Genetic Determinants of Drug-induced Cholestasis and Intrahepatic Cholestasis of Pregnancy

Christiane Pauli-Magnus; Peter J Meier; Bruno Stieger

doi:10.1055/s-0030-1253224

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2010; 30(2): 147-159
DOI: 10.1055/s-0030-1253224

Genetic Determinants of Drug-induced Cholestasis and Intrahepatic Cholestasis of Pregnancy

Christiane Pauli-Magnus¹ , Peter J. Meier² , Bruno Stieger³ ^, ⁴

¹University Hospital Basel, Basel, Switzerland
²University Basel, Basel, Switzerland
³Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital Zürich, Zürich, Switzerland
⁴AMC Liver Center, Academic Medical Center, Amsterdam, The Netherlands

Abstract

ABSTRACT

Intrahepatic cholestasis of pregnancy and drug-induced cholestasis are two clinically important forms of acquired cholestatic liver disease. The understanding of the underlying mechanisms of acquired cholestasis has recently made considerable progress by the identification of canalicular ATP-binding cassette (ABC) transporters as likely targets for these forms of cholestasis. Cholestasis of pregnancy is linked to estrogen and progesterone metabolites. These metabolites have been shown to impair the bile salt export pump (BSEP) function by an indirect mechanism. In addition, genetic variants (as well as mutants) of the genes coding for the phosphatidylcholine translocator MDR3 and BSEP and for the farnesoid X receptor, which is critical in the transcriptional activation of MDR3 (ABCB4) and BSEP (ABCB11) have been associated with intrahepatic cholestasis of pregnancy. The pathogenesis of drug-induced liver injury encompasses a wide spectrum of mechanisms, some of which are still poorly understood. BSEP is now known to be subject to drug inhibition in susceptible patients. Information on genetic factors rendering individuals susceptible to inhibition of BSEP by drugs or their metabolites is still scarce. Besides rare mutations that have been linked to drug-induced cholestasis, the common p.V444A polymorphism of BSEP has been identified as a potential risk factor. In this review, the authors summarize key concepts of physiology of bile formation, diagnostic principles to indentify these forms of acquired cholestasis, as well as pathogenetic mechanisms leading to intrahepatic cholestasis of pregnancy or drug-induced cholestasis. In addition, they review the current knowledge on genetic susceptibility factors for these two forms of cholestasis.

