp protein expression was reported after 48 h of reperfusion in vivo. Interestingly the same report detected no changes in Mdr1 mRNA, indicative of a postranscriptional regulation of Pgp in this model (Thorling et al., 2014). This study also reported an increased in Rhodamine 123 liver accumulation 24 h after reperfusion. Parasrampuria et al. (2012) showed that the biliary excretion of rhodamine 123 and its glucuronide conjugate returns to normal levels after 72 h of reperfusion. Contrary to these results, hepatic ischemia has been reported to elevate hepatic Mdr1b mRNA (Tanaka et al., 2008;

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Miah et al., 2014) and Pgp protein levels ( 20%) (Ikemura et al., 2009). These discrepancies could be explained by a report from Miah et al. (2014), showing that althought Pgp protein levels in liver membrane fractions were signiﬁcantly upregulated after 24 h of hepatic ischemia, an opposite and concurrent effect on hepatic ATP concentrations, the indispensable energy source to drive ATP function, is also observed. Interestingly, hepatic ischemia–reperfusion injury is accompanied by upregulation of Mrp2 and Mrp4 mRNA and protein in kidneys (Tanaka et al., 2008). These data suggest that there is a shift from biliary to renal excretion of chemicals generated by hepatic ischemia and reperfusion.

2.09.3.8

Hepatitis B Virus Infection

Chronic hepatitis B virus (HBV) infection is one of the major risk factors for the development of HCC (Ayub et al., 2013). HBV enters into hepatocytes via speciﬁc viral receptors, NTCP and the hepatic asialoglycoprotein receptor (Yang et al., 2006; Treichel et al., 1997). Recently, Yan et al. (2012) demonstrated that the pre-S1 domain of the large envelope protein of the HBV, is a key determinant for receptor(s) binding and that this speciﬁc region interacts with NTCP by using near zero distance photo-cross-linking and tandem afﬁnity puriﬁcation. Additionally, the same authors demonstrated that silencing NTCP inhibits both HBV and HDV infections, while overexpression of NTCP transformed nonsusceptible hepatocarcinoma cells to be susceptible of these viral infections (Ni et al., 2014; Yan et al., 2012). NTCP is mainly or exclusively expressed in the liver, and this membrane protein is at least one of the factors determining the species speciﬁcity and hepatotropism of HBV (Li and Tong 2015; Yan et al., 2012). Two shortsequence motifs in human NTCP have been identiﬁed to be required for species speciﬁcity (Ni et al., 2014). Other evidence that supports the role of NTCP in the pathophysiology of HBV is that its inhibitors (cyclosporine A, ibersartan, ritonavir, Vanitaracin A) or substrates (bile salts) could inhibit HBV or HDV infection in NTCP-reconstituted cells, HepaRG cells and Tupaia hepatocytes (Kaneko et al., 2015; Veloso Alves Pereira et al., 2015; Yan et al., 2014; Nkongolo et al., 2014; Ni et al., 2014). NTCP inhibition prevents the spread of HBV-infected hepatocytes in mice with a humanized liver (Nakabori et al., 2016). The main ﬂavonoid present in green tea extract, epigallocatechin-3-gallate, was described as an inhibitor of HBV entry into immortalized human primary hepatocytes (Huang et al., 2014). Interestingly, this compound induced clathrin-dependent endocytosis of NTCP from the plasma membrane followed by protein degradation. An association between NTCP polymorphisms and susceptibility to HVB infection has also been estalished (Yang et al., 2016; Hu et al., 2015; Peng et al., 2015). A highly signiﬁcant association of the Ser267 / Phe variant with healthy status and resistance to chronic hepatitis B clearly points out toward the protective role of this genetic variant in HBV infection (Hu et al., 2015; Peng et al., 2015). The presence of the rs4646287-T polymorphism, which is located in the ﬁrst intron, approximately 1 kb downstream of the ﬁrst exon, may also be an important variant that inﬂuences NTCP expression (Yang et al., 2016). The authors found that C> T introduced a new DNA binding site for p300, which might decrease the expression and hence function of NTCP, suggesting to be a protective factor in response to the HBV infection.

