Prediction of drug-induced intrahepatic cholestasis: In vitro screening and QSAR analysis of drugs inhibiting the human bile salt export pump

Expert Opinion on Drug Safety

Volumn 6, Issue 1, 2007, Pages 71-86

  Sakurai, Aki ^a   Kurata, Atsuo ^a   Onishi, Yuko ^a   Hirano, Hiroyuki ^a   Ishikawa, Toshihisa ^a  

^a TOKYO INSTITUTE OF TECHNOLOGY   (Japan)

Author keywords

ABC transporter; ABCB11; Bile salt; Intrahepatic cholestasis; Troglitazone

Indexed keywords

ABC TRANSPORTER; BEPRIDIL; BILE ACID; BILE SALT; BOSENTAN; CLOXACILLIN; CYCLOSPORIN A; DILTIAZEM; EPIRIZOLE; ETOPOSIDE; FENDILINE; GLIBENCLAMIDE; GLYCOPROTEIN P; IBUPROFEN; MIDECAMYCIN; NEFAZODONE; NIFEDIPINE; NOVOBIOCIN; PACLITAXEL; PENICILLIN G; PRAZOSIN; PROTEIN ABCB11; QUINIDINE; RIFAMPICIN; ROSUVASTATIN; TAMOXIFEN; TROGLITAZONE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALINOMYCIN; VERAPAMIL;

BILE FLOW; CHEMICAL STRUCTURE; DRUG SCREENING; DRUG STRUCTURE; ENTEROHEPATIC CIRCULATION; GENE MUTATION; GENETIC POLYMORPHISM; HUMAN; IN VITRO STUDY; INHIBITION KINETICS; INTRAHEPATIC CHOLESTASIS; LIVER CELL; LIVER TOXICITY; MEMBRANE VESICLE; NONHUMAN; PREDICTION; PROTEIN EXPRESSION; QUANTITATIVE STRUCTURE ACTIVITY RELATION; REVIEW; TRANSCRIPTION REGULATION;

ATP-BINDING CASSETTE TRANSPORTERS; BILE ACIDS AND SALTS; CHOLESTASIS, INTRAHEPATIC; DRUG EVALUATION, PRECLINICAL; HUMANS; PHARMACEUTICAL PREPARATIONS; PREDICTIVE VALUE OF TESTS; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33846446071     PISSN: 14740338     EISSN: None     Source Type: Journal    
DOI: 10.1517/14740338.6.1.71     Document Type: Review

References (75)