KEYWORDS

Pharmacogenetics - cholestasis - drug-induced - pregnancy

Full Text

References

REFERENCES

1 Russell D W. Fifty years of advances in bile acid synthesis and metabolism. J Lipid Res. 2009; 50(Suppl) S120-S125
2 Meier P J, Stieger B. Bile salt transporters. Annu Rev Physiol. 2002; 64 635-661
3 Trauner M, Boyer J L. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev. 2003; 83(2) 633-671
4 Pauli-Magnus C, Stieger B, Meier Y, Kullak-Ublick G A, Meier P J. Enterohepatic transport of bile salts and genetics of cholestasis. J Hepatol. 2005; 43(2) 342-357
5 Hofmann A F, Hagey L R. Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci. 2008; 65(16) 2461-2483
6 Hofmann A F. The enterohepatic circulation of bile acids in mammals: form and functions. Front Biosci. 2009; 14 2584-2598
7 Dawson P A, Lan T, Rao A. Bile acid transporters. J Lipid Res. 2009; 50(12) 2340-2357
8 Hagenbuch B, Dawson P. The sodium bile salt cotransport family SLC10. Pflugers Arch. 2004; 447(5) 566-570
9 Kullak-Ublick G A, Stieger B, Meier P J. Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology. 2004; 126(1) 322-342
10 Hagenbuch B, Meier P J. Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch. 2004; 447(5) 653-665
11 Stieger B, Meier Y, Meier P J. The bile salt export pump. Pflugers Arch. 2007; 453(5) 611-620
12 Stieger B. Recent insights into the function and regulation of the bile salt export pump (ABCB11). Curr Opin Lipidol. 2009; 20(3) 176-181
13 Reichen J, Paumgartner G. Uptake of bile acids by perfused rat liver. Am J Physiol. 1976; 231(3) 734-742
14 Oude Elferink R P, Paulusma C C. Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein). Pflugers Arch. 2007; 453(5) 601-610
15 Small D M. Role of ABC transporters in secretion of cholesterol from liver into bile. Proc Natl Acad Sci U S A. 2003; 100(1) 4-6
16 Oude Elferink R P, Paulusma C C, Groen A K. Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Gastroenterology. 2006; 130(3) 908-925
17 Hazard S E, Patel S B. Sterolins ABCG5 and ABCG8: regulators of whole body dietary sterols. Pflugers Arch. 2007; 453(5) 745-752
18 Alnouti Y. Bile acid sulfation: a pathway of bile acid elimination and detoxification. Toxicol Sci. 2009; 108(2) 225-246
19 Zollner G, Trauner M. Molecular mechanisms of cholestasis. Wien Med Wochenschr. 2006; 156(13-14) 380-385
20 Nies A T, Keppler D. The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Arch. 2007; 453(5) 643-659
21 Geier A, Wagner M, Dietrich C G, Trauner M. Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. Biochim Biophys Acta. 2007; 1773(3) 283-308
22 Ballatori N, Li N, Fang F, Boyer J L, Christian W V, Hammond C L. OST alpha-OST beta: a key membrane transporter of bile acids and conjugated steroids. Front Biosci. 2009; 14 2829-2844
23 Geyer J, Wilke T, Petzinger E. The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships. Naunyn Schmiedebergs Arch Pharmacol. 2006; 372(6) 413-431
24 Alrefai W A, Gill R K. Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm Res. 2007; 24(10) 1803-1823
25 Weinman S A. Electrogenicity of Na(+)-coupled bile acid transporters. Yale J Biol Med. 1997; 70(4) 331-340
26 Hagenbuch B, Gui C. Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica. 2008; 38(7-8) 778-801
27 Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009; 158(3) 693-705
28 Kitamura S, Maeda K, Wang Y, Sugiyama Y. Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos. 2008; 36(10) 2014-2023
29 Link E, Parish S, Armitage J SEARCH Collaborative Group et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med. 2008; 359(8) 789-799
30 Satlin L M, Amin V, Wolkoff A W. Organic anion transporting polypeptide mediates organic anion/HCO3- exchange. J Biol Chem. 1997; 272(42) 26340-26345
31 Li L, Lee T K, Meier P J, Ballatori N. Identification of glutathione as a driving force and leukotriene C4 as a substrate for OATP1, the hepatic sinusoidal organic solute transporter. J Biol Chem. 1998; 273(26) 16184-16191