2.09.3.9

Hepatitis C Virus Infection

The hepatitis C virus (HCV) is now recognized as the most common chronic blood-borne pathogen in the United States (Alter et al., 1999). The prevalence of this viral infection is 2–3% world-wide, affecting 130–170 million people (Lavanchy, 2011). Although the incidence of HCV infection has declined markedly in the past 2 decades, chronic infection in approximately 3 million residents in the United States now accounts for more disease and deaths than does the HIV (Klevens et al., 2012). 17% of individuals infected with HCV will progress to cirrhosis, HCC, and liver failure. Given the high incidence of HCV infection in the general population, it is critical to understand the inﬂuence of viral hepatitis on hepatobiliary transporter expression since altered regulation of transporters could impact drug disposition and susceptibility of HCV-infected patients to liver damage. There are conﬂicting data regarding expression of MRP and MDR isoforms in HCV-infected patients. A study of four noninfected and six HCV-infected individuals at the University of Leuven (Leuven, Belgium) demonstrated upregulation of MDR1 and MRP3 mRNA in HCV patients, with stable gene expression of MDR3, MRP1, MRP2, and BSEP (Ros et al., 2003a). In line with these data, Dumoulin et al. conﬁrmed a lack of change in MDR3 in HCV patients (Dumoulin et al., 1997). In a study of 18 noninfected and 24 HCV-infected Japanese individuals, expression of MRP2 mRNA and protein was reduced in HCV-infected patients (Hinoshita et al., 2001). MRP2 mRNA inversely correlated with the degree of HCV activity and inﬂammation. There are similar trends of reduced MDR1, MDR3, MRP1, and MRP3 mRNA in HCV-infected livers, although these decreases did not reach statistical signiﬁcance. By contrast, Ogasawara et al. (2010) reported that in HCV-infected patients, mRNA levels of OCT1 and OATP1B1 tended to decrease according to ﬁbrosis stage progression. The same report also demonstrated lower levels of MATE1, MRP2 and BCRP in HCV, whereas PGP, MRP1 and MRP4 expression levels were higher. Another study performed in 18 HCV patients and 12 controls (Kurzawski et al., 2012) showed increased Mrp3, Mrp4 and Pgp, and decreased Bcrp gene expression. The induction of Mrp4 protein expression was conﬁrmed by immunohistochemistry. Differential results in hepatic transporters expression have been reported in vitro studies. With the use of cell lines expressing the HCV replicon, it was demonstrated that HCV replication transcriptionally increased MRP2 expression primarily through increased interaction of HNF1 with the MRP2 promoter (Qadri et al., 2006). A dose-dependent down-regulation of MDR1 expression has been also documented in hepatoma cells expressing the HCV nonstructural 5A (NS5A) phosphoprotein. In contrast, a signiﬁcant increase in Bcrp expression by both the HCV replicon and NS5A cell systems was recorded, which was in agreement with the results

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of functional dye efﬂux assay (Rivero et al., 2013). Additional studies are necessary to clarify these conﬂicting data and expand our knowledge of how HCV infection inﬂuences hepatobiliary transporter expression. Interestingly, a recent study in Huh7.5 hepatoma cells shows that pharmacological induction of ABCA1 expression with the liver X receptor receptor agonist GW3965 impairs HCV infection (Bocchetta et al., 2014). The authors demonstrated that enhanced cholesterol efﬂux by ABCA1 induction disrupts membrane cholesterol homeostasis, leading to inhibition of virus–cell fusion and HCV cell entry. This ﬁnding was conﬁrmed using human primary hepatocytes, leading to the proposal of modulating ABCA1 function as a potential target for controlling HCV infectivity (Bocchetta et al., 2014). Finally it is important to point out that the presence of polymorphic forms of Bsep or Mdr1 can be associated with the progression of HCV disease (Iwata et al., 2011a,b) and differences in effectiveness of HCV treatment (Cusato et al., 2015; Fujita et al., 2013; Iwata et al., 2011a) consisting of a combination of telaprevir, pegylated interferon and ribavirin.