1. SERVICE RF: Surviving the blockbuster syndrome. Science (2004) 303(5665):1796-1799.
2. SZUROMI P, VINSON V, MARSHALL E: Rethinking drug discovery. Science (2004) 303:1795.
3. MERVIS J: Productivity counts - but the definition is key. Science (2005) 309(5735):726.
4. ISHIKAWA T, YOSHIKAWA M: ABC transporters: a new approach to toxicogenomics. Inoue T, Pennie WD (Eds), Springer, Tokyo (2003): 109-114.
5. ISHIKAWA T, IKEGAMI Y, SANO K, NAKAGAWA H, SAWADA S: Transport mechanism-based drug molecular design: novel camptothecin analogues to circumvent ABCG 2-associated drug resistance of human tumor cells. Curr. Pharm. Des. (2006) 12(3):313-325.
6. ISHIKAWA T: The ATP-dependent glutathione S-conjugate export pump. Trends Biochem. Sci. (1992) 17(11):463-468.
7. NATHANSON MH, BOYER JL: Mechanisms and regulation of bile secretion. Hepatology ( 1991) 14(3):551-566.
8. TRAUNER M, BOYER JL: Bile salt transporters: molecular characterization, function, and regulation. Physiol. Rev. (2003) 83(2):633-671.
9. KULLAK-UBLICK GA, STIEGER B, MEIER PJ: Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology (2004) 126(1):322-342.
10. CAREY MC, SMALL DM: The physical chemistry of cholesterol solubility in bile. Relationship to gallstone formation and dissolution in man. J. Clin. Invest. (1978) 61 (4):998-1026.
11. HIGUCHI H, GORES GJ: Bile acid regulation of hepatic physiology: IV. Bile acids and death receptors. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) 284(5):G734-G738.
12. ISHIKAWA T: Multidrug Resistance: Genetics of ABC Transporters. In: Nature Encyclopedia of the Human Genome. Cooper DN (Ed.), Nature Publishing Group, London, UK (2003): 154-160.
13. MEIER PJ, STIEGER B: Bile salt transporters. Ann. Rev. Physiol. (2002) 64:635-661.
14. KULLAK-UBLICK GA, STIEGER B, HAGENBUCH B, MEIER PJ: Hepatic transport of bile salts. Semin. Liver Dis. (2000) 20(3):273-292.
15. HOFMANN AF: Bile acids: the good, the bad, and the ugly. News Physiol. Sci. (1999) 14:24-29.
16. WANG W, XUE S, INGLES SA et al.: An association between genetic polymorphisms in the ileal sodium-dependent bile acid transporter gene and the risk of colorectal adenomas. Cancer Epidemiol. Biomarkers Prev. (2001) 10(9):931-936.
17. +/bile acid cotransporting protein from rabbit ileum. J. Biol. Chem. (2001) 276(38):36020-36027.
18. CRADDOCK AL, LOVE MW, DANIEL RW et al.: Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter. Am. J. Physiol. (1998) 274(1 Pt 1):G157-G169.
19. DAWSON PA, HUBBERT M, HAYWOOD J et al.: The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. J. Biol. Chem. (2005) 280(8):6960-6968.
20. WOLKOFF AW, COHEN DE: Bile acid regulation of hepatic physiology: I. Hepatocyte transport of bile acids. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) 284(2):G175-G179.
21. +/bile acid cotransporter. J. Clin. Invest. (1994) 93(3):1326-1331.
22. KONIG J, CUI Y, NIES AT, KEPPLER D: A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am. J. Physiol. Gastrointest. Liver Physiol. (2000) 278(1):G156-G164.
23. HSIANG B, ZHU Y, WANG Z et al.: A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J. Biol. Chem. (1999) 274(52):37161-37168.
24. ABE T, KAKYO M, TOKUI T et al.: Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J. Biol. Chem. (1999) 274(24):17159-17163.
25. CUI Y, KONIG J, LEIER I, BUCHHOLZ U, KEPPLER D: Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J. Biol. Chem. (2001) 276(13):9626-9630.
26. KULLAK-UBLICK GA, ISMAIR MG, STIEGER B et al.: Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology (2001) 120(2):525-533.
27. FAUBION WA, GUICCIARDI ME, MIYOSHI H et al.: Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J. Clin. Invest. (1999) 103(1):137-145.
28. NAKATA K, TANAKA Y, NAKANO T et al.: Nuclear receptor-mediated xenobiotic procession loops in phase I, II, and III xenobiotic metabolizing systems. Drug Metab. Pharmacokinet. (2006) 21:437-457. •A comprehensive review article providing new aspects on nuclear receptors and trasnscriptional regulation of phase I, II, and III xenobiotic-metabolising systems.
29. SUCHY FJ, ANANTHANARAYANAN M: Bile salt excretory pump: biology and pathobiology. J. Pediatr. Gastroenterol. Nutr. (2006) 43(1 Suppl.):S10-S16.
30. CHIANG JY: Bile acid regulation of hepatic physiology: III. Bile acids and nuclear receptors. Am. J. Physiol. Gastrointest. Liver PhysioL (2003) 284(3):G349-G356.
31. CHILDS S, YEH RL, GEORGES E, LING V: Identification of a sister gene to P-glycoprotein. Cancer Res. (1995) 55(10):2029-2034.
32. 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.
33. WANG R, SALEM M, YOUSEF IM et al.: Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis. Proc. Natl. Acad. Sci. USA (2001) 98(4):2011-2016.
34. BORST P, ELFERINK RO: Mammalian ABC transporters in health and disease. Ann. Rev. Biochem. (2002) 71:537-592.
35. STRAUTNIEKS SS, BULL LN, KNISELY AS et al.: A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat. Genet. (1998) 20(3):233-238.
36. ARRESE M, ANANTHANARAYANAN M: The bile salt export pump: molecular properties, function and regulation. Pflugers Arch. (2004) 449(2):123-131.
37. NOE J, STIEGER B, MEIER PJ: Functional expression of the canalicular bile salt export pump of human liver. Gastroenterology (2002) 123(5):1659-1666.
38. WANG L, SOROKA CJ, BOYER JL: The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II. J. Clin. Invest. (2002) 110(7):965-972.
39. PAULI-MAGNUS C, LANG T, MEIERY et al.: Sequence analysis of bile salt export pump (ABCB 11) and multidrug resistance P-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics (2004) 14(2):91-102.
