Skip to main content

The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation

  • Chapter
  • First Online:
Drug Transporters

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 201))

Abstract

Bile formation is an important function of the liver. Bile salts are a major constituent of bile and are secreted by hepatocytes into bile and delivered into the small intestine, where they assist in fat digestion. In the small intestine, bile salts are almost quantitatively reclaimed and transported back via the portal circulation to the liver. In the liver, hepatocytes take up bile salts and secrete them again into bile for ongoing enterohepatic circulation. Uptake of bile salts into hepatocytes occurs largely in a sodium-dependent manner by the sodium taurocholate cotransporting polypeptide NTCP. The transport properties of NTCP have been extensively characterized. It is an electrogenic member of the solute carrier family of transporters (SLC10A1) and transports predominantly bile salts and sulfated compounds, but is also able to mediate transport of additional substrates, such as thyroid hormones, drugs and toxins. It is highly regulated under physiologic and pathophysiologic conditions. Regulation of NTCP copes with changes of bile salt load to hepatocytes and prevents entry of cytotoxic bile salts during liver disease. Canalicular export of bile salts is mediated by the ATP-binding cassette transporter bile salt export pump BSEP (ABCB11). BSEP constitutes the rate limiting step of hepatocellular bile salt transport and drives enterohepatic circulation of bile salts. It is extensively regulated to keep intracellular bile salt levels low under normal and pathophysiologic situations. Mutations in the BSEP gene lead to severe progressive familial intrahepatic cholestasis. The substrates of BSEP are practically restricted to bile salts and their metabolites. It is, however, subject to inhibition by endogenous metabolites or by drugs. A sustained inhibition will lead to acquired cholestasis, which can end in liver injury.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Adachi Y, Kobayashi H, Kurumi Y, Shouji M, Kitano M, Yamamoto T (1991) ATP-dependent taurocholate transport by rat liver canalicular membrane vesicles. Hepatology 14:655–659

    CAS  PubMed  Google Scholar 

  • Agellon LB, Torchia EC (2000) Intracellular transport of bile acids. Biochim Biophys Acta 1486:198–209

    CAS  PubMed  Google Scholar 

  • Akita H, Suzuki H, Ito K, Kinoshita S, Sato N, Takikawa H, Sugiyama Y (2001) Characterization of bile acid transport mediated by multidrug resistance associated protein 2 and bile salt export pump. Biochim Biophys Acta 1511:7–16

    Article  CAS  PubMed  Google Scholar 

  • Alissa FT, Jaffe R, Shneider BL (2008) Update on progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr 46:241–252

    Article  PubMed  Google Scholar 

  • Alnouti Y (2009) Bile acid sulfation: a pathway of bile acid elimination and detoxification. Toxicol Sci 108:225–246

    Article  CAS  PubMed  Google Scholar 

  • Alrefai WA, Gill RK (2007) Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm Res 24:1803–1823

    Article  CAS  PubMed  Google Scholar 

  • Ananthanarayanan M, Ng OC, Boyer JL, Suchy FJ (1994) Characterization of cloned rat liver Na(+)-bile acid cotransporter using peptide and fusion protein antibodies. Am J Physiol 267:G637–G643

    CAS  PubMed  Google Scholar 

  • Andrade RJ, Lucena MI, Fernandez MC, Pelaez G, Pachkoria K, Garcia-Ruiz E, Garcia-Munoz B, Gonzalez-Grande R, Pizarro A, Duran JA, Jimenez M, Rodrigo L, Romero-Gomez M, Navarro JM, Planas R, Costa J, Borras A, Soler A, Salmeron J, Martin-Vivaldi R (2005) Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 129:512–521

    PubMed  Google Scholar 

  • Anwer MS (2004) Cellular regulation of hepatic bile acid transport in health and cholestasis. Hepatology 39:581–590

    Article  CAS  PubMed  Google Scholar 

  • Anwer MS, Kroker R, Hegner D (1976) Effect of albumin on bile acid uptake by isolated rat hepatocytes. Is there a common bile acid carrier? Biochem Biophys Res Commun 73:63–71

    Article  CAS  PubMed  Google Scholar 

  • Arias IM (1993) Cyclosporin, the biology of the bile canaliculus, and cholestasis. Gastroenterology 104:1558–1560

    CAS  PubMed  Google Scholar 

  • Arrese M, Trauner M, Ananthanarayanan M, Pizarro M, Solis N, Accatino L, Soroka C, Boyer JL, Karpen SJ, Miquel JF, Suchy FJ (2003) Down-regulation of the Na+/taurocholate cotransporting polypeptide during pregnancy in the rat. J Hepatol 38:148–155

    Article  CAS  PubMed  Google Scholar 

  • Atherfold PA, Jankowski JA (2006) Molecular biology of Barrett’s cancer. Best Pract Res Clin Gastroenterol 20:813–827

    Article  CAS  PubMed  Google Scholar 

  • Azer SA, Stacey NH (1993) Differential effects of cyclosporin A on the transport of bile acids by human hepatocytes. Biochem Pharmacol 46:813–819

    Article  CAS  PubMed  Google Scholar 

  • Baringhaus KH, Matter H, Stengelin S, Kramer W (1999) Substrate specificity of the ileal and the hepatic Na(+)/bile acid cotransporters of the rabbit. II. A reliable 3D QSAR pharmacophore model for the ileal Na(+)/bile acid cotransporter. J Lipid Res 40:2158–2168

    CAS  PubMed  Google Scholar 

  • Beuers U (2006) Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol 3:318–328

    Article  CAS  PubMed  Google Scholar 

  • Bleibel W, Kim S, D’Silva K, Lemmer ER (2007) Drug-induced liver injury: review article. Dig Dis Sci 52:2463–2471

    Article  PubMed  Google Scholar 

  • Blitzer BL, Lyons L (1985) Enhancement of Na+-dependent bile acid uptake by albumin: direct demonstration in rat basolateral liver plasma membrane vesicles. Am J Physiol 249:G34–G38

    CAS  PubMed  Google Scholar 

  • Blitzer BL, Ratoosh SL, Donovan CB, Boyer JL (1982) Effects of inhibitors of Na+-coupled ion transport on bile acid uptake by isolated rat hepatocytes. Am J Physiol 243:G48–G53

    CAS  PubMed  Google Scholar 

  • Bode KA, Donner MG, Leier I, Keppler D (2002) Inhibition of transport across the hepatocyte canalicular membrane by the antibiotic fusidate. Biochem Pharmacol 64:151–158

    Article  CAS  PubMed  Google Scholar 

  • Bohme M, Muller M, Leier I, Jedlitschky G, Keppler D (1994) Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in rat liver. Gastroenterology 107:255–265

    CAS  PubMed  Google Scholar 

  • Bolder U, Schmidt A, Landmann L, Kidder V, Tange S, Jauch KW (2002) Heat stress prevents impairment of bile acid transport in endotoxemic rats by a posttranscriptional mechanism. Gastroenterology 122:963–973

    Article  CAS  PubMed  Google Scholar 

  • Borst P, Elferink RO (2002) Mammalian ABC transporters in health and disease. Annu Rev Biochem 71:537–592

    Article  CAS  PubMed  Google Scholar 

  • Bossard R, Stieger B, O'Neill B, Fricker G, Meier PJ (1993) Ethinylestradiol treatment induces multiple canalicular membrane transport alterations in rat liver. J Clin Invest 91:2714–2720

    Article  CAS  PubMed  Google Scholar 

  • Bouchard G, Nelson HM, Lammert F, Rowe LB, Carey MC, Paigen B (1999) High-resolution maps of the murine Chromosome 2 region containing the cholesterol gallstone locus, Lith1. Mamm Genome 10:1070–1074

    Article  CAS  PubMed  Google Scholar 

  • Boyer JL, Graf J, Meier PJ (1992) Hepatic transport systems regulating pHi, cell volume, and bile secretion. Annu Rev Physiol 54:415–438

    CAS  PubMed  Google Scholar 

  • Boyer JL, Hagenbuch B, Ananthanarayanan M, Suchy F, Stieger B, Meier PJ (1993) Phylogenic and ontogenic expression of hepatocellular bile acid transport. Proc Natl Acad Sci USA 90:435–438

    Article  CAS  PubMed  Google Scholar 

  • Boyer JL, Ng OC, Ananthanarayanan M, Hofmann AF, Schteingart CD, Hagenbuch B, Stieger B, Meier PJ (1994) Expression and characterization of a functional rat liver Na+ bile acid cotransport system in COS-7 cells. Am J Physiol 266:G382–G387

    CAS  PubMed  Google Scholar 

  • Briz O, Serrano MA, Rebollo N, Hagenbuch B, Meier PJ, Koepsell H, Marin JJ (2002) Carriers involved in targeting the cytostatic bile acid-cisplatin derivatives cis-diammine-chloro-cholylglycinate-platinum(II) and cis-diammine-bisursodeoxycholate-platinum(II) toward liver cells. Mol Pharmacol 61:853–860

    Article  CAS  PubMed  Google Scholar 

  • Brown RS Jr, Lomri N, De VJ, Rahmaoui CM, Xie MH, Hua T, Lidofsky SD, Scharschmidt BF (1995) Enhanced secretion of glycocholic acid in a specially adapted cell line is associated with overexpression of apparently novel ATP-binding cassette proteins. Proc Natl Acad Sci USA 92:5421–5425