2.09.3.10 Liver Regeneration The liver has the ability to regenerate. There are a number of stimuli that activate normally quiescent hepatocytes to undergo cell division. Chemical exposure to nonlethal doses of toxicants such as APAP and carbon tetrachloride causes hepatocytes to undergo mitosis to repopulate the liver lobule. During severe liver injury, partial tissue resection or when parenchymal cell proliferation is inhibited, progenitor cells become activated and proliferate to replace hepatocytes and cholangiocytes. In addition to chemicalinduced damage, hepatic regeneration can be modeled in rodents using surgical removal of 70% of the liver, the most common (partial hepatectomy; PHx), or 90% of the liver mass (massive hepatectomy; MHx) (Meier et al., 2016). Sham-operated rodents are typically used as controls for these experiments. Within 24–36 h of removing three liver lobes, parenchymal cells undergo synchronized DNA synthesis and cell division. By 7–14 days, the original liver cell mass is restored and hepatocytes return to quiescence. This model is used to simulate what happens in humans after liver transplantation because post-operative liver damage, including marked cholestasis and various degrees of portal hypertension with prolonged hyperbilirubinemia during liver regeneration, is one of the major hurdles to expand the indications for liver surgery (Kawasaki et al., 1998; Emond et al., 1996). In rats, bile ﬂow and biliary secretion of bile acids are increased within 24 h after PHx (Vos et al., 1999: Hoshino et al., 1995). By contrast, biliary secretion of GSH is reduced. It is important to note that these parameters are expressed as secretion into bile per gram of liver, rather than normalized to total body weight, while bile ﬂow and bile salt secretion per 100 g body weight did not change. Other authors have reported similar ﬁndings in mice (Csanaky et al., 2009). Similarly, bile acid and total bilirubin levels are elevated in plasma of rats 24 h after PHx (Chang et al., 2004; Vos et al., 1999). Taken together, these data suggest that hepatocytes adapt to cell loss by differentially regulating bile acid transporters in an attempt to reduce accumulation of toxic bile acids in remnant hepatocytes. Compared to sham-operated rats, remnant livers from PHx rats demonstrate early reductions (3–24 h) in the mRNA expression of Oatp1a1, Oatp1a4, and Ntcp, which are restored to normal levels by 2–4 days (Gerloff et al., 1999; Vos et al., 1999). Gerloff et al. (1999) report a decrease in Oatp1a1 protein from 1 to 4 days following PHx, although no change was observed by Vos et al. (1999). Microarray analysis conﬁrmed reduced mRNA levels of Oatp1a4, Oatp1b2, and Ntcp in rat livers between 12 and 48 h after PHx (Dransfeld et al., 2005). Downregulation of Oatp1, Oatp2, Oatp4 and Ntcp mRNA expression after 24 h of PHx, returing to normal values by 168 h, was also reported in MHx performed in rats by Kimura et al. (2012). Interestingly, Oatp1a6 mRNA is induced by 3 h and remains elevated over a 48 h period (Dransfeld et al., 2005). Reduced expression of Ntcp and Oatp isoforms corresponds with reduced taurocholate uptake in basolateral plasma membrane vesicles generated from rat liver following PHx (Gerloff et al., 1999; Vos et al., 1999; Green et al., 1997). There are conﬂicting reports regarding expression of canalicular Bsep and Mrp2 transport proteins after PHx. Differences in transporter expression proﬁles following PHx may be related to the different strains of rodents and species used in the different studies. In Wistar rats, hepatocyte expression of Bsep and Mrp2 mRNA and protein is fairly stable 24 h after PHx (Dransfeld et al., 2005; Ros et al., 2003b; Vos et al., 1999). In addition, the subcellular localization of Bsep and Mrp2 to the canalicular membrane is not affected by PHx (Dransfeld et al., 2005). By contrast, PHx increases Bsep and Mrp2 proteins in some reports between 12 h and 2 days in Sprague–Dawley rats (Gerloff et al., 1999), whereas a marked reduction in Mrp2 has been described at the protein and mRNA level by other studies (Kimura et al., 2012; Chang et al., 2004). Interestingly, increased Bsep and Mrp2 mRNA levels are not observed until 2–4 days, suggesting that early protein changes occur through posttranscriptional processes (Gerloff et al., 1999). Similar increases in Bsep mRNA are seen in mice following PHx (Huang et al., 2006). Normal or enhanced Bsep and Mrp2 expression after PHx is consistent with functional bile ﬂow and bile acid excretion in the remnant liver and the need of an animal with a smaller liver mass to transport the same pool of bile acids, endo-, and xenobiotics encountered in animals with regular liver mass. In mice, PHx produces also an increase in serum bile acids with conservation of Ntcp expression and increased Bsep, Mrp3 and Mrp2 abundance (Csanaky et al., 2009). A decreased Mrp2 expression was also reported in MHx which is associated with increased serum levels of bile salts resulting from a a shift in vectorial excretion (Miura et al., 2011). Dramatic increases in Mdr1b are observed within 3 h following PHx, which persist through 48 h (Vos et al., 1999). Levels of Mdr1b increase approximately 40-fold in rat liver after PHx, with no change in Mdr1a (Ros et al., 2003b; Vos et al., 1999). Mdr2 mRNA is unchanged at 24 h after PHx. This corresponds with unaltered phospholipid secretion into the bile (Vos et al., 1999). By 48 h, Mdr2 mRNA increases (Csanaky et al., 2009). In MHx, Bcrp expression is also increased as in PHx rats (Kimura et al., 2012). Expression of basolateral Mrp1 and Mrp3 transporters is induced in rats following PHx. Mrp1 mRNA expression is enhanced within 3 h following PHx and remains elevated at 48 h (Vos et al., 1999). Mrp3 protein is dramatically upregulated in remnant

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livers from rats following 70% and 90% liver removal (Chang et al., 2004). These protein expression ﬁndings are consistent with gene expression changes. Mrp1 and Mrp3 mRNA tended to be overexpressed in regenerating liver after MHx in rats (Kimura et al., 2012). mRNA analysis also revealed a twofold increase in Mrp4 in rat hepatocytes 24 h after PHx (Ros et al., 2003b). On day one after PHx, a transient doubling of serum bile salts is observed in association with down-regulation of the bile acid uptake protein Ntcp and up-regulation of Mrp4 and Cyp7A1 (Miura et al., 2011). Since Mrp3 and Mrp4 transport mono- and bivalent bile acids, overexpression of these transporters in response to PHx likely contributes to enhanced basolateral egress and elevated plasma bile acid levels. From the intestine, BA are actively absorbed and return to the liver through enterohepatic circulation. Mrp3, which is located in the enterocyte basolateral membrane, is responsible for the transport of bile acids from enterocytes into the blood (Hofmann, 2009). Enterohepatic recirculation of bile acids is necessary for liver PXR activation and tissue regeneration (Huang et al., 2006). Furthermore, early acute increase in blood bile acids concentrations may also constitute a previously unrecognized endocrine signal to trigger liver regeneration after PH (Doignon et al., 2011). Interestingly, the lack of Mrp3 delays bile acids-induced hepatocyte proliferation and liver regeneration after PHx. This was demonstrated with the use of Mrp3 null mice (FernándezBarrena et al., 2012). This effect is due to reduced FXR activation in liver after cholic acid administration in these knockout mice, which could in turn be associated with a decrease in bile acids absorption from intestine and a subsequent decreased in their concentration in the enterohepatic circulation. Subsequent experiments explored the expression of hepatic efﬂux transporters in rat liver progenitor cells. Pretreatment of rats with 2-acetyl-aminoﬂuorene prior to PHx prevented hepatocytes from dividing and in turn activated proliferation of progenitor cells in the liver, also known as oval cells. Evaluation of livers 9 days after PHx revealed elevated expression of Mdr1b, Mdr2, Mrp1, and Mrp4 mRNA compared to vehicle-treated, sham-operated controls (Ros et al., 2003b). Collectively, these data suggest that efﬂux transporter expression can be stimulated in hepatocytes and progenitor cells during liver regeneration and that the speciﬁc cell type engaged in proliferation and transporter expression is dependent upon the degree of tissue injury. In conclusion, despite some differences among rodent species, PHx results in serum bile salts elevations due to decreased liver uptake and increased efﬂux, while biliary bile acids efﬂux is either conserved or increased. Modulation of ABC transporters during regeneration following tissue mass loss is crucial for maintaining adequate levels of intrahepatic bile acids. FXR is the primary sensor of bile acids, and liver regeneration after PHx is defective in FXR / mice (Huang et al., 2006). Increases in intrahepatic concentration of bile acids to optimal values could induce FXR and contribute, at least in part, to liver regeneration, but modulation of ABC transporters during tissue mass loss can also contribute to maintaining intrahepatic levels of bile acids that are not cytotoxic, but stimulatory of hepatic regeneration (Zhang et al., 2009).