32 Li L, Meier P J, Ballatori N. OATP2 mediates bidirectional organic solute transport: a role for intracellular glutathione. Mol Pharmacol. 2000; 58(2) 335-340
33 Briz O, Romero M R, Martinez-Becerra P et al.. OATP8/1B3-mediated cotransport of bile acids and glutathione: an export pathway for organic anions from hepatocytes?. J Biol Chem. 2006; 281(41) 30326-30335
34 Leuthold S, Hagenbuch B, Mohebbi N, Wagner C A, Meier P J, Stieger B. Mechanisms of pH-gradient driven transport mediated by organic anion polypeptide transporters. Am J Physiol Cell Physiol. 2009; 296(3) C570-C582
35 Zheng H X, Huang Y, Frassetto L A, Benet L Z. Elucidating rifampin's inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite. Clin Pharmacol Ther. 2009; 85(1) 78-85
36 Kellner H M, Christ O, Rupp W, Heptner W. [Resorption, distribution and excretion after administration of 14C-labelled HB 419 in rabbits, rats and dogs]. Arzneimittelforschung. 1969; 19(8, Suppl) 1388-1400
37 Stieger B, Fattinger K, Madon J, Kullak-Ublick G A, Meier P J. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology. 2000; 118(2) 422-430
38 Hayashi H, Takada T, Suzuki H, Onuki R, Hofmann A F, Sugiyama Y. Transport by vesicles of glycine- and taurine-conjugated bile salts and taurolithocholate 3-sulfate: a comparison of human BSEP with rat Bsep. Biochim Biophys Acta. 2005; 1738(1-3) 54-62
39 Gerloff T, Stieger B, Hagenbuch B et al.. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem. 1998; 273(16) 10046-10050
40 Carlton V E, Harris B Z, Puffenberger E G et al.. Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nat Genet. 2003; 34(1) 91-96
41 Stieger B, O'Neill B, Meier P J. ATP-dependent bile-salt transport in canalicular rat liver plasma-membrane vesicles. Biochem J. 1992; 284(Pt 1) 67-74
42 Strautnieks S S, Bull L N, Knisely A S et al.. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet. 1998; 20(3) 233-238
43 Jansen P LM, Strautnieks S S, Jacquemin E et al.. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology. 1999; 117(6) 1370-1379
44 Byrne J A, Strautnieks S S, Mieli-Vergani G, Higgins C F, Linton K J, Thompson R J. The human bile salt export pump: characterization of substrate specificity and identification of inhibitors. Gastroenterology. 2002; 123(5) 1649-1658
45 Noé J, Stieger B, Meier P J. Functional expression of the canalicular bile salt export pump of human liver. Gastroenterology. 2002; 123(5) 1659-1666
46 Stieger B. Role of the bile salt export pump, BSEP, in acquired forms of cholestasis. Drug Metab Rev. 2009; , December 29 (Epub adhead of print)
47 Akita H, Suzuki H, Ito K et al.. Characterization of bile acid transport mediated by multidrug resistance associated protein 2 and bile salt export pump. Biochim Biophys Acta. 2001; 1511(1) 7-16
48 Vallejo M, Briz O, Serrano M A, Monte M J, Marin J J. Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy. J Hepatol. 2006; 44(6) 1150-1157
49 Huang L, Smit J W, Meijer D K, Vore M. Mrp2 is essential for estradiol-17beta(beta-D-glucuronide)-induced cholestasis in rats. Hepatology. 2000; 32(1) 66-72
50 Gonzalez M C, Reyes H, Arrese M et al.. Intrahepatic cholestasis of pregnancy in twin pregnancies. J Hepatol. 1989; 9(1) 84-90
51 Reyes H, Sjövall J. Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy. Ann Med. 2000; 32(2) 94-106
52 Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis. 2007; 2 26
53 Hay J E. Liver disease in pregnancy. Hepatology. 2008; 47(3) 1067-1076
54 Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol. 2009; 15(17) 2049-2066
55 Gonzales E, Davit-Spraul A, Baussan C, Buffet C, Maurice M, Jacquemin E. Liver diseases related to MDR3 (ABCB4) gene deficiency. Front Biosci. 2009; 14 4242-4256
56 Kenyon A P, Piercy C N, Girling J, Williamson C, Tribe R M, Shennan A H. Obstetric cholestasis, outcome with active management: a series of 70 cases. BJOG. 2002; 109(3) 282-288