    Article  CAS  PubMed  Google Scholar 

  • Byrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ (2002) The human bile salt export pump: characterization of substrate specificity and identification of inhibitors. Gastroenterology 123:1649–1658

    Article  CAS  PubMed  Google Scholar 

  • Byrne JA, Strautnieks SS, Ihrke G, Pagani F, Knisely AS, Linton KJ, Mieli-Vergani G, Thompson RJ (2009) Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing. Hepatology 49:553–567

    Article  CAS  PubMed  Google Scholar 

  • Cai SY, Wang L, Ballatori N, Boyer JL (2001) Bile salt export pump is highly conserved during vertebrate evolution and its expression is inhibited by PFIC type II mutations. Am J Physiol Gastrointest Liver Physiol 281:G316–G322

    CAS  PubMed  Google Scholar 

  • Cao J, Huang L, Liu Y, Hoffman T, Stieger B, Meier PJ, Vore M (2001) Differential regulation of hepatic bile salt and organic anion transporters in pregnant and postpartum rats and the role of prolactin. Hepatology 33:140–147

    Article  CAS  PubMed  Google Scholar 

  • Carlton VE, Harris BZ, Puffenberger EG, Batta AK, Knisely AS, Robinson DL, Strauss KA, Shneider BL, Lim WA, Salen G, Morton DH, Bull LN (2003) Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nat Genet 34:91–96

    Article  CAS  PubMed  Google Scholar 

  • Cattori V, Eckhardt U, Hagenbuch B (1999) Molecular cloning and functional characterization of two alternatively spliced Ntcp isoforms from mouse liver1. Biochim Biophys Acta 1445:154–159

    CAS  PubMed  Google Scholar 

  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J (2008) Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 135:1924–1934

    Article  PubMed  Google Scholar 

  • Chan W, Calderon G, Swift AL, Moseley J, Li S, Hosoya H, Arias IM, Ortiz DF (2005) Myosin II regulatory light chain is required for trafficking of bile salt export protein to the apical membrane in Madin-Darby canine kidney cells. J Biol Chem 280:23741–23747

    Article  CAS  PubMed  Google Scholar 

  • Chen HL, Chen HL, Liu YJ, Feng CH, Wu CY, Shyu MK, Yuan RH, Chang MH (2005) Developmental expression of canalicular transporter genes in human liver. J Hepatol 43:472–477

    Article  CAS  PubMed  Google Scholar 

  • Chen Q, Kon J, Ooe H, Sasaki K, Mitaka T (2007) Selective proliferation of rat hepatocyte progenitor cells in serum-free culture. Nat Protoc 2:1197–1205

    Article  CAS  PubMed  Google Scholar 

  • Chen HL, Liu YJ, Chen HL, Wu SH, Ni YH, Ho MC, Lai HS, Hsu WM, Hsu HY, Tseng HC, Jeng YM, Chang MH (2008a) Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia. Pediatr Res 63:667–673

    Article  CAS  PubMed  Google Scholar 

  • Chen HL, Liu YJ, Su YN, Wang NY, Wu SH, Ni YH, Hsu HY, Wu TC, Chang MH (2008b) Diagnosis of BSEP/ABCB11 mutations in Asian patients with cholestasis using denaturing high performance liquid chromatography. J Pediatr 153:825–832

    Article  CAS  PubMed  Google Scholar 

  • Chen WM, Erdos MR, Jackson AU, Saxena R, Sanna S, Silver KD, Timpson NJ, Hansen T, Orru M, Grazia PM, Bonnycastle LL, Willer CJ, Lyssenko V, Shen H, Kuusisto J, Ebrahim S, Sestu N, Duren WL, Spada MC, Stringham HM, Scott LJ, Olla N, Swift AJ, Najjar S, Mitchell BD, Lawlor DA, Smith GD, Ben-Shlomo Y, Andersen G, Borch-Johnsen K, Jorgensen T, Saramies J, Valle TT, Buchanan TA, Shuldiner AR, Lakatta E, Bergman RN, Uda M, Tuomilehto J, Pedersen O, Cao A, Groop L, Mohlke KL, Laakso M, Schlessinger D, Collins FS, Altshuler D, Abecasis GR, Boehnke M, Scuteri A, Watanabe RM (2008c) Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels. J Clin Invest 118:2620–2628

    CAS  PubMed  Google Scholar 

  • Cheng Q, Aleksunes LM, Manautou JE, Cherrington NJ, Scheffer GL, Yamasaki H, Slitt AL (2008) Drug-metabolizing enzyme and transporter expression in a mouse model of diabetes and obesity. Mol Pharm 5:77–91

    Article  CAS  PubMed  Google Scholar 

  • Childs S, Yeh RL, Georges E, Ling V (1995) Identification of a sister gene to P-glycoprotein. Cancer Res 55:2029–2034

    CAS  PubMed  Google Scholar 

  • Chinese Human Liver Proteome Profiling Consortium (2010) First insight into the human liver proteome from PROTEOME(SKY)-LIVER(Hu) 1.0, a publicly available database. J Proteome Res 9(1):79–94

    Article  CAS  Google Scholar 

  • Cohn MA, Rounds DJ, Karpen SJ, Ananthanarayanan M, Suchy FJ (1995) Assignment of a rat liver Na+/bile acid cotransporter gene to chromosome 6q24. Mamm Genome 6:60

    Article  CAS  PubMed  Google Scholar 

  • Craddock AL, Love MW, Daniel RW, Kirby LC, Walters HC, Wong MH, Dawson PA (1998) Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter. Am J Physiol 274:G157–G169

    CAS  PubMed  Google Scholar 

  • Crawford JM (1996) Role of vesicle-mediated transport pathways in hepatocellular bile secretion. Semin Liver Dis 16:169–189

    Article  CAS  PubMed  Google Scholar 

  • Crawford JM, Berken CA, Gollan JL (1988) Role of the hepatocyte microtubular system in the excretion of bile salts and biliary lipid: implications for intracellular vesicular transport. J Lipid Res 29:144–156

    CAS  PubMed  Google Scholar 

  • Crocenzi FA, Mottino AD, Cao J, Veggi LM, Pozzi EJ, Vore M, Coleman R, Roma MG (2003a) Estradiol-17beta-d-glucuronide induces endocytic internalization of Bsep in rats. Am J Physiol Gastrointest Liver Physiol 285:G449–G459

    CAS  PubMed  Google Scholar 

  • Crocenzi FA, Mottino AD, Sanchez Pozzi EJ, Pellegrino JM, Rodriguez Garay EA, Milkiewicz P, Vore M, Coleman R, Roma MG (2003b) Impaired localisation and transport function of canalicular Bsep in taurolithocholate induced cholestasis in the rat. Gut 52:1170–1177

    Article  CAS  PubMed  Google Scholar 

  • Crocenzi FA, Basiglio CL, Perez LM, Portesio MS, Pozzi EJ, Roma MG (2005) Silibinin prevents cholestasis-associated retrieval of the bile salt export pump, Bsep, in isolated rat hepatocyte couplets: possible involvement of cAMP. Biochem Pharmacol 69:1113–1120

    Article  CAS  PubMed  Google Scholar 

  • Davis RA, Attie AD (2008) Deletion of the ileal basolateral bile acid transporter identifies the cellular sentinels that regulate the bile acid pool. Proc Natl Acad Sci U S A 105:4965–4966

    Article  CAS  PubMed  Google Scholar 

  • Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E (2009) Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis 4:1

    Article  PubMed  Google Scholar 

  • Dawson PA, Lan T, Rao A (2009) Bile acid transporters. J Lipid Res 50(12):2340–2357

    Article  CAS  PubMed  Google Scholar 

  • de Waart DR, Hausler S, Vlaming ML, Kunne C, Hanggi E, Gruss HJ, Oude Elferink RP, Stieger B (2010) Hepatic transport mechanisms of cholyl-L-lysyl-fluorescein. J Pharmacol Exp Ther 334:78–86

    Article  PubMed  CAS  Google Scholar 

  • de Zwart L, Scholten M, Monbaliu JG, Annaert PP, Van Houdt JM, Van den Wyngaert I, De Schaepdrijver LM, Bailey GP, Coogan TP, Coussement WC, Mannens GS (2008) The ontogeny of drug metabolizing enzymes and transporters in the rat. Reprod Toxicol 26:220–230

    Article  PubMed  CAS  Google Scholar 

  • Dietmaier A, Gasser R, Graf J, Peterlik M (1976) Investigations on the sodium dependence of bile acid fluxes in the isolated perfused rat liver. Biochim Biophys Acta 443:81–91

    Article  CAS  PubMed  Google Scholar 

  • Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F, Kubitz R, Keitel V, Glantz A, Mattsson LA, Marschall HU, Molokhia M, Moore GE, Linton KJ, Williamson C (2009) Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut 58:537–544

    Article  CAS  PubMed  Google Scholar 

  • Dombrowski F, Stieger B, Beuers U (2006) Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver. Lab Invest 86:166–174

    Article  CAS  PubMed  Google Scholar 

  • Donner MG, Schumacher S, Warskulat U, Heinemann J, Haussinger D (2007) Obstructive cholestasis induces TNF-alpha- and IL-1 -mediated periportal downregulation of Bsep and zonal regulation of Ntcp, Oatp1a4, and Oatp1b2. Am J Physiol Gastrointest Liver Physiol 293:G1134–G1146