2.09.4

Signaling Pathways Underlying Transporter Expression During Liver Injury

2.09.4.1

Transcriptional Regulation via Nuclear Hormone Receptors

Transcriptional regulation of transporters during liver injury is mediated in part by nuclear hormone receptors. These ligandactivated receptors dimerize with retinoic acid X receptor a and bind to cognate response elements in the upstream regions of target genes. FXR, pregnane X receptor (PXR, NR1I2), and constitutive androstane receptor (CAR, NR1I3) appear to be particularly important in regulating transporters during periods of cholestatic liver injury. FXR is a bile acid sensor and a key regulator of hepatic transporters in response to accumulating bile acids (particularly during periods of cholestasis). FXR transactivates the Bsep gene (Ananthanarayanan et al., 2001; Plass et al., 2002; Yu et al., 2002a). Basal Bsep protein levels are reduced in livers from FXR-null mice (Zollner et al., 2003a). Similarly, induction of Bsep mRNA following BDL, PHx, cholic acid feeding, or treatment with ANIT is absent in FXR-null mice (Cui et al., 2009; Huang et al., 2006; Wagner et al., 2003; Zollner et al., 2003a). In addition to Bsep, FXR is necessary for upregulation of Ostb expression during BDL- and ANITinduced injury (Cui et al., 2009; Boyer et al., 2006). In contrast to the positive regulation of Bsep and Ostb by FXR, Ntcp expression is negatively controlled by this nuclear receptor. Downregulation of Ntcp mRNA is lost in FXR-null mice after BDL and cholic acid feeding, suggesting that its regulation occurs via FXR signaling in response to elevated bile acid concentrations (Zollner et al., 2005a). Additionally, four FXR splice variants (FXRa1–4) were recently described, showing differences in spatial and temporal expression as well as transcriptional activity (Zhang et al., 2003; Huber et al., 2002). BSEP is regulated by FXR in an isoformdependent manner. FXRa2 exhibits a much more potent activity than FXRa1 in transactivating human BSEP, both in vitro and in vivo (Song et al., 2008). The ratio of FXRa1/FXRa2 has been associated with BSEP expression in HCC tumors, and hepatoma Huh 7 and HepG2 cells (Chen et al., 2013b). In studies where individual expression of FXRa2 or FXRa4 was reinstated in FXR/ KO mice using liver-speciﬁc self-complementary adeno-associated viral vectors, higher Abcb11/Bsep expression and bile ﬂow were observed in FXRa2 than in FXRa4 expressing mice (Boesjes et al., 2014). PXR is also a sensor of bile acids as well as xenobiotics. Induction of liver Oatp1a4 mRNA occurs in wild-type mice treated with PXR ligands with no change observed in PXR-null mice (Cheng and Klaassen, 2006; Staudinger et al., 2001a,b, 2003). Transactivation of the Oatp1a4 gene is mediated by direct binding of PXR to its promoter (Guo et al., 2002b). Induction of Oatp1a4 mRNA during BDL and lithocholic acid-induced cholestasis is dependent upon PXR expression (Stedman et al., 2005; Zhang et al., 2004). In addition to Oatp1a4, PXR likely participates in the regulation of Mrp2. Activation of PXR using spironolactone in conjunction with EE exposure restores bile ﬂow and biliary excretion of GSH. Improved liver injury in these animals is accompanied by induction of Mrp2 mRNA and protein (Ruiz et al., 2007). Similarly, ANIT-induced upregulation of Mrp2 mRNA is not observed in PXRnull mice (Cui et 2009). Decreased expression of Mrp2 resulting from endotoxin-induced injury is absent in PXR-null mice

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suggesting that PXR possesses differential roles in the regulation of Mrp2 during cholestasis (Teng and Piquette-Miller, 2005). The identiﬁcation of alternative splicing and transcript variants of PXR (PXR1–4) in human livers has led to the postulation that these variants, which may have different transactivation activity, could contribute to the interindividual variability in the expression of efﬂux transporters, such Pgp (Fukuen et al., 2002). PXR2 binds to to its DNA response elements but fails to activate the expression of PXR target genes in response to PXR ligands (Lin et al., 2009). Instead, PXR2 functions as a dominant negative cofactor repressing PXR1 function. Similarly, PXR3 and PXR4 lack transcriptional activity in inducing target gene expression (Breuker et al., 2014). Thus, it is possible to speculate that the relative expression levels of PXR transcript variants in liver may affect ABC prrotein expression and overall pharmacokinetics of chemotherapeutic agents. A complete review of PXR variants and their functions can be found in Brewer and Chen (2016). An important role for CAR activation in the detoxiﬁcation of bile acids was ﬁrst noted in FXR:PXR double knockout mice (Guo et al., 2003b). In the absence of FXR and PXR, CAR-mediated signaling pathways are activated in response to cholic acid. Furthermore, treatment of mice with a CAR ligand partially protects mice from cholic acid toxicity (Guo et al., 2003b). During lithocholic acid-induced injury, induction of Mrp3 mRNA is absent in CAR-null mice (Zhang et al., 2004). It is well establised that prototypical inducers of CAR signaling increase the expression of numerous transporters including Mrp2, 3, 4, 6, and Oatp1a4 (Aleksunes et al., 2012; Maher et al., 2005b; Assem et al., 2004; Guo et al., 2002a; Kast et al., 2002). Furthermore, a statistically positive correlation between CAR nuclear translocation and MRP4 mRNA expression in liver samples of patients with obstructive cholestasis has been established (Chai et al., 2011). The role of CAR in modulating the expression of ABCG2 is also well established. Jigorel et al. (2006) reported that phenobarbital, a CAR activator, induces ABCG2 mRNA levels in cultured human hepatocytes. In addition, treatment of epileptic patients with carbamazepine, another human CAR activator, increases liver ABCG2 mRNA levels (Oscarson et al., 2006). Finally, Benoki et al. (2012) demonstrated that CAR transactivates ABCG2 through the DR5 motif located in its distal promoter in human hepatocytes.