57 Jacquemin E, De Vree J M, Cresteil D et al.. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology. 2001; 120(6) 1448-1458
58 Bacq Y, Sapey T, Bréchot M C, Pierre F, Fignon A, Dubois F. Intrahepatic cholestasis of pregnancy: a French prospective study. Hepatology. 1997; 26(2) 358-364
59 Arrese M, Reyes H. Intrahepatic cholestasis of pregnancy: a past and present riddle. Ann Hepatol. 2006; 5(3) 202-205
60 Lammert F, Marschall H U, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol. 2000; 33(6) 1012-1021
61 Heikkinen J, Mäentausta O, Ylöstalo P, Jänne O. Changes in serum bile acid concentrations during normal pregnancy, in patients with intrahepatic cholestasis of pregnancy and in pregnant women with itching. Br J Obstet Gynaecol. 1981; 88(3) 240-245
62 Lunzer M, Barnes P, Byth K, O'Halloran M. Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis. Gastroenterology. 1986; 91(4) 825-829
63 Meng L J, Reyes H, Axelson M et al.. Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: effect of ursodeoxycholic acid therapy. Hepatology. 1997; 26(6) 1573-1579
64 Meng L J, Reyes H, Palma J, Hernandez I, Ribalta J, Sjövall J. Profiles of bile acids and progesterone metabolites in the urine and serum of women with intrahepatic cholestasis of pregnancy. J Hepatol. 1997; 27(2) 346-357
65 Meng L J, Reyes H, Palma J, Hernandez I, Ribalta J, Sjövall J. Effects of ursodeoxycholic acid on conjugated bile acids and progesterone metabolites in serum and urine of patients with intrahepatic cholestasis of pregnancy. J Hepatol. 1997; 27(6) 1029-1040
66 Pauli-Magnus C, Lang T, Meier Y et al.. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics. 2004; 14(2) 91-102
67 Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Semin Liver Dis. 2001; 21(4) 551-562
68 Kreek M J. Female sex steroids and cholestasis. Semin Liver Dis. 1987; 7(1) 8-23
69 Reyes H, Simon F R. Intrahepatic cholestasis of pregnancy: an estrogen-related disease. Semin Liver Dis. 1993; 13(3) 289-301
70 Laatikainen T, Karjalainen O. Exertion of progesterone metabolites in urine and bile of pregnant women with intrahepatic cholestasis. J Steroid Biochem. 1973; 4(6) 641-648
71 Lindberg M C. Hepatobiliary complications of oral contraceptives. J Gen Intern Med. 1992; 7(2) 199-209
72 Meyers M, Slikker W, Pascoe G, Vore M. Characterization of cholestasis induced by estradiol-17 beta-D-glucuronide in the rat. J Pharmacol Exp Ther. 1980; 214(1) 87-93
73 Bossard R, Stieger B, O'Neill B, Fricker G, Meier P J. Ethinylestradiol treatment induces multiple canalicular membrane transport alterations in rat liver. J Clin Invest. 1993; 91(6) 2714-2720
74 Madon J, Eckhardt U, Gerloff T, Stieger B, Meier P J. Functional expression of the rat liver canalicular isoform of the multidrug resistance-associated protein. FEBS Lett. 1997; 406(1-2) 75-78
75 Simon F R, Fortune J, Iwahashi M, Gartung C, Wolkoff A, Sutherland E. Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters. Am J Physiol. 1996; 271(6 Pt 1) G1043-G1052
76 Micheline D, Emmanuel J, Serge E. Effect of ursodeoxycholic acid on the expression of the hepatocellular bile acid transporters (Ntcp and bsep) in rats with estrogen-induced cholestasis. J Pediatr Gastroenterol Nutr. 2002; 35(2) 185-191
77 Geier A, Dietrich C G, Gerloff T et al.. Regulation of basolateral organic anion transporters in ethinylestradiol-induced cholestasis in the rat. Biochim Biophys Acta. 2003; 1609(1) 87-94
78 Lee J M, Trauner M, Soroka C J, Stieger B, Meier P J, Boyer J L. Expression of the bile salt export pump is maintained after chronic cholestasis in the rat. Gastroenterology. 2000; 118(1) 163-172
79 Carreras F I, Lehmann G L, Ferri D, Tioni M F, Calamita G, Marinelli R A. Defective hepatocyte aquaporin-8 expression and reduced canalicular membrane water permeability in estrogen-induced cholestasis. Am J Physiol Gastrointest Liver Physiol. 2007; 292(3) G905-G912