40. LAM CW, CHEUNG KM, TSUI MS et al.: A patient with novel ABCB 11 gene mutations with phenotypic transition between BRIC2 and PFIC2. J. Hepatol. (2006) 44(1):240-242.
41. MEIER Y, PAULI-MAGNUS C, ZANGER UM et al.: Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology (2006) 44(1):62-74.
42. STIEGER B, MEIER Y, MEIER PJ: The bile salt export pump. Pflugers Arch. (2006) (In Press).
43. NOE J, KULLAK-UBLICK GA, 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.
44. PAULI-MAGNUS C, KERB R, FATTINGER K et al.: BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology (2004) 39(3):779-791.
45. VAN MIL SW, VAN DER WOERD WL, VAN DER BRUGGE G et al.: Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology (2004) 127(2):379-384.
46. GOTO K, SUGIYAMA K, SUGIURA T et al.: Bile salt export pump gene mutations in two Japanese patients with progressive familial intrahepatic cholestasis. J. Pediatr. Gastroenterol. Nutr. (2003) 36(5):647-650.
47. JANSEN PL, STRAUTNIEKS SS, JACQUEMIN E et al.: Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology (1999) 117(6): 1370-1379.
48. KUBITZ R, KEITEL V, SCHEURING S, KOHRER K, HAUSSINGER D: Benign recurrent intrahepatic cholestasis associated with mutations of the bile salt export pump. J. Clin. Gastroenterol. (2006) 40(2):171-175.
49. SUMMERSKILL WH, WALSHE JM: Benign recurrent intrahepatic 'obstructive' jaundice. Lancet (1959) 2:686-690.
50. VALLEJO M, BRIZ O, SERRANO MA, MONTE MJ, MARIN JJ: 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.
51. SMIT JJ, SCHINKEL AH, OUDE ELFERINK RP et al.: Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell (1993) 75(3):451-462.
52. PAULI-MAGNUS C, MEIER PJ: Hepatobiliary transporters and drug-induced cholestasis. Hepatology (2006) 44(4):778-787.
53. WANG EJ, CASCIANO CN, CLEMENT RP, JOHNSON WW: Fluorescent substrates of sister-P-glycoprotein (BSEP) evaluated as markers of active transport and inhibition: evidence for contingent unequal binding sites. Pharm. Res. (2003) 20(4):537-544.
54. STIEGER B, FATTINGER K, MADON J, KULLAK-UBLICK GA, MEIER PJ: Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology (2000) 118(2):422-430.
55. NOE J, HAGENBUCH B, MEIER PJ, ST-PIERRE MV: Characterization of the mouse bile salt export pump overexpressed in the baculovirus system. Hepatology (2001) 33(5):1223-1231.
56. KOSTRUBSKY SE, STROM SC, KALGUTKAR AS et al.: Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol. Sci. (2006) 90(2):451-459.
57. HORIKAWA M, KATO Y, TYSON CA, SUGIYAMA Y: Potential cholestatic activity of various therapeutic agents assessed by bile canalicular membrane vesicles isolated from rats and humans. Drug Metab. Pharmacokinet. (2003) 18(1):16-22.
58. 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.
59. FUNK C, PANTZE M, JEHLE L et al.: Troglitazone-induced intrahepatic cholestasis by ah interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate. Toxicology (2001) 167(1):83-98.
60. 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.
61. BYRNE JA, STRAUTNIEKS SS, MIELI-VERGANI G et al.: The human bile salt export pump: characterization of substrate specificity and identification of inhibitors. Gastroenterology (2002) 123(5):1649-1658.
62. HIRANO M, MAEDA K, HAYASHI H, KUSUHARA H, SUGIYAMA Y: Bile salt export pump (BSEP/ABCB 11) can transport a nonbile acid substrate, pravastatin. J. Pharmacol. Exp. Ther. (2005) 314(2):876-882.
63. ISHIKAWA T, SAKURAI A, KANAMORI Y et al.: High-speed screening of human ATP-binding cassette transporter function and genetic polymorphisms: new strategies in pharmacogenomics. Methods Enzymol. (2005) 400:485-510.
64. HIRANO H, KURATA A, ONISHI Y et al.: High-speed screening and QSAR analysis of human ATP-binding cassette transporter ABCB 11 (bile salt export pump) to predict drug-induced intrahepatic cholestasis. Mol. Pharm. (2006) 3(3):252-265.
65. ISHIKAWA T, ONISHI Y, HIRANO H et al.: Pharmacogenomics of drug transporters: a new approach to functional analysis of the genetic polymorphisms of ABCB 1 (P-glycoprotein/MDR1). Biol. Pharm. Bull. (2004) 27(7):939-948.
66. ISHIKAWA T, HIRANO H, ONISHI Y, SAKURAI A, TARUI S: Functional evaluation of ABCB 1 (P-glycoprotein) polymorphisms: high-speed screening and structure-activity relationship analyses. Drug Metab. Pharmacokinet. (2004) 19(1):1-14.
67. HANSCH C: Quantitative structure-activity relationships and the unnamed science. Acc. Chem. Res. (1993) 26(4): 147-153.
68. HANSCH C: The physicochemical approach to drug design and discovery (QSAR). Drug Dev. Res. (1981) 1(4):267-309.
69. FUJITA T: Application of quantitative structure-activity relationship in drug design. Acta Pharm. Jugosl. (1987) 37:43-51.
70. SAITO H, HIRANO H, NAKAGAWA H et al.: A new strategy of high-speed screening and quantitative structure-activity relationship analysis to evaluate human ATP-binding cassette transporter ABCG2-drug interactions. J. Pharmacol. Exp. Ther. (2006) 317(3): 1114-1124.
71. MASUBUCHI Y: Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab. Pharmacokinet. (2006) 21(5):347-356.
72. SMITH MT: Mechanisms of troglitazone hepatotoxicity. Chem. Res. Toxicol. (2003) 16(6):679-687.
73. PARK BK, KITTERINGHAM NR, MAGGS JL, PIRMOHAMED M, WILLIAMS DP: The role of metabolic activation in drug-induced hepatotoxicity. Ann. Rev. Pharmacol. Toxicol. (2005) 45:177-202.
74. KAPLOWITZ N: Idiosyncratic drug hepatotoxicity. Nat. Rev. Drug Discov. (2005) 4(6):489-499.
75. AUSTIN CP, BRADY LS, INSEL TR, COLLINS FS: NIH Molecular Libraries Initiative. Science (2004) 306(5699): 1138-1139.