2.09.4.2

Transcriptional Regulation via Transcription Factors

In addition to ligand-activated nuclear receptors, transcription factors also participate in the regulation of hepatobiliary transporter expression during liver injury. Some of these factors include the hepatocyte nuclear factor 1a (HNF1a) and CCAAT/enhancer binding protein (C/EBP) as well as the oxidative stress sensor, Nrf2. As a member of the liver-enriched transcription factor family, HNF1a regulates the expression of genes involved in carbohydrate and lipid metabolism, albumin production, and detoxiﬁcation (Cereghini, 1996). Regulation of hepatic transporter gene expression is a novel function identiﬁed for HNF1a. Livers from rats treated with CCl4, endotoxin, or EE have reduced HNF1a binding activity and lower Ntcp mRNA levels (Geier et al. 2002b, 2003a; Trauner et al. 1998). HNF1a appears to be important in modulating rat Ntcp but not the mouse or human genes (Jung et al., 2004; Karpen et al., 1996). Although mice lacking HNF1a have unaltered hepatic Ntcp expression, they do express reduced levels of Oatp1a1 and 1b2 mRNA, which correlates with elevated serum bile acid levels (Maher et al., 2006; Shih et al., 2001). Similarly, human OATP1B1 and 1B3 are regulated by HNF1a (Ohtsuka et al., 2006; Jung et al., 2001). HNF1a binding to the mouse Oatp1b2 promoter is decreased within 2 h after LPS (Li and Klaassen, 2004). Regulation of Ntcp and Oatp genes by HNF1a may be one mechanism for the liver-predominant expression of these transporters. C/EBPa and b are basic region-leucine zipper transcription factors that regulate a number of cell processes including cellular differentiation and cell cycle. The location of putative binding sites as well as the transcriptional activation of human NTCP, MDR3, and MRP2 via C/EBP isoforms have been reported (Shiao et al., 2000; Smit et al., 1995; Tanaka et al., 1999). In addition to reduced HNF1a binding during endotoxin- and 17a-EE-induced cholestasis, levels of C/EBP are lower, which may also account for decreases in Oatp1b2 and Ntcp mRNA (Li and Klaassen, 2004; Geier et al., 2003a). The transcription factor Nrf2 belongs to the basic region-leucine zipper family and is activated in response to electrophiles and reactive oxygen species. During periods of oxidative stress, Nrf2 is released from sequestration in the cytoplasm and translocates to the nucleus. Nrf2 binds antioxidant response elements (AREs) in the regulatory regions of target genes and activates transcription. ARE sequences exist in the mouse Mrp1, Mrp2, Mrp3, and Mrp4 promoters (Hayashi et al., 2003; Maher et al., 2007; Vollrath et al., 2006). Treatment of mice with Nrf2-activating chemicals coordinately induces hepatic Mrp2–6 mRNA (Maher et al., 2007, 2005a). Induction of Mrp3 and Mrp4 mRNA and protein following APAP treatment was shown to be dependent upon Nrf2 expression (Aleksunes et al., 2008a). Regulation of Mrp transporters via Nrf2 suggests that enhanced efﬂux is a component of the coordinated response to cellular oxidative stress.

2.09.4.3 Mechanisms of Regulation of ABC Transporters by Cytokines and the Interplay With Nuclear Receptors, Transcription Factors and Epigenetic Regulation Throughtout this chapter, we have summarized the effects of various liver diseases and pathological conditions in ABC drug transporter modulation. Despite the vastly different etiologies of the acute and chronic liver diseases presented here, such as bile acidinduced cholestasis, xenobiotic-induced liver toxicity, viral hepatitis and hepatocellular carcinomas, many of these conditions share the commmon feature of activation and release of a variety of proinﬂammatory cytokines (Sewnath et al., 2002; Plebani et al., 1999; DeCicco et al., 1998; Buccoleri et al., 1997; Luster et al., 1994; Bird et al., 1990). However, the cytokine patterns differ signiﬁcantly depending on the causative inﬂammatory and/or oxidative stress condition. Although LPS-induced cholestasis is associated with