80 Kamisako T, Ogawa H. Alteration of the expression of adenosine triphosphate-binding cassette transporters associated with bile acid and cholesterol transport in the rat liver and intestine during cholestasis. J Gastroenterol Hepatol. 2005; 20(9) 1429-1434
81 Ruiz M L, Villanueva S S, Luquita M G, Vore M, Mottino A D, Catania V A. Ethynylestradiol increases expression and activity of rat liver MRP3. Drug Metab Dispos. 2006; 34(6) 1030-1034
82 Yamamoto Y, Moore R, Hess H A et al.. Estrogen receptor alpha mediates 17alpha-ethynylestradiol causing hepatotoxicity. J Biol Chem. 2006; 281(24) 16625-16631
83 Barth A, Klinger G, Rost M. Influence of ethinyloestradiol propanolsulphonate on serum bile acids in healthy volunteers. Exp Toxicol Pathol. 2003; 54(5-6) 381-386
84 Koopen N R, Wolters H, Havinga R et al.. Impaired activity of the bile canalicular organic anion transporter (Mrp2/cmoat) is not the main cause of ethinylestradiol-induced cholestasis in the rat. Hepatology. 1998; 27(2) 537-545
85 Mottino A D, Cao J, Veggi L M, Crocenzi F, Roma M G, Vore M. Altered localization and activity of canalicular Mrp2 in estradiol-17beta-D-glucuronide-induced cholestasis. Hepatology. 2002; 35(6) 1409-1419
86 Crocenzi F A, Mottino A D, Cao J et al.. Estradiol-17beta-D-glucuronide induces endocytic internalization of Bsep in rats. Am J Physiol Gastrointest Liver Physiol. 2003; 285(2) G449-G459
87 Roma M G, Crocenzi F A, Mottino A D. Dynamic localization of hepatocellular transporters in health and disease. World J Gastroenterol. 2008; 14(44) 6786-6801
88 Crocenzi F A, Sánchez Pozzi E J, Ruiz M L et al.. Ca(2+)-dependent protein kinase C isoforms are critical to estradiol 17beta-D-glucuronide-induced cholestasis in the rat. Hepatology. 2008; 48(6) 1885-1895
89 Hartgens F, Kuipers H. Effects of androgenic-anabolic steroids in athletes. Sports Med. 2004; 34(8) 513-554
90 Maravelias C, Dona A, Stefanidou M, Spiliopoulou C. Adverse effects of anabolic steroids in athletes. A constant threat. Toxicol Lett. 2005; 158(3) 167-175
91 Parkinson A B, Evans N A. Anabolic androgenic steroids: a survey of 500 users. Med Sci Sports Exerc. 2006; 38(4) 644-651
92 Ishak K G. Hepatic lesions caused by anabolic and contraceptive steroids. Semin Liver Dis. 1981; 1(2) 116-128
93 Gurakar A, Caraceni P, Fagiuoli S, Van Thiel D H. Androgenic/anabolic steroid-induced intrahepatic cholestasis: a review with four additional case reports. J Okla State Med Assoc. 1994; 87(9) 399-404
94 Nasr J, Ahmad J. Severe cholestasis and renal failure associated with the use of the designer steroid Superdrol (methasteron): a case report and literature review. Dig Dis Sci. 2009; 54(5) 1144-1146
95 Krishnan P V, Feng Z Z, Gordon S C. Prolonged intrahepatic cholestasis and renal failure secondary to anabolic androgenic steroid-enriched dietary supplements. J Clin Gastroenterol. 2009; 43(7) 672-675
96 Bellmann R, Feistritzer C, Zoller H et al.. Treatment of intractable pruritus in drug induced cholestasis with albumin dialysis: a report of two cases. ASAIO J. 2004; 50(4) 387-391
97 Phillips M J, Oda M, Funatsu K. Evidence for microfilament involvement in norethandrolone-induced intrahepatic cholestasis. Am J Pathol. 1978; 93(3) 729-744
98 Jacquemin E, Cresteil D, Manouvrier S, Boute O, Hadchouel M. Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy. Lancet. 1999; 353(9148) 210-211
99 Wasmuth H E, Glantz A, Keppeler H et al.. Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene. Gut. 2007; 56(2) 265-270
100 Floreani A, Carderi I, Variola A, Rizzotto E R, Nicol J, Bergasa N V. A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus. Hepatology. 2006; 43(5) 1152-1154
101 Schneider G, Paus T C, Kullak-Ublick G A et al.. Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy. Hepatology. 2007; 45(1) 150-158
102 Eloranta M L, Heiskanen J T, Hiltunen M J, Mannermaa A J, Punnonen K R, Heinonen S T. Multidrug resistance 3 gene mutation 1712delT and estrogen receptor alpha gene polymorphisms in Finnish women with obstetric cholestasis. Eur J Obstet Gynecol Reprod Biol. 2002; 105(2) 132-135