    Article  CAS  PubMed  Google Scholar 

  • Dransfeld O, Gehrmann T, Kohrer K, Kircheis G, Holneicher C, Haussinger D, Wettstein M (2005) Oligonucleotide microarray analysis of differential transporter regulation in the regenerating rat liver. Liver Int 25:1243–1258

    Article  CAS  PubMed  Google Scholar 

  • Duffy MC, Blitzer BL, Boyer JL (1983) Direct determination of the driving forces for taurocholate uptake into rat liver plasma membrane vesicles. J Clin Invest 72:1470–1481

    Article  CAS  PubMed  Google Scholar 

  • Dumont M, Jacquemin E, D’Hont C, Descout C, Cresteil D, Haouzi D, Desrochers M, Stieger B, Hadchouel M, Erlinger S (1997) Expression of the liver Na+-independent organic anion transporting polypeptide (oatp-1) in rats with bile duct ligation. J Hepatol 27:1051–1056

    Article  CAS  PubMed  Google Scholar 

  • Elferink MG, Olinga P, Draaisma AL, Merema MT, Faber KN, Slooff MJ, Meijer DK, Groothuis GM (2004) LPS-induced downregulation of MRP2 and BSEP in human liver is due to a posttranscriptional process. Am J Physiol Gastrointest Liver Physiol 287:G1008–G1016

    Article  CAS  PubMed  Google Scholar 

  • El-Seaidy AZ, Mills CO, Elias E, Crawford JM (1997) Lack of evidence for vesicle trafficking of fluorescent bile salts in rat hepatocyte couplets. Am J Physiol 272:G298–G309

    CAS  PubMed  Google Scholar 

  • Erlinger S (1996) Do intracellular organelles have any role in transport of bile acids by hepatocytes? J Hepatol 24(Suppl 1):88–93

    CAS  PubMed  Google Scholar 

  • Esteller A (2008) Physiology of bile secretion. World J Gastroenterol 14:5641–5649

    Article  CAS  PubMed  Google Scholar 

  • Fattinger K, Cattori V, Hagenbuch B, Meier PJ, Stieger B (2000) Rifamycin SV and rifampicin exhibit differential inhibition of the hepatic rat organic anion transporting polypeptides, Oatp1 and Oatp2. Hepatology 32:82–86

    Article  CAS  PubMed  Google Scholar 

  • Fattinger K, Funk C, Pantze M, Weber C, Reichen J, Stieger B, Meier PJ (2001) The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther 69:223–231

    Article  CAS  PubMed  Google Scholar 

  • Favre N, Abergel A, Blanc P, Sapin V, Roszyk L, Gallot D (2009) Unusual presentation of severe intrahepatic cholestasis of pregnancy leading to fetal death. Obstet Gynecol 114:491–493

    Article  PubMed  Google Scholar 

  • Feng B, Xu JJ, Bi YA, Mireles R, Davidson R, Duignan DB, Campbell S, Kostrubsky VE, Dunn MC, Smith AR, Wang HF (2009) Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724, 714. Toxicol Sci 108:492–500

    Article  CAS  PubMed  Google Scholar 

  • Figge A, Lammert F, Paigen B, Henkel A, Matern S, Korstanje R, Shneider BL, Chen F, Stoltenberg E, Spatz K, Hoda F, Cohen DE, Green RM (2004) Hepatic overexpression of murine Abcb11 increases hepatobiliary lipid secretion and reduces hepatic steatosis. J Biol Chem 279:2790–2799

    Article  CAS  PubMed  Google Scholar 

  • Fitz JG, Scharschmidt BF (1987) Intracellular chloride activity in intact rat liver: relationship to membrane potential and bile flow. Am J Physiol 252:G699–G706

    CAS  PubMed  Google Scholar 

  • Follmann W, Petzinger E, Kinne RK (1990) Alterations of bile acid and bumetanide uptake during culturing of rat hepatocytes. Am J Physiol 258:C700–C712

    CAS  PubMed  Google Scholar 

  • Fouassier L, Kinnman N, Lefevre G, Lasnier E, Rey C, Poupon R, Elferink RP, Housset C (2002) Contribution of mrp2 in alterations of canalicular bile formation by the endothelin antagonist bosentan. J Hepatol 37:184–191

    Article  CAS  PubMed  Google Scholar 

  • Fouassier L, Beaussier M, Schiffer E, Rey C, Barbu V, Mergey M, Wendum D, Callard P, Scoazec JY, Lasnier E, Stieger B, Lienhart A, Housset C (2007) Hypoxia-induced changes in the expression of rat hepatobiliary transporter genes. Am J Physiol Gastrointest Liver Physiol 293:G25–G35

    Article  CAS  PubMed  Google Scholar 

  • Friesema EC, Docter R, Moerings EP, Stieger B, Hagenbuch B, Meier PJ, Krenning EP, Hennemann G, Visser TJ (1999) Identification of thyroid hormone transporters. Biochem Biophys Res Commun 254:497–501

    Article  CAS  PubMed  Google Scholar 

  • Fung KL, Gottesman MM (2009) A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta 1794:860–871

    CAS  PubMed  Google Scholar 

  • Funk C (2008) The role of hepatic transporters in drug elimination. Expert Opin Drug Metab Toxicol 4:363–379

    Article  CAS  PubMed  Google Scholar 

  • Funk C, Ponelle C, Scheuermann G, Pantze M (2001) Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat. Mol Pharmacol 59:627–635

    CAS  PubMed  Google Scholar 

  • Ganguly TC, Liu Y, Hyde JF, Hagenbuch B, Meier PJ, Vore M (1994) Prolactin increases hepatic Na+/taurocholate co-transport activity and messenger RNA post partum. Biochem J 303:33–36

    CAS  PubMed  Google Scholar 

  • Gao B, St Pierre MV, Stieger B, Meier PJ (2004) Differential expression of bile salt and organic anion transporters in developing rat liver. J Hepatol 41:201–208

    Article  CAS  PubMed  Google Scholar 

  • Gartung C, Ananthanarayanan M, Rahman MA, Schuele S, Nundy S, Soroka CJ, Stolz A, Suchy FJ, Boyer JL (1996) Down-regulation of expression and function of the rat liver Na+/bile acid cotransporter in extrahepatic cholestasis. Gastroenterology 110:199–209

    Article  CAS  PubMed  Google Scholar 

  • Gartung C, Schuele S, Schlosser SF, Boyer JL (1997) Expression of the rat liver Na+/taurocholate cotransporter is regulated in vivo by retention of biliary constituents but not their depletion. Hepatology 25:284–290

    CAS  PubMed  Google Scholar 

  • Gatmaitan ZC, Nies AT, Arias IM (1997) Regulation and translocation of ATP-dependent apical membrane proteins in rat liver. Am J Physiol 272:G1041–G1049

    CAS  PubMed  Google Scholar 

  • Geier A, Dietrich CG, Lammert F, Orth T, Mayet WJ, Matern S, Gartung C (2002a) Regulation of organic anion transporters in a new rat model of acute and chronic cholangitis resembling human primary sclerosing cholangitis. J Hepatol 36:718–724

    Article  CAS  PubMed  Google Scholar 

  • Geier A, Kim SK, Gerloff T, Dietrich CG, Lammert F, Karpen SJ, Stieger B, Meier PJ, Matern S, Gartung C (2002b) Hepatobiliary organic anion transporters are differentially regulated in acute toxic liver injury induced by carbon tetrachloride. J Hepatol 37:198–205

    Article  CAS  PubMed  Google Scholar 

  • Geier A, Dietrich CG, Voigt S, Kim SK, Gerloff T, Kullak-Ublick GA, Lorenzen J, Matern S, Gartung C (2003) Effects of proinflammatory cytokines on rat organic anion transporters during toxic liver injury and cholestasis. Hepatology 38:345–354

    Article  CAS  PubMed  Google Scholar 

  • Geier A, Wagner M, Dietrich CG, Trauner M (2007) Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. Biochim Biophys Acta 1773:283–308

    Article  CAS  PubMed  Google Scholar 

  • Gerloff T, Stieger B, Hagenbuch B, Madon J, Landmann L, Roth J, Hofmann AF, Meier PJ (1998) The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem 273:10046–10050

    Article  CAS  PubMed  Google Scholar 

  • Gerloff T, Geier A, Stieger B, Hagenbuch B, Meier PJ, Matern S, Gartung C (1999) Differential expression of basolateral and canalicular organic anion transporters during regeneration of rat liver. Gastroenterology 117:1408–1415

    Article  CAS  PubMed  Google Scholar 

  • Geuken E, Visser D, Kuipers F, Blokzijl H, Leuvenink HG, de Jong KP, Peeters PM, Jansen PL, Slooff MJ, Gouw AS, Porte RJ (2004) Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation. J Hepatol 41:1017–1025

    Article  CAS  PubMed  Google Scholar 

  • Geyer J, Wilke T, Petzinger E (2006) The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships. Naunyn Schmiedebergs Arch Pharmacol 372:413–431

    Article  CAS  PubMed  Google Scholar 

  • Green RM, Beier D, Gollan JL (1996) Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents. Gastroenterology 111:193–198

    Article  CAS  PubMed  Google Scholar 

  • Green RM, Gollan JL, Hagenbuch B, Meier PJ, Beier DR (1997) Regulation of hepatocyte bile salt transporters during hepatic regeneration. Am J Physiol 273:G621–G627