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increased serum levels of TNF-a, IL-1 and IL-6 (Luster et al., 1994), in obstructive cholestasis only TNF-a and IL-1 increase, with no changes in IL-6 levels (Plebani et al. 1999; Sewnath et al., 2002). Elevated TNF-a has been similarly reported in other forms of liver injury, including alcoholic hepatitis in humans (Bird et al., 1990) and during carbon tetrachloride or (DeCicco et al., 1998: Bruccoleri et al., 1997) or APAP hepatotoxicity in rodents (Guo et al., 2016; Lawson et al., 2000). These cytokines are produced by macrophages, including Kupffer cells. This leads to local ampliﬁcation and prolongation of defensive mechanisms in the damaged liver. However, the cytokine-mediated mechanisms underlying the regulation of hepatocellular transport systems during liver injury is not completely elucidated. In this section we highlight the existing evidence of the mechanisms of action involved in the modulation of transporters expression and function by cytokines. Pharmacological inhibition of TNF-a using entanercept prevents the decrease in liver NTCP, Oatp1 and Oatp2 by CCl4 intoxication in rats (Geier et al., 2003a). The same study also showed that this effect by TNF-a is hepatocyte nuclear factor 1 (HNF1)-dependent, with no effects by other known transactivators such as, C/EBP, PXR, and CAR observed. Furthermore, this study also demosntrated that pharmacological inhibition of IL-1b using anakinra plays only a minor role in modulating expression of basolateral transporters during CCl4 intoxication. By contrast, inhibition of IL-1b in LPS-induced cholestasis prevents decreased Mrp2 expression and NTCP partially, while Oatp1 and Oatp2 seem to be regulated by TNF-a/IL-1b independent pathways. In vitro studies have shown that RXRa/RARa mediates IL-1b-induced down-regulation of Ntcp and Mrp2 genes (Denson et al., 2000; Trauner et al., 1998). Also, endotoxemic rats exhibit increased liver mRNA expression and nuclear translocation of the Y-box binding protein-1 (YB-1), a protein which belongs to the family called cold shock proteins (Mertens et al., 2012). Previously, YB-1 was demonstrated to have binding activity and to work as trans-repressor of Mrp2 gene expression (Geier et al., 2003c). Also, Mertens et al. (2012) reported an increase in YB-1 binding to the Mrp2 promoter in endotoxemic rats, and that this effect is primarily mediated by IL1b and not TNF-a stimulation. Diverse regulatory mechanisms have been described by the same cytokines. Kawase et al. (2014) demonstrated that in adjuvant-induced arthritis, another model of inﬂammation with increased levels of IL-1b, there is also decreased Mrp2 expression associated with reduced plasma membrane localization of radixin, as similarly described in during cholestasis. The same author also demonstrated that the addition of IL-1b to HepG2 cells or primary hepatocytes produces a decrease in mRNA levels of radixin. The contribution of IL-6 in the modulation of ABC transporters was demonstrated using IL6 / knockout mice injected with turpentine, which generates an aseptic inﬂammation or by LPS treatment (Siewert et al., 2004). While a partial and late effect on mRNA expression of Bsep and Ntcp mRNA in endotoxemic IL6 / knockout mice was observed, the absence of IL-6 completely abolished the decrease in Ntcp, Oatp, Mrp2, Mrp3 and Bsep produced by aseptic inﬂammation (Siewert et al., 2004). Chai et al. (2012) studied the mechanism(s) involved in the induction of hepatic MRP3 expression (mRNA and protein) in patients with obstructive cholestasis. They reported a signiﬁcant and positive correlation between MRP3 mRNA expression and serum levels of TNF-a, but not IL-1b (Chai et al., 2012). This study also demonstrated increased SP1 and LRH-1 expression in the liver of the cholestacic patients, but not in controls. Besides increased expression of these transcritpion factors, enhanced SP1 and LRH-1 binding to the MRP3/ABCC3 promoter was detected in nuclear extracts from cholestatic patients. Therefore, the authors concluded that TNFa induces hepatic MRP3/ABCC3 expression through activation of the JNK/SAPK-signaling pathway, leading to an increase in SP1 and LRH-1 expression and function in human obstructive cholestasis. Additionally, other cytokines modulate ABC transportes. Liu et al. (2015) demonstrated that IL-18, a member of the IL-1 cytokine family, which is elevated in patients with obstructive jaundice (El-Sayed et al., 2003), can repress MRP2 expression through FXR in BDL rats. The same authors showed that this effect is mediated by activation of the NF-kappaB signaling pathway. NF-kappaB in turn enhances the expression of the transcription factor YY1, which inversely regulates FXR. As previously stated, FXR is a master regulator controlling the expression of various transporters involved in bile acid homeostasis. Epigenetic regulation of cytokine response and its impact on transporter expression is an area that deserved more attention. For example, miR-155, a well-known microRNA that mediates inﬂammatory responses by regulating the expression of various proinﬂammatory target genes (Du et al., 2014; Zheng et al., 2012). Speciﬁcally in liver, toxic APAP treatment results in a signiﬁcant increase in miR-155 levels. miR155 in turn negatively regulates p65 and IKKε expression, leading to the reduced activation of NFkappa-B signaling (Yuan et al., 2016). It is known that the modulation of NFkappa-B signaling is a modulator of drug resistance and ABC transporters (Seubwai et al., 2016; Shi et al., 2015). Clearly, the potential impact for downstream effects of miR-155 and other epigenetic events on hepatic transporter regulation warrants further investigation. Overall, the results presented in this section underscore the complexity of cytokine networks and how they regulate the expression of ABC transporters. Clearly much more needs to be done to better elucidate not only the role of invidiual cytokines in the modulation of drug transporters during liver diseases, but also how the combined effect of more than one inﬂammatory mediator affects transporter expression and function and the cellular mediating these responses.

2.09.4.4

Epigenetic Regulation

Epigenetics is the study of heritable changes in gene expression (active versus inactive genes) that does not involve changes in DNA sequence. In other words, these are changes that affect how cells read genes, resulting in different phenotypes without changes in genotype. Epigenetics is also considered a normal physiological process involved in embryogenesis, cell differentiation and development but can also be inﬂuenced by various other factors such as age, environment and lifestyle inﬂueces, and disease states. At least, three mechanism for epigenetic regulation, including DNA methylation or acetylation, histone modiﬁcation and non coding RNA (ncRNA), among them microRNAs (miRNAs) and long RNAs (LncRNAs) are well known.

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CpG dinucleotide methylation can recruit chromatin-remodeling factors, such as methyl CpG binding proteins and histone deacetylases, which produce steric impediments in the transactivation of neighboring genes by most transcription factors. Therefore, gene expression is inversely correlated to DNA methylation of the 50 -ﬂanking region of many genes. Tissue-speciﬁc differences in ABC transporters expression between liver, kidney and brain are strongly associated with tissue-dependent epigenetic gene regulation (e.g., DNA methylation and histone acetylation status for Oatp1b2, Ntcp, Bsep, and Abcg5/g8 in mice (Imai et al. 2008). For example, hypermethylation of OCT3 promoter results in negative modulation of its expression in human liver (Chen et al., 2013a). Also, gene acetylation has been reported as another factor that can modulate hepatic ABC transporters. A differential transcriptional regulation of the two isoforms of Pgp, Abcb1b and Abcb1a, has been reported with increased acetylation levels of histone H3 lysine 9 at the promoter regions, respectively, while Abcb1b was upregulated and Abcb1a decreased in hepatoma cells (Sike et al., 2014). In addition to liver, the importance of DNA methylation in the regulation of ABC transporters has been demosntrated in other tissues. The methylation status of the ABCB1 promoter shows high interindividual variability in colonic epithelia of healthy Chinese subjects, and is inversely correlated to acetylated histone H3, ABCB1 mRNA expression and protein activity (Wu et al., 2015). Additionally, hypomethylation of the ABCB1 promoter is associated with a decreased response to clopidogrel in ischemic stroke patients via increased ABCB1 mRNA expression (Yang et al., 2015b). Other evidence indicates that the methylation status of a speciﬁc region of the ABCB1 promoter modiﬁes the binding of proteins that possitively regulate its gene expression (Corrêa et al., 2014). Complete demethylation of ABCG2 promoter by drug treatment in a leukemic cell line results in a dramatic induction of ABCG2 mRNA levels and, consequenty, the acquisition of an ABCG2-dependent MDR phenotype (Bram et al., 2009). The same inverse correlation has been described in sheep liver (Babu et al., 2012) and in colorrectal cancer cell lines (Moon et al., 2016). Over 2000 miRNAs have been reported in humans. They are a class of small (18–25 nucleotides in length) ncRNAs that control post-transcriptional regulation of target genes (Kasinski and Slack, 2011). They bind to miRNA response elements within the 39untranslated regions (39UTRs) of mRNA targets and usually reduce their expression through inhibition of translation or by accelerating their degradation. The liver-speciﬁc miR-122 is frequently downregulated in HCC and is usually associated to drug resistance. Xu et al. (2011) demonstrated that restoration of miR-122 in HCC cells could render cells sensitive to the chemotherapeutic agents adriamycin and vincristine by reducing the expression of Pgp and MRP1. Also, overexpression of miR-223 and miR 27a decreases the expression of Pgp, which confers susceptibility chemotherapy-induced cytotoxicity of HCC cells (Yang et al. 2013b; Chen et al. 2013c). Also, treatment of HEPG2 cells with various nucleoside reverse transcriptase inhibitors increases miR-124a expression, which inversely regulates ABCC4 expression (Nagiah et al. 2016). miRNA regulation of ABC transporters in other tissues under both physiological and phathological conditions (e.g., cancer) have been extensively studied, and the details can be found the the reviews by Haenisch and Cascorbi (2012) and Lopes-Rodrigues et al. (2014). LncRNAs are nonprotein-coding RNA transcripts longer than 200 nucleotides (Kapranov et al. 2007) that play an important role in regulating transcriptional processes, gene splicing, mRNA translation and overall cell development (Wilusz et al. 2009). Hepatocarcinoma cells can release extracellular vesicles such as exosomes, which contain proteins, lipids and RNA (including LncRNAs) derived from their donor cell cytoplasm (Théry et al. 2009). Endosomes can be taken up and modulate cellular processes in recipient cells (Skog et al., 2008; Valadi et al., 2007) These vesicles have been reported to be secreted into the medium from a variety of normal or tumor cells in culture. HCC cell-derived endosomes contain miRNAs that can modulate transformed cell behavior of recipient cells (Kogure et al., 2011). LncRNA-VLDLR was signiﬁcantly upregulated in malignant hepatocytes. Exposure of HCC cells to diverse anticancer agents such as sorafenib, camptothecin, and doxorubicin increases lnc-VLDLR expression in cells as well its concentration within extracellular vesicles (Takahashi et al., 2014). The authors of this study also demonstrated that incubation with these vesicles with recipient cells reduces chemotherapy-induced cell death and also increased lnc-VLDLR expression. Moreover, knockdown of VLDLR reduces expression of ABCG2 (Takahashi et al., 2014). Other lnc-RNAs, such as MRUL and PVT1, have been shown to modify the expression of ABCB1 in gastric cancer cell lines (Zhang et al., 2015; Wang et al., 2014). Additionally, it has been demonstrated that overexpression of the lnc-RNAs HOX antisense intergenic RNA (HOTAIR) modulates the expression MRP1 indirectly by inhibiting miR-126 (Yan et al., 2016).