103 Dixon P H, Weerasekera N, Linton K J et al.. Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Hum Mol Genet. 2000; 9(8) 1209-1217
104 Meier Y, Zodan T, Lang C et al.. Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T> C polymorphism in the bile salt export pump. World J Gastroenterol. 2008; 14(1) 38-45
105 Dixon P H, van Mil S W, Chambers J et al.. Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut. 2009; 58(4) 537-544
106 Noe J, Kullak-Ublick G A, Jochum W et al.. Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. J Hepatol. 2005; 43(3) 536-543
107 Meier Y, Pauli-Magnus C, Zanger U M et al.. Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology. 2006; 44(1) 62-74
108 Byrne J A, Strautnieks S S, Ihrke G et al.. Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing. Hepatology. 2009; 49(2) 553-567
109 Ho R H, Leake B F, Kilkenny D M et al.. Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability. Pharmacogenet Genomics. 2010; 20(1) 45-57
110 Van Mil S W, Milona A, Dixon P H et al.. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology. 2007; 133(2) 507-516
111 Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf D J, Suchy F J. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem. 2001; 276(31) 28857-28865
112 Huang L, Zhao A, Lew J L et al.. Farnesoid X receptor activates transcription of the phospholipid pump MDR3. J Biol Chem. 2003; 278(51) 51085-51090
113 Keitel V, Vogt C, Häussinger D, Kubitz R. Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy. Gastroenterology. 2006; 131(2) 624-629
114 Zimmer V, Müllenbach R, Simon E, Bartz C, Matern S, Lammert F. Combined functional variants of hepatobiliary transporters and FXR aggravate intrahepatic cholestasis of pregnancy. Liver Int. 2009; 29(8) 1286-1288
115 Lang C, Meier Y, Stieger B et al.. Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury. Pharmacogenet Genomics. 2007; 17(1) 47-60
116 Lee W M. Drug-induced hepatotoxicity. N Engl J Med. 2003; 349(5) 474-485
117 Meier Y, Cavallaro M, Roos M et al.. Incidence of drug-induced liver injury in medical inpatients. Eur J Clin Pharmacol. 2005; 61(2) 135-143
118 Shapiro M A, Lewis J H. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. Clin Liver Dis. 2007; 11(3) 477-505, v , v
119 Bleibel W, Kim S, D'Silva K, Lemmer E R. Drug-induced liver injury: review article. Dig Dis Sci. 2007; 52(10) 2463-2471
120 Schuster D, Laggner C, Langer T. Why drugs fail—a study on side effects in new chemical entities. Curr Pharm Des. 2005; 11(27) 3545-3559
121 Smith D A, Schmid E F. Drug withdrawals and the lessons within. Curr Opin Drug Discov Devel. 2006; 9(1) 38-46
122 Abboud G, Kaplowitz N. Drug-induced liver injury. Drug Saf. 2007; 30(4) 277-294
123 Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathol. 2009; 62(6) 481-492
124 Chitturi S, George J. Hepatotoxicity of commonly used drugs: nonsteroidal anti-inflammatory drugs, antihypertensives, antidiabetic agents, anticonvulsants, lipid-lowering agents, psychotropic drugs. Semin Liver Dis. 2002; 22(2) 169-183
125 Bell L N, Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury. Semin Liver Dis. 2009; 29(4) 337-347
126 Liss G, Lewis J H. Drug-induced liver injury: what was new in 2008?. Expert Opin Drug Metab Toxicol. 2009; 5(8) 843-860
127 Bénichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990; 11(2) 272-276
128 Pizzagalli F, Varga Z, Huber R D, Folkers G, Meier P J, St-Pierre M V. Identification of steroid sulfate transport processes in the human mammary gland. J Clin Endocrinol Metab. 2003; 88(8) 3902-3912
129 Grube M, Köck K, Karner S et al.. Modification of OATP2B1-mediated transport by steroid hormones. Mol Pharmacol. 2006; 70(5) 1735-1741
130 Gui C, Miao Y, Thompson L et al.. Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3. Eur J Pharmacol. 2008; 584(1) 57-65