    CAS  PubMed  Google Scholar 

  • Green RM, Ananthanarayanan M, Suchy FJ, Beier DR (1998) Genetic mapping of the Na(+)-taurocholate cotransporting polypeptide to mouse chromosome 12. Mamm Genome 9:598

    Article  CAS  PubMed  Google Scholar 

  • Green RM, Hoda F, Ward KL (2000) Molecular cloning and characterization of the murine bile salt export pump. Gene 241:117–123

    Article  CAS  PubMed  Google Scholar 

  • Gundala S, Wells LD, Milliano MT, Talkad V, Luxon BA, Neuschwander-Tetri BA (2004) The hepatocellular bile acid transporter Ntcp facilitates uptake of the lethal mushroom toxin alpha-amanitin. Arch Toxicol 78:68–73

    Article  CAS  PubMed  Google Scholar 

  • Hagenbuch B (1997) Molecular properties of hepatic uptake systems for bile acids and organic anions. J Membr Biol 160:1–8

    Article  CAS  PubMed  Google Scholar 

  • Hagenbuch B, Dawson P (2004) The sodium bile salt cotransport family SLC10. Pflugers Arch 447:566–570

    Article  CAS  PubMed  Google Scholar 

  • Hagenbuch B, Meier PJ (1994) Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter. J Clin Invest 93:1326–1331

    Article  CAS  PubMed  Google Scholar 

  • Hagenbuch B, Meier PJ (1996) Sinusoidal (basolateral) bile salt uptake systems of hepatocytes. Semin Liver Dis 16:129–136

    Article  CAS  PubMed  Google Scholar 

  • Hagenbuch B, Lubbert H, Stieger B, Meier PJ (1990) Expression of the hepatocyte Na+/bile acid cotransporter in Xenopus laevis oocytes. J Biol Chem 265:5357–5360

    CAS  PubMed  Google Scholar 

  • Hagenbuch B, Stieger B, Foguet M, Lubbert H, Meier PJ (1991) Functional expression cloning and characterization of the hepatocyte Na+/bile acid cotransport system. Proc Natl Acad Sci USA 88:10629–10633

    Article  CAS  PubMed  Google Scholar 

  • Hallen S, Mareninova O, Branden M, Sachs G (2002) Organization of the membrane domain of the human liver sodium/bile acid cotransporter. Biochemistry 41:7253–7266

    Article  CAS  PubMed  Google Scholar 

  • Hardikar W, Ananthanarayanan M, Suchy FJ (1995) Differential ontogenic regulation of basolateral and canalicular bile acid transport proteins in rat liver. J Biol Chem 270:20841–20846

    Article  CAS  PubMed  Google Scholar 

  • Hartmann G, Cheung AK, Piquette-Miller M (2002) Inflammatory cytokines, but not bile acids, regulate expression of murine hepatic anion transporters in endotoxemia. J Pharmacol Exp Ther 303:273–281

    Article  CAS  PubMed  Google Scholar 

  • Hata S, Wang P, Eftychiou N, Ananthanarayanan M, Batta A, Salen G, Pang KS, Wolkoff AW (2003) Substrate specificities of rat oatp1 and ntcp: implications for hepatic organic anion uptake. Am J Physiol Gastrointest Liver Physiol 285:G829–G839

    CAS  PubMed  Google Scholar 

  • Hayakawa T, Bruck R, Ng OC, Boyer JL (1990) DBcAMP stimulates vesicle transport and HRP excretion in isolated perfused rat liver. Am J Physiol 259:G727–G735

    CAS  PubMed  Google Scholar 

  • Hayashi H, Sugiyama Y (2007) 4-phenylbutyrate enhances the cell surface expression and the transport capacity of wild-type and mutated bile salt export pumps. Hepatology 45:1506–1516

    Article  CAS  PubMed  Google Scholar 

  • Hayashi H, Sugiyama Y (2009) Short-chain ubiquitination is associated with the degradation rate of a cell-surface-resident bile salt export pump (BSEP/ABCB11). Mol Pharmacol 75:143–150

    Article  CAS  PubMed  Google Scholar 

  • Hayashi H, Takada T, Suzuki H, Akita H, Sugiyama Y (2005a) Two common PFIC2 mutations are associated with the impaired membrane trafficking of BSEP/ABCB11. Hepatology 41:916–924

    Article  CAS  PubMed  Google Scholar 

  • Hayashi H, Takada T, Suzuki H, Onuki R, Hofmann AF, Sugiyama Y (2005b) 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 1738:54–62

    CAS  PubMed  Google Scholar 

  • Hediger MA, Romero MF, Peng JB, Rolfs A, Takanaga H, Bruford EA (2004) The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction. Pflugers Arch 447:465–468

    Article  CAS  PubMed  Google Scholar 

  • Heemskerk S, van Koppen A, van den Broek L, Poelen GJ, Wouterse AC, Dijkman HB, Russel FG, Masereeuw R (2007) Nitric oxide differentially regulates renal ATP-binding cassette transporters during endotoxemia. Pflugers Arch 454:321–334

    Article  CAS  PubMed  Google Scholar 

  • Henkel A, Wei Z, Cohen DE, Green RM (2005) Mice overexpressing hepatic Abcb11 rapidly develop cholesterol gallstones. Mamm Genome 16:903–908

    Article  CAS  PubMed  Google Scholar 

  • Higgins CF (1992) ABC transporters: from microorganisms to man. Annu Rev Cell Biol 8:67–113

    Article  CAS  PubMed  Google Scholar 

  • Higgins CF, Gottesman MM (1992) Is the multidrug transporter a flippase? Trends Biochem Sci 17:18–21

    Article  CAS  PubMed  Google Scholar 

  • Hilgendorf C, Ahlin G, Seithel A, Artursson P, Ungell AL, Karlsson J (2007) Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines. Drug Metab Dispos 35:1333–1340

    Article  CAS  PubMed  Google Scholar 

  • Hirano M, Maeda K, Hayashi H, Kusuhara H, Sugiyama Y (2005) Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin. J Pharmacol Exp Ther 314:876–882

    Article  CAS  PubMed  Google Scholar 

  • Hirano H, Kurata A, Onishi Y, Sakurai A, Saito H, Nakagawa H, Nagakura M, Tarui S, Kanamori Y, Kitajima M, Ishikawa T (2006) High-speed screening and QSAR analysis of human ATP-binding cassette transporter ABCB11 (bile salt export pump) to predict drug-induced intrahepatic cholestasis. Mol Pharm 3:252–265

    Article  CAS  PubMed  Google Scholar 

  • Ho RH, Leake BF, Roberts RL, Lee W, Kim RB (2004) Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition. J Biol Chem 279:7213–7222

    Article  CAS  PubMed  Google Scholar 

  • Ho RH, Tirona RG, Leake BF, Glaeser H, Lee W, Lemke CJ, Wang Y, Kim RB (2006) Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 130:1793–1806

    Article  CAS  PubMed  Google Scholar 

  • Hoekstra H, Porte RJ, Tian Y, Jochum W, Stieger B, Moritz W, Slooff MJ, Graf R, Clavien PA (2006) Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2+/− mice. Hepatology 43:1022–1031

    Article  CAS  PubMed  Google Scholar 

  • Hoekstra H, Tian Y, Jochum W, Stieger B, Graf R, Porte RJ, Clavien PA (2008) Dearterialization of the liver causes intrahepatic cholestasis due to reduced bile transporter expression. Transplantation 85:1159–1166

    Article  PubMed  Google Scholar 

  • Hofmann AF (1999) Bile acids: the good, the bad, and the ugly. News Physiol Sci 14:24–29

    CAS  PubMed  Google Scholar 

  • Hofmann AF (2009) Bile acids: trying to understand their chemistry and biology with the hope of helping patients. Hepatology 49:1403–1418

    Article  CAS  PubMed  Google Scholar 

  • Hofmann AF, Hagey LR (2008) Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci 65:2461–2483

    Article  CAS  PubMed  Google Scholar 

  • Hofmann AF, Mangelsdorf DJ, Kliewer SA (2009) Chronic diarrhea due to excessive bile acid synthesis and not defective ileal transport: a new syndrome of defective fibroblast growth factor 19 release. Clin Gastroenterol Hepatol 7:1151–1154

    Article  CAS  PubMed  Google Scholar 

  • Honscha W, Platte HD, Oesch F, Friedberg T (1995) Relationship between the microsomal epoxide hydrolase and the hepatocellular transport of bile acids and xenobiotics. Biochem J 311:975–979

    CAS  PubMed  Google Scholar 

  • Horikawa M, Kato Y, Tyson CA, Sugiyama Y (2003) Potential cholestatic activity of various therapeutic agents assessed by bile canalicular membrane vesicles isolated from rats and humans. Drug Metab Pharmacokinet 18:16–22

    Article  CAS  PubMed  Google Scholar 

  • Houten SM, Watanabe M, Auwerx J (2006) Endocrine functions of bile acids. EMBO J 25:1419–1425

    Article  CAS  PubMed  Google Scholar 

  • Hsu YC, Chen HL, Wu MZ, Liu YJ, Lee PH, Sheu JC, Chen CH (2009) Adult progressive intrahepatic cholestasis associated with genetic variations in ATP8B1 and ABCB11. Hepatol Res 39:625–631

    Article  CAS  PubMed  Google Scholar 

  • Huang L, Smit JW, Meijer DK, Vore M (2000) Mrp2 is essential for estradiol-17beta(beta-d-glucuronide)-induced cholestasis in rats. Hepatology 32:66–72

    Article  CAS  PubMed  Google Scholar 

  • Ikegawa S, Yamamoto T, Ito H, Ishiwata S, Sakai T, Mitamura K, Maeda M (2008) Immunoprecipitation and MALDI-MS identification of lithocholic acid-tagged proteins in liver of bile duct-ligated rats. J Lipid Res 49:2463–2473

    Article  CAS  PubMed  Google Scholar 

  • Imai S, Kikuchi R, Kusuhara H, Yagi S, Shiota K, Sugiyama Y (2009) Analysis of DNA methylation and histone modification profiles of liver-specific transporters. Mol Pharmacol 75:568–576

    Article  CAS  PubMed  Google Scholar 

  • Inoue M, Kinne R, Tran T, Arias IM (1982) Taurocholate transport by rat liver sinusoidal membrane vesicles: evidence of sodium cotransport. Hepatology 2:572–579

    Article  CAS  PubMed  Google Scholar 

  • Ismair MG, Hausler S, Stuermer CA, Guyot C, Meier PJ, Roth J, Stieger B (2009) ABC-transporters are localized in caveolin-1-positive and reggie-1-negative and reggie-2-negative microdomains of the canalicular membrane in rat hepatocytes. Hepatology 49:1673–1682

    Article  CAS  PubMed  Google Scholar 

  • Jansen PL, Strautnieks SS, Jacquemin E, Hadchouel M, Sokal EM, Hooiveld GJ, Koning JH, De Jager-Krikken A, Kuipers F, Stellaard F, Bijleveld CM, Gouw A, Van GH, Thompson RJ, Muller M (1999) Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology 117:1370–1379

    Article  CAS  PubMed  Google Scholar 

  • Jara P, Hierro L, Martinez-Fernandez P, Alvarez-Doforno R, Yanez F, Diaz MC, Camarena C, De la Vega A, Frauca E, Munoz-Bartolo G, Lopez-Santamaria M, Larrauri J, Alvarez L (2009) Recurrence of bile salt export pump deficiency after liver transplantation. N Engl J Med 361:1359–1367

    Article  CAS  PubMed  Google Scholar 

  • Kagawa T, Watanabe N, Mochizuki K, Numari A, Ikeno Y, Itoh J, Tanaka H, Arias IM, Mine T (2008) Phenotypic differences in PFIC2 and BRIC2 correlate with protein stability of mutant Bsep and impaired taurocholate secretion in MDCK II cells. Am J Physiol Gastrointest Liver Physiol 294:G58–G67

    Article  CAS  PubMed  Google Scholar 

  • Kaplowitz N (2005) Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 4:489–499

    Article  CAS  PubMed  Google Scholar 

  • Kato T, Hayashi H, Sugiyama Y (2010) Short- and medium-chain fatty acids enhance the cell surface expression and transport capacity of the bile salt export pump (BSEP/ABCB11). Biochim Biophys Acta 1801:1005–1012

    CAS  PubMed  Google Scholar 

  • Keitel V, Burdelski M, Warskulat U, Kuhlkamp T, Keppler D, Haussinger D, Kubitz R (2005) Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis. Hepatology 41:1160–1172

    Article  CAS  PubMed  Google Scholar 

  • Keitel V, Vogt C, Haussinger D, Kubitz R (2006) Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy. Gastroenterology 131:624–629

    Article  CAS  PubMed  Google Scholar 

  • Keitel V, Kubitz R, Haussinger D (2008) Endocrine and paracrine role of bile acids. World J Gastroenterol 14:5620–5629

    Article  CAS  PubMed  Google Scholar 

  • Keitel V, Burdelski M, Vojnisek Z, Schmitt L, Haussinger D, Kubitz R (2009) De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis. Hepatology 50:510–517

    Article  CAS  PubMed  Google Scholar 

  • Kemp DC, Zamek-Gliszczynski MJ, Brouwer KL (2005) Xenobiotics inhibit hepatic uptake and biliary excretion of taurocholate in rat hepatocytes. Toxicol Sci 83:207–214

    Article  CAS  PubMed  Google Scholar 

  • Kim RB, Leake B, Cvetkovic M, Roden MM, Nadeau J, Walubo A, Wilkinson GR (1999) Modulation by drugs of human hepatic sodium-dependent bile acid transporter (sodium taurocholate cotransporting polypeptide) activity. J Pharmacol Exp Ther 291:1204–1209

    CAS  PubMed  Google Scholar 

  • Kim JY, Kim KH, Lee JA, Namkung W, Sun AQ, Ananthanarayanan M, Suchy FJ, Shin DM, Muallem S, Lee MG (2002) Transporter-mediated bile acid uptake causes Ca2+-dependent cell death in rat pancreatic acinar cells. Gastroenterology 122:1941–1953

    Article  CAS  PubMed  Google Scholar 

  • Kim SR, Saito Y, Itoda M, Maekawa K, Kawamoto M, Kamatani N, Ozawa S, Sawada J (2009) Genetic variations of the ABC transporter gene ABCB11 encoding the human bile salt export pump (BSEP) in a Japanese population. Drug Metab Pharmacokinet 24:277–281

    Article  CAS  PubMed  Google Scholar 

  • Kipp H, Arias IM (2002) Trafficking of canalicular ABC transporters in hepatocytes. Annu Rev Physiol 64:595–608

    Article  CAS  PubMed  Google Scholar 

  • Kipp H, Pichetshote N, Arias IM (2001) Transporters on demand: intrahepatic pools of canalicular ATP binding cassette transporters in rat liver. J Biol Chem 276:7218–7224

    Article  CAS  PubMed  Google Scholar 

  • Kis E, Ioja E, Nagy T, Szente L, Heredi-Szabo K, Krajcsi P (2009a) Effect of membrane cholesterol on BSEP/Bsep activity: species specificity studies for substrates and inhibitors. Drug Metab Dispos 37:1878–1886

    Article  CAS  PubMed  Google Scholar 

  • Kis E, Rajnai Z, Ioja E, Heredi SK, Nagy T, Mehn D, Krajcsi P (2009b) Mouse Bsep ATPase assay: a nonradioactive tool for assessment of the cholestatic potential of drugs. J Biomol Screen 14:10–15

    Article  CAS  PubMed  Google Scholar 

  • Klein I, Sarkadi B, Varadi A (1999) An inventory of the human ABC proteins. Biochim Biophys Acta 1461:237–262

    Article  CAS  PubMed  Google Scholar 

  • Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, Bull LN, Pawlikowska L, Bilezikci B, Ozcay F, Laszlo A, Tiszlavicz L, Moore L, Raftos J, Arnell H, Fischler B, Nemeth A, Papadogiannakis N, Cielecka-Kuszyk J, Jankowska I, Pawlowska J, Melin-Aldana H, Emerick KM, Whitington PF, Mieli-Vergani G, Thompson RJ (2006) Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology 44:478–486

    Article  CAS  PubMed  Google Scholar 

  • Kojima H, Nies AT, Konig J, Hagmann W, Spring H, Uemura M, Fukui H, Keppler D (2003) Changes in the expression and localization of hepatocellular transporters and radixin in primary biliary cirrhosis. J Hepatol 39:693–702

    Article  CAS  PubMed  Google Scholar 

  • Kong FM, Sui CY, Li YJ, Guo KJ, Guo RX (2006) Hepatobiliary membrane transporters involving in the formation of cholesterol calculus. Hepatobiliary Pancreat Dis Int 5:286–289

    CAS  PubMed  Google Scholar 

  • Konieczko EM, Ralston AK, Crawford AR, Karpen SJ, Crawford JM (1998) Enhanced Na+-dependent bile salt uptake by WIF-B cells, a rat hepatoma hybrid cell line, following growth in the presence of a physiological bile salt. Hepatology 27:191–199

    Article  CAS  PubMed  Google Scholar 

  • Koopen NR, Wolters H, Muller M, Schippers IJ, Havinga R, Roelofsen H, Vonk RJ, Stieger B, Meier PJ, Kuipers F (1997) Hepatic bile salt flux does not modulate level and activity of the sinusoidal Na+-taurocholate cotransporter (ntcp) in rats. J Hepatol 27:699–706

    Article  CAS  PubMed  Google Scholar 

  • Kosters A, Karpen SJ (2008) Bile acid transporters in health and disease. Xenobiotica 38:1043–1071

    Article  CAS  PubMed  Google Scholar 

  • Kostrubsky VE, Strom SC, Hanson J, Urda E, Rose K, Burliegh J, Zocharski P, Cai H, Sinclair JF, Sahi J (2003) Evaluation of hepatotoxic potential of drugs by inhibition of bile-acid transport in cultured primary human hepatocytes and intact rats. Toxicol Sci 76:220–228

    Article  CAS  PubMed  Google Scholar 

  • Kostrubsky SE, Strom SC, Kalgutkar AS, Kulkarni S, Atherton J, Mireles R, Feng B, Kubik R, Hanson J, Urda E, Mutlib AE (2006) Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol Sci 90:451–459

    Article  CAS  PubMed  Google Scholar 

  • Kouzuki H, Suzuki H, Ito K, Ohashi R, Sugiyama Y (1998) Contribution of sodium taurocholate co-transporting polypeptide to the uptake of its possible substrates into rat hepatocytes. J Pharmacol Exp Ther 286:1043–1050

    CAS  PubMed  Google Scholar 

  • Krahenbuhl S, Talos C, Fischer S, Reichen J (1994) Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria. Hepatology 19:471–479

    CAS  PubMed  Google Scholar 

  • Kramer W, Stengelin S, Baringhaus KH, Enhsen A, Heuer H, Becker W, Corsiero D, Girbig F, Noll R, Weyland C (1999) Substrate specificity of the ileal and the hepatic Na(+)/bile acid cotransporters of the rabbit. I. Transport studies with membrane vesicles and cell lines expressing the cloned transporters. J Lipid Res 40:1604–1617

    CAS  PubMed  Google Scholar 

  • Kubitz R, Saha N, Kuhlkamp T, Dutta S, vom Dahl S, Wettstein M, Haussinger D (2004a) Ca2+-dependent protein kinase C isoforms induce cholestasis in rat liver. J Biol Chem 279:10323–10330

    Article  CAS  PubMed  Google Scholar 

  • Kubitz R, Sutfels G, Kuhlkamp T, Kolling R, Haussinger D (2004b) Trafficking of the bile salt export pump from the Golgi to the canalicular membrane is regulated by the p38 MAP kinase. Gastroenterology 126:541–553

    Article  CAS  PubMed  Google Scholar 

  • Kubitz R, Keitel V, Scheuring S, Kohrer K, Haussinger D (2006) Benign recurrent intrahepatic cholestasis associated with mutations of the bile salt export pump. J Clin Gastroenterol 40:171–175

    Article  PubMed  Google Scholar 

  • Kuhlkamp T, Keitel V, Helmer A, Haussinger D, Kubitz R (2005) Degradation of the sodium taurocholate cotransporting polypeptide (NTCP) by the ubiquitin-proteasome system. Biol Chem 386:1065–1074

    Article  PubMed  CAS  Google Scholar 

  • Kuhn WF, Gewirtz DA (1988) Stimulation of taurocholate and glycocholate efflux from the rat hepatocyte by arginine vasopressin. Am J Physiol 254:G732–G740

    CAS  PubMed  Google Scholar 

  • Kullak-Ublick GA, Beuers U, Paumgartner G (1996) Molecular and functional characterization of bile acid transport in human hepatoblastoma HepG2 cells. Hepatology 23:1053–1060

    Article  CAS  PubMed  Google Scholar 

  • Kullak-Ublick GA, Glasa J, Boker C, Oswald M, Grutzner U, Hagenbuch B, Stieger B, Meier PJ, Beuers U, Kramer W, Wess G, Paumgartner G (1997) Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas. Gastroenterology 113:1295–1305

    Article  CAS  PubMed  Google Scholar 

  • Kullak-Ublick GA, Ismair MG, Kubitz R, Schmitt M, Haussinger D, Stieger B, Hagenbuch B, Meier PJ, Beuers U, Paumgartner G (2000a) Stable expression and functional characterization of a Na+-taurocholate cotransporting green fluorescent protein in human hepatoblastoma HepG2 cells. Cytotechnology 34:1–9

    Article  CAS  PubMed  Google Scholar 

  • Kullak-Ublick GA, Stieger B, Hagenbuch B, Meier PJ (2000b) Hepatic transport of bile salts. Semin Liver Dis 20:273–292

    Article  CAS  PubMed  Google Scholar 

  • Kullak-Ublick GA, Stieger B, Meier PJ (2004) Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 126:322–342

    Article  CAS  PubMed  Google Scholar 

  • Lam P, Wang R, Ling V (2005) Bile acid transport in sister of P-glycoprotein (ABCB11) knockout mice. Biochemistry 44:12598–12605

    Article  CAS  PubMed  Google Scholar 

  • Lam CW, Cheung KM, Tsui MS, Yan MS, Lee CY, Tong SF (2006) A patient with novel ABCB11 gene mutations with phenotypic transition between BRIC2 and PFIC2. J Hepatol 44:240–242

    Article  CAS  PubMed  Google Scholar 

  • Lam P, Pearson CL, Soroka CJ, Xu S, Mennone A, Boyer JL (2007) Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases. Am J Physiol Cell Physiol 293:C1709–C1716

    Article  CAS  PubMed  Google Scholar 

  • Lamri Y, Roda A, Dumont M, Feldmann G, Erlinger S (1988) Immunoperoxidase localization of bile salts in rat liver cells. Evidence for a role of the Golgi apparatus in bile salt transport. J Clin Invest 82:1173–1182

    Article  CAS  PubMed  Google Scholar 

  • Lang T, Haberl M, Jung D, Drescher A, Schlagenhaufer R, Keil A, Mornhinweg E, Stieger B, Kullak-Ublick GA, Kerb R (2006) Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11). Drug Metab Dispos 34:1582–1599

    Article  CAS  PubMed  Google Scholar 

  • Lang C, Meier Y, Stieger B, Beuers U, Lang T, Kerb R, Kullak-Ublick GA, Meier PJ, Pauli-Magnus C (2007) Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury. Pharmacogenet Genomics 17:47–60

    Article  CAS  PubMed  Google Scholar 

  • Langmann T, Mauerer R, Zahn A, Moehle C, Probst M, Stremmel W, Schmitz G (2003) Real-time reverse transcription-PCR expression profiling of the complete human ATP-binding cassette transporter superfamily in various tissues. Clin Chem 49:230–238

    Article  CAS  PubMed  Google Scholar 

  • Le VM, Jigorel E, Glaise D, Gripon P, Guguen-Guillouzo C, Fardel O (2006) Functional expression of sinusoidal and canalicular hepatic drug transporters in the differentiated human hepatoma HepaRG cell line. Eur J Pharm Sci 28:109–117

    Article  CAS  Google Scholar 

  • Le VM, Gripon P, Stieger B, Fardel O (2008) Down-regulation of organic anion transporter expression in human hepatocytes exposed to the proinflammatory cytokine interleukin 1beta. Drug Metab Dispos 36:217–222

    Article  CAS  Google Scholar 

  • Le VM, Lecureur V, Moreau A, Stieger B, Fardel O (2009) Differential regulation of drug transporter expression by hepatocyte growth factor in primary human hepatocytes. Drug Metab Dispos 37:2228–2235

    Article  CAS  Google Scholar 

  • Leazer TM, Klaassen CD (2003) The presence of xenobiotic transporters in rat placenta. Drug Metab Dispos 31:153–167

    Article  CAS  PubMed  Google Scholar 

  • Lecureur V, Sun D, Hargrove P, Schuetz EG, Kim RB, Lan LB, Schuetz JD (2000) Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein. Mol Pharmacol 57:24–35

    CAS  PubMed  Google Scholar 

  • Lee JM, Trauner M, Soroka CJ, Stieger B, Meier PJ, Boyer JL (2000) Expression of the bile salt export pump is maintained after chronic cholestasis in the rat. Gastroenterology 118:163–172

    Article  CAS  PubMed  Google Scholar 

  • Leslie EM, Watkins PB, Kim RB, Brouwer KL (2007) Differential inhibition of rat and human Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1) by bosentan: a mechanism for species differences in hepatotoxicity. J Pharmacol Exp Ther 321:1170–1178

    Article  CAS  PubMed  Google Scholar 

  • Liang D, Hagenbuch B, Stieger B, Meier PJ (1993) Parallel decrease of Na(+)-taurocholate cotransport and its encoding mRNA in primary cultures of rat hepatocytes. Hepatology 18:1162–1166

    CAS  PubMed  Google Scholar 

  • Lindberg MC (1992) Hepatobiliary complications of oral contraceptives. J Gen Intern Med 7:199–209

    Article  CAS  PubMed  Google Scholar 

  • Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R (2008) SLCO1B1 variants and statin-induced myopathy – a genomewide study. N Engl J Med 359:789–799

    Article  CAS  PubMed  Google Scholar 

  • Little JM, Richey JE, Van Thiel DH, Lester R (1979) Taurocholate pool size and distribution in the fetal rat. J Clin Invest 63:1042–1049

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Suchy FJ, Silverman JA, Vore M (1997) Prolactin increases ATP-dependent taurocholate transport in canalicular plasma membrane from rat liver. Am J Physiol 272:G46–G53

    CAS  PubMed  Google Scholar 

  • Locher KP (2009) Review. Structure and mechanism of ATP-binding cassette transporters. Philos Trans R Soc Lond B Biol Sci 364:239–245

    Article  CAS  PubMed  Google Scholar 

  • Lomri N, Fitz JG, Scharschmidt BF (1996) Hepatocellular transport: role of ATP-binding cassette proteins. Semin Liver Dis 16:201–210

    Article  CAS  PubMed  Google Scholar 

  • Lucena MI, Andrade RJ, Kaplowitz N, Garcia-Cortes M, Fernandez MC, Romero-Gomez M, Bruguera M, Hallal H, Robles-Diaz M, Rodriguez-Gonzalez JF, Navarro JM, Salmeron J, Martinez-Odriozola P, Perez-Alvarez R, Borraz Y, Hidalgo R (2009) Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatology 49:2001–2009

    Article  PubMed  Google Scholar 

  • Ma K, Xiao R, Tseng HT, Shan L, Fu L, Moore DD (2009) Circadian dysregulation disrupts bile acid homeostasis. PLoS ONE 4:e6843

    Article  PubMed  CAS  Google Scholar 

  • Macias RI, Marin JJ, Serrano MA (2009) Excretion of biliary compounds during intrauterine life. World J Gastroenterol 15:817–828

    Article  CAS  PubMed  Google Scholar 

  • Maeda K, Kambara M, Tian Y, Hofmann AF, Sugiyama Y (2006) Uptake of ursodeoxycholate and its conjugates by human hepatocytes: role of Na(+)-taurocholate cotransporting polypeptide (NTCP), organic anion transporting polypeptide (OATP) 1B1 (OATP-C), and oatp1B3 (OATP8). Mol Pharm 3:70–77

    Article  CAS  PubMed  Google Scholar 

  • Mano Y, Usui T, Kamimura H (2007) Effects of bosentan, an endothelin receptor antagonist, on bile salt export pump and multidrug resistance-associated protein 2. Biopharm Drug Dispos 28:13–18

    Article  CAS  PubMed  Google Scholar 

  • Mareninova O, Shin JM, Vagin O, Turdikulova S, Hallen S, Sachs G (2005) Topography of the membrane domain of the liver Na+-dependent bile acid transporter. Biochemistry 44:13702–13712

    Article  CAS  PubMed  Google Scholar 

  • Marin JJ, Macias RI, Briz O, Perez MJ, Blazquez AG, Arrese M, Serrano MA (2008) Molecular bases of the fetal liver-placenta-maternal liver excretory pathway for cholephilic compounds. Liver Int 28:435–454

    Article  CAS  PubMed  Google Scholar 

  • Marin JJ, Briz O, Perez MJ, Romero MR, Monte MJ (2009) Hepatobiliary transporters in the pharmacology and toxicology of anticancer drugs. Front Biosci 14:4257–4280

    Article  CAS  PubMed  Google Scholar 

  • Marion TL, Leslie EM, Brouwer KL (2007) Use of sandwich-cultured hepatocytes to evaluate impaired bile acid transport as a mechanism of drug-induced hepatotoxicity. Mol Pharm 4:911–918

    Article  CAS  PubMed  Google Scholar 

  • Marks DL, LaRusso NF, McNiven MA (1995) Isolation of the microtubule-vesicle motor kinesin from rat liver: selective inhibition by cholestatic bile acids. Gastroenterology 108:824–833

    Article  CAS  PubMed  Google Scholar 

  • Marschall HU, Wagner M, Zollner G, Fickert P, Diczfalusy U, Gumhold J, Silbert D, Fuchsbichler A, Benthin L, Grundstrom R, Gustafsson U, Sahlin S, Einarsson C, Trauner M (2005) Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology 129:476–485

    PubMed  Google Scholar 

  • McRae MP, Lowe CM, Tian X, Bourdet DL, Ho RH, Leake BF, Kim RB, Brouwer KL, Kashuba AD (2006) Ritonavir, saquinavir, and efavirenz, but not nevirapine, inhibit bile acid transport in human and rat hepatocytes. J Pharmacol Exp Ther 318:1068–1075

    Article  CAS  PubMed  Google Scholar 

  • Meier PJ, Stieger B (2002) Bile salt transporters. Annu Rev Physiol 64:635–661

    Article  CAS  PubMed  Google Scholar 

  • Meier PJ, Eckhardt U, Schroeder A, Hagenbuch B, Stieger B (1997) Substrate specificity of sinusoidal bile acid and organic anion uptake systems in rat and human liver. Hepatology 26:1667–1677

    Article  CAS  PubMed  Google Scholar 

  • Meier Y, Cavallaro M, Roos M, Pauli-Magnus C, Folkers G, Meier PJ, Fattinger K (2005) Incidence of drug-induced liver injury in medical inpatients. Eur J Clin Pharmacol 61:135–143

    Article  PubMed  Google Scholar 

  • Meier Y, Pauli-Magnus C, Zanger UM, Klein K, Schaeffeler E, Nussler AK, Nussler N, Eichelbaum M, Meier PJ, Stieger B (2006) Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology 44:62–74

    Article  CAS  PubMed  Google Scholar 

  • Meier Y, Zodan T, Lang C, Zimmermann R, Kullak-Ublick GA, Meier PJ, Stieger B, Pauli-Magnus C (2008) 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 14:38–45

    Article  CAS  PubMed  Google Scholar 

  • Mendoza ME, Monte MJ, Serrano MA, Pastor-Anglada M, Stieger B, Meier PJ, Medarde M, Marin JJ (2003) Physiological characteristics of allo-cholic acid. J Lipid Res 44:84–92

    Article  CAS  PubMed  Google Scholar 

  • Misra S, Ujhazy P, Varticovski L, Arias IM (1999) Phosphoinositide 3-kinase lipid products regulate ATP-dependent transport by sister of P-glycoprotein and multidrug resistance associated protein 2 in bile canalicular membrane vesicles. Proc Natl Acad Sci USA 96:5814–5819

    Article  CAS  PubMed  Google Scholar 

  • Mita S, Suzuki H, Akita H, Stieger B, Meier PJ, Hofmann AF, Sugiyama Y (2005) Vectorial transport of bile salts across MDCK cells expressing both rat Na+-taurocholate cotransporting polypeptide and rat bile salt export pump. Am J Physiol Gastrointest Liver Physiol 288:G159–G167

    Article  CAS  PubMed  Google Scholar 

  • Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF, Sugiyama Y (2006a) Inhibition of bile acid transport across Na+/taurocholate cotransporting polypeptide (SLC10A1) and bile salt export pump (ABCB 11)-coexpressing LLC-PK1 cells by cholestasis-inducing drugs. Drug Metab Dispos 34:1575–1581

    Article  CAS  PubMed  Google Scholar 

  • Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF, Sugiyama Y (2006b) Vectorial transport of unconjugated and conjugated bile salts by monolayers of LLC-PK1 cells doubly transfected with human NTCP and BSEP or with rat Ntcp and Bsep. Am J Physiol Gastrointest Liver Physiol 290:G550–G556

    Article  CAS  PubMed  Google Scholar 

  • Miyata M, Kudo G, Lee YH, Yang TJ, Gelboin HV, Fernandez-Salguero P, Kimura S, Gonzalez FJ (1999) Targeted disruption of the microsomal epoxide hydrolase gene. Microsomal epoxide hydrolase is required for the carcinogenic activity of 7, 12-dimethylbenz[a]anthracene. J Biol Chem 274:23963–23968

    Article  CAS  PubMed  Google Scholar 

  • Mochizuki K, Kagawa T, Numari A, Harris MJ, Itoh J, Watanabe N, Mine T, Arias IM (2007) Two N-linked glycans are required to maintain the transport activity of the bile salt export pump (ABCB11) in MDCK II cells. Am J Physiol Gastrointest Liver Physiol 292:G818–G828

    Article  CAS  PubMed  Google Scholar 

  • Molina H, Azocar L, Ananthanarayanan M, Arrese M, Miquel JF (2008) Localization of the sodium-taurocholate cotransporting polypeptide in membrane rafts and modulation of its activity by cholesterol in vitro. Biochim Biophys Acta 1778:1283–1291

    Article  CAS  PubMed  Google Scholar 

  • Moseley RH, Johnson TR, Morrissette JM (1990) Inhibition of bile acid transport by cyclosporine A in rat liver plasma membrane vesicles. J Pharmacol Exp Ther 253:974–980

    CAS  PubMed  Google Scholar 

  • Moseley RH, Wang W, Takeda H, Lown K, Shick L, Ananthanarayanan M, Suchy FJ (1996) Effect of endotoxin on bile acid transport in rat liver: a potential model for sepsis-associated cholestasis. Am J Physiol 271:G137–G146

    CAS  PubMed  Google Scholar 

  • Muehlenberg K, Wiedmann K, Keppeler H, Sauerbruch T, Lammert F (2008) Recurrent intrahepatic cholestasis of pregnancy and chain-like choledocholithiasis in a female patient with stop codon in the ABDC4-gene of the hepatobiliary phospholipid transporter. Z Gastroenterol 46:48–53

    Article  CAS  PubMed  Google Scholar 

  • Mukhopadhayay S, Ananthanarayanan M, Stieger B, Meier PJ, Suchy FJ, Anwer MS (1997) cAMP increases liver Na+-taurocholate cotransport by translocating transporter to plasma membranes. Am J Physiol 273:G842–G848

    CAS  PubMed  Google Scholar 

  • Mukhopadhyay S, Ananthanarayanan M, Stieger B, Meier PJ, Suchy FJ, Anwer MS (1998a) Sodium taurocholate cotransporting polypeptide is a serine, threonine phosphoprotein and is dephosphorylated by cyclic adenosine monophosphate. Hepatology 28:1629–1636

    Article  CAS  PubMed  Google Scholar 

  • Mukhopadhyay S, Webster CR, Anwer MS (1998b) Role of protein phosphatases in cyclic AMP-mediated stimulation of hepatic Na+/taurocholate cotransport. J Biol Chem 273:30039–30045

    Article  CAS  PubMed  Google Scholar 

  • Muller M, Ishikawa T, Berger U, Klunemann C, Lucka L, Schreyer A, Kannicht C, Reutter W, Kurz G, Keppler D (1991) ATP-dependent transport of taurocholate across the hepatocyte canalicular membrane mediated by a 110-kDa glycoprotein binding ATP and bile salt. J Biol Chem 266:18920–18926

    CAS  PubMed  Google Scholar 

  • Nakano A, Tietz PS, LaRusso NF (1990) Circadian rhythms of biliary protein and lipid excretion in rats. Am J Physiol 258:G653–G659

    CAS  PubMed  Google Scholar 

  • Ng KH, Le GC, Amborade E, Stieger B, Deschatrette J (2000) Reversible induction of rat hepatoma cell polarity with bile acids. J Cell Sci 113(Pt 23):4241–4251

    CAS  PubMed  Google Scholar 

  • Niinuma K, Kato Y, Suzuki H, Tyson CA, Weizer V, Dabbs JE, Froehlich R, Green CE, Sugiyama Y (1999) Primary active transport of organic anions on bile canalicular membrane in humans. Am J Physiol 276:G1153–G1164

    CAS  PubMed  Google Scholar 

  • Nishida T, Gatmaitan Z, Che M, Arias IM (1991) Rat liver canalicular membrane vesicles contain an ATP-dependent bile acid transport system. Proc Natl Acad Sci U S A 88:6590–6594

    Article  CAS  PubMed  Google Scholar 

  • Noe J, Hagenbuch B, Meier PJ, St-Pierre MV (2001) Characterization of the mouse bile salt export pump overexpressed in the baculovirus system. Hepatology 33:1223–1231

    Article  CAS  PubMed  Google Scholar 

  • Noe J, Stieger B, Meier PJ (2002) Functional expression of the canalicular bile salt export pump of human liver. Gastroenterology 123:1659–1666

    Article  CAS  PubMed  Google Scholar 

  • Noe J, Kullak-Ublick GA, Jochum W, Stieger B, Kerb R, Haberl M, Mullhaupt B, Meier PJ, Pauli-Magnus C (2005) Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. J Hepatol 43:536–543

    Article  CAS  PubMed  Google Scholar 

  • Novak DA, Ryckman FC, Suchy FJ (1989) Taurocholate transport by basolateral plasma membrane vesicles isolated from human liver. Hepatology 10:447–453

    Article  CAS  PubMed  Google Scholar 

  • Ortiz DF, Moseley J, Calderon G, Swift AL, Li S, Arias IM (2004) Identification of HAX-1 as a protein that binds bile salt export protein and regulates its abundance in the apical membrane of Madin-Darby canine kidney cells. J Biol Chem 279:32761–32770

    Article  CAS  PubMed  Google Scholar 

  • Oshima H, Kon J, Ooe H, Hirata K, Mitaka T (2008) Functional expression of organic anion transporters in hepatic organoids reconstructed by rat small hepatocytes. J Cell Biochem 104:68–81

    Article  CAS  PubMed  Google Scholar 

  • Oude Elferink RP, Paulusma CC, Groen AK (2006) Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Gastroenterology 130:908–925

    Article  PubMed  CAS  Google Scholar 

  • Palmeira CM, Rolo AP (2004) Mitochondrially-mediated toxicity of bile acids. Toxicology 203:1–15

    Article  CAS  PubMed  Google Scholar 

  • Patel P, Weerasekera N, Hitchins M, Boyd CA, Johnston DG, Williamson C (2003) Semi quantitative expression analysis of MDR3, FIC1, BSEP, OATP-A, OATP-C, OATP-D, OATP-E and NTCP gene transcripts in 1st and 3rd trimester human placenta. Placenta 24:39–44

    Article  CAS  PubMed  Google Scholar 

  • Pauli-Magnus C, Meier PJ (2006) Hepatobiliary transporters and drug-induced cholestasis. Hepatology 44:778–787

    Article  CAS  PubMed  Google Scholar 

  • Pauli-Magnus C, Kerb R, Fattinger K, Lang T, Anwald B, Kullak-Ublick GA, Beuers U, Meier PJ (2004a) BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 39:779–791

    Article  CAS  PubMed  Google Scholar 

  • Pauli-Magnus C, Lang T, Meier Y, Zodan-Marin T, Jung D, Breymann C, Zimmermann R, Kenngott S, Beuers U, Reichel C, Kerb R, Penger A, Meier PJ, Kullak-Ublick GA (2004b) Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics 14:91–102

    Article  CAS  PubMed  Google Scholar 

  • Pauli-Magnus C, Stieger B, Meier Y, Kullak-Ublick GA, Meier PJ (2005) Enterohepatic transport of bile salts and genetics of cholestasis. J Hepatol 43:342–357

    Article  CAS  PubMed  Google Scholar 

  • Pauli-Magnus C, Meier PJ, Stieger B (2010) Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy. Semin Liver Dis 30:147–159

    Article  CAS  PubMed  Google Scholar 

  • Paulusma CC, de Waart DR, Kunne C, Mok KS, Elferink RP (2009) Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content. J Biol Chem 284:9947–9954

    Article  CAS  PubMed  Google Scholar 

  • Pellicoro A, Faber KN (2007) Review article: the function and regulation of proteins involved in bile salt biosynthesis and transport. Aliment Pharmacol Ther 26(Suppl 2):149–160

    Article  CAS  PubMed  Google Scholar 

  • Perwaiz S, Forrest D, Mignault D, Tuchweber B, Phillip MJ, Wang R, Ling V, Yousef IM (2003) Appearance of atypical 3 alpha, 6 beta, 7 beta, 12 alpha-tetrahydroxy-5 beta-cholan-24-oic acid in spgp knockout mice. J Lipid Res 44:494–502

    Article  CAS  PubMed  Google Scholar 

  • Pizarro M, Balasubramaniyan N, Solis N, Solar A, Duarte I, Miquel JF, Suchy FJ, Trauner M, Accatino L, Ananthanarayanan M, Arrese M (2004) Bile secretory function in the obese Zucker rat: evidence of cholestasis and altered canalicular transport function. Gut 53:1837–1843

    Article  CAS  PubMed  Google Scholar 

  • Plass JR, Mol O, Heegsma J, Geuken M, de Bruin J, Elling G, Muller M, Faber KN, Jansen PL (2004) A progressive familial intrahepatic cholestasis type 2 mutation causes an unstable, temperature-sensitive bile salt export pump. J Hepatol 40:24–30

    Article  CAS  PubMed  Google Scholar 

  • Platte HD, Honscha W, Schuh K, Petzinger E (1996) Functional characterization of the hepatic sodium-dependent taurocholate transporter stably transfected into an immortalized liver-derived cell line and V79 fibroblasts. Eur J Cell Biol 70:54–60

    CAS  PubMed  Google Scholar 

  • Rao A, Haywood J, Craddock AL, Belinsky MG, Kruh GD, Dawson PA (2008) The organic solute transporter alpha-beta, Ostalpha-Ostbeta, is essential for intestinal bile acid transport and homeostasis. Proc Natl Acad Sci U S A 105:3891–3896

    Article  CAS  PubMed  Google Scholar 

  • Rees DC, Johnson E, Lewinson O (2009) ABC transporters: the power to change. Nat Rev Mol Cell Biol 10:218–227

    Article  CAS  PubMed  Google Scholar 

  • Reichen J, Paumgartner G (1976) Uptake of bile acids by perfused rat liver. Am J Physiol 231:734–742

    CAS  PubMed  Google Scholar 

  • Rippin SJ, Hagenbuch B, Meier PJ, Stieger B (2001) Cholestatic expression pattern of sinusoidal and canalicular organic anion transport systems in primary cultured rat hepatocytes. Hepatology 33:776–782

    Article  CAS  PubMed  Google Scholar 

  • Roma MG, Crocenzi FA, Mottino AD (2008) Dynamic localization of hepatocellular transporters in health and disease. World J Gastroenterol 14:6786–6801

    Article  CAS  PubMed  Google Scholar 

  • Ros JE, Libbrecht L, Geuken M, Jansen PL, Roskams TA (2003) High expression of MDR1, MRP1, and MRP3 in the hepatic progenitor cell compartment and hepatocytes in severe human liver disease. J Pathol 200:553–560

    Article  CAS  PubMed  Google Scholar 

  • Russell DW (2009) Fifty years of advances in bile acid synthesis and metabolism. J Lipid Res 50(Suppl):S120–S125

    Article  PubMed  CAS  Google Scholar 

  • Russmann S, Kaye JA, Jick SS, Jick H (2005) Risk of cholestatic liver disease associated with flucloxacillin and flucloxacillin prescribing habits in the UK: cohort study using data from the UK General Practice Research Database. Br J Clin Pharmacol 60:76–82

    Article  CAS  PubMed  Google Scholar 

  • Sabordo L, Sallustio BC (1997) Effects of gemfibrozil and clofibric acid on the uptake of taurocholate by isolated rat hepatocytes. Biochem Pharmacol 54:215–218

    Article  CAS  PubMed  Google Scholar 

  • Saeki T, Kuroda T, Matsumoto M, Kanamoto R, Iwami K (2002) Effects of Cys mutation on taurocholic acid transport by mouse ileal and hepatic sodium-dependent bile acid transporters. Biosci Biotechnol Biochem 66:467–470

    Article  CAS  PubMed  Google Scholar 

  • Saito S, Iida A, Sekine A, Miura Y, Ogawa C, Kawauchi S, Higuchi S, Nakamura Y (2002a) Three hundred twenty-six genetic variations in genes encoding nine members of ATP-binding cassette, subfamily B (ABCB/MDR/TAP), in the Japanese population. J Hum Genet 47:38–50

    Article  CAS  PubMed  Google Scholar 

  • Saito S, Iida A, Sekine A, Ogawa C, Kawauchi S, Higuchi S, Nakamura Y (2002b) Catalog of 238 variations among six human genes encoding solute carriers (hSLCs) in the Japanese population. J Hum Genet 