2.09.4.5

Interplay Between Epigenetics and Nuclear Receptor or Transcription Factors

We have described above various genetic and epigenetic mechanisms mediating regulation of ABC transporters. But it also worth noting that the interplay between these genetic and epigenetic regulatory mechanisms must be further addressed. Douet et al. (2007) reported that the level of Abcc6 promoter methylation in various mouse tissues is inversely correlated to its gene expression. Moreover, the same work demonstrates that CpG methylation of the Abcc6 proximal promoter region interfers with binding of the Sp1 transcription factor, thereby inhibiting Sp1-dependent transactivation. In cholestasis, the epigenetic mark H3K4me3 is essential for the activation of both FXR and GR, which control the expression of various transporters mediating transport of bile acids and bile ﬂow, such as BSEP, MRP2, and NTCP (Ananthanarayanan et al., 2011).

2.09.5

Concluding Remarks

Changes in the expression of hepatobiliary transporters are common in multiple forms of liver injury. The need for differentially regulating transporters is obvious for conditions and chemical treatments resulting in cholestasis. The liver responds to cholestasis

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and the subsequent intracellular accumulation of bile acids by decreasing expression of bile acid uptake transporters. There is a simultaneous increase in the levels of basolateral efﬂux transporters that redirect bile acids from the enterohepatic circulation to the kidneys for excretion. This has the net effect of reducing the hepatocellular concentration of toxic bile acids and other potentially cytotoxic compounds than are normally handled by the liver. A similar response is seen in animal models of liver injury induced by chemicals such as APAP and CCl4 despite normal bile ﬂow and bile acid concentrations. Interestingly, some of the same hepatic transporter changes are also observed in humans exposed to toxic doses of APAP. A reduction in the expression of uptake transporters and induction of both canalicular and basolateral efﬂux transporters by hepatotoxicants suggest that the liver is coping with injury by limiting the chemical burden of hepatocytes at a critical juncture where injury can further progress into organ failure, or repair can result in tissue regeneration. These changes in transporters could be operational not only to enhance the ability of hepatocytes to remove the insulting toxicant and its metabolites, but also to remove endogenous mediators of injury generated by cellular damage. A recent and more attractive hypothesis is that induction of members of the Mrp family of transporters may serve to efﬂux and deliver signaling molecules from toxicant-stressed hepatocytes to adjacent healthy hepatocytes and nonparenchymal cells to engage them in tissue repair. Alternatively, changes in transpoter expression could serve to reduce intracellular concentrations of molecules that maintain hepatocytes in a quiescent state. Such events might be critical for promoting hepatocyte proliferation. Similar changes in drug transporters are observed in the other liver disease models discussed in this chapter. For example, Mrp3 and Mrp4 expression also increases with obesity and fatty liver disease. Hepatic oxidative stress and inﬂammation are pathological insults common not only to obesity and fatty liver, but also to chemical-induced liver injury. The nuclear transcription factor Nrf2 and acute phase cytokines are well documented regulators of hepatic Mrp proteins in conditions where oxidative stress and inﬂammation are involved. In addition to Nrf2 and cytokines, other transcription factors such as CAR, FXR, and PXR also participate in the regulation of hepatic transporters under certain pathological conditions. In the case of HCCs, enhanced plasma membrane expression of efﬂux transporters, such as Pgp, is well known to contribute to the multidrug resistance phenotype of these cancer cells. More recently epigentic regulation of transporters in liver diseases is gaining considrable attention. Alterations in the expression of drug transporters have profound clinical implications, and the role of drug transporters in clinical drug interactions continues to be an active ﬁeld of investigation. Preclinical and clinical studies have revealed that drug transporters play an important role in clinically relevant drug interactions. The pharmaceutical sector is also making strides to understand the importance of transporters in drug development from a human safety and drug disposition standpoint. The study of genetic polymorphisms in drug transporters has continues to be a fertile ﬁeld of investigation. Presently, the clinical impact of the many polymorphisms in drug transporters identiﬁed so far remains largely unkown. Since polymorphic forms of these proteins could inﬂuence drug tissue dosimetry, it is imperative to study them further as potential genetic determinants of idiosyncratic drug reactions. This is highly relevant since many drugs and their metabolites exhibiting hepatic and intestinal toxicity liabilities are often substrates for hepatobiliary transporters. Many challenges remain, and multiple questions must be answered. For example, is transporter expression affected by chemical contaminants, particularly at environmentally relevant concentrations? Can changes in transporter expression serve as biomarkers of environmental exposure? Does exposure to such contaminants affect hepatic transporter function, leading to changes in pharmacokinetic and pharmacodynamic parameters for other environmental contaminants and therapeutic agents? Are polymorphisms in transporters risk factors for enviromental liver diseases? Finally, the role of transporters in chemical interactions (e.g., mixtures) and the potential for altered susceptibility to toxicity remain open ﬁelds of investigation that pose many great challenges.

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Regulation of Hepatobiliary Transporters During Liver Injury☆

Regulation of Hepatobiliary Transporters During Liver Injury☆

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