131 Sugiyama D, Kusuhara H, Shitara Y, Abe T, Sugiyama Y. Effect of 17 beta-estradiol-D-17 beta-glucuronide on the rat organic anion transporting polypeptide 2-mediated transport differs depending on substrates. Drug Metab Dispos. 2002; 30(2) 220-223
132 Arias I M. Cyclosporin, the biology of the bile canaliculus, and cholestasis. Gastroenterology. 1993; 104(5) 1558-1560
133 Böhme M, Müller M, Leier I, Jedlitschky G, Keppler D. Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in rat liver. Gastroenterology. 1994; 107(1) 255-265
134 Krähenbühl S, Talos C, Fischer S, Reichen J. Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria. Hepatology. 1994; 19(2) 471-479
135 Treiber A, Schneiter R, Häusler S, Stieger B. Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab Dispos. 2007; 35(8) 1400-1407
136 Fattinger K, Funk C, Pantze M et al.. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther. 2001; 69(4) 223-231
137 Fouassier L, Kinnman N, Lefèvre G et al.. Contribution of mrp2 in alterations of canalicular bile formation by the endothelin antagonist bosentan. J Hepatol. 2002; 37(2) 184-191
138 Mano Y, Usui T, Kamimura H. Effects of bosentan, an endothelin receptor antagonist, on bile salt export pump and multidrug resistance-associated protein 2. Biopharm Drug Dispos. 2007; 28(1) 13-18
139 Borst P, Zelcer N, van de Wetering K, Poolman B. On the putative co-transport of drugs by multidrug resistance proteins. FEBS Lett. 2006; 580(4) 1085-1093
140 Meier P J. Canalicular bile formation: beyond single transporter functions. J Hepatol. 2002; 37(2) 272-273
141 Takada T, Weiss H M, Kretz O, Gross G, Sugiyama Y. Hepatic transport of PKI166, an epidermal growth factor receptor kinase inhibitor of the pyrrolo-pyrimidine class, and its main metabolite, ACU154. Drug Metab Dispos. 2004; 32(11) 1272-1278
142 Masubuchi Y. Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab Pharmacokinet. 2006; 21(5) 347-356
143 Julie N L, Julie I M, Kende A I, Wilson G L. Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone. Diabetologia. 2008; 51(11) 2108-2116
144 Preininger K, Stingl H, Englisch R et al.. Acute troglitazone action in isolated perfused rat liver. Br J Pharmacol. 1999; 126(1) 372-378
145 Funk C, Ponelle C, Scheuermann G, Pantze M. Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat. Mol Pharmacol. 2001; 59(3) 627-635
146 Marion T L, Leslie E M, Brouwer K L. Use of sandwich-cultured hepatocytes to evaluate impaired bile acid transport as a mechanism of drug-induced hepatotoxicity. Mol Pharm. 2007; 4(6) 911-918
147 Snow K L, Moseley R H. Effect of thiazolidinediones on bile acid transport in rat liver. Life Sci. 2007; 80(8) 732-740
148 Daly A K, Donaldson P T, Bhatnagar P DILIGEN Study et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009; 41(7) 816-819
149 Daly A K, Day C P. Genetic association studies in drug-induced liver injury. Semin Liver Dis. 2009; 29(4) 400-411
150 Pauli-Magnus C, Meier P J. Hepatobiliary transporters and drug-induced cholestasis. Hepatology. 2006; 44(4) 778-787
151 Tirona R G, Leake B F, Merino G, Kim R B. Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem. 2001; 276(38) 35669-35675
152 Nishizato Y, Ieiri I, Suzuki H et al.. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther. 2003; 73(6) 554-565
153 Mwinyi J, Johne A, Bauer S, Roots I, Gerloff T. Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics. Clin Pharmacol Ther. 2004; 75(5) 415-421
154 Niemi M, Schaeffeler E, Lang T et al.. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics. 2004; 14(7) 429-440
155 Nozawa T, Minami H, Sugiura S, Tsuji A, Tamai I. Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos. 2005; 33(3) 434-439
156 Ho R H, Tirona R G, Leake B F et al.. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology. 2006; 130(6) 1793-1806

Peter J Meier-AbtM.D.

University Basel, Petersplatz 35

4003 Basel, Switzerland

Email: peter.meier-abt@unibas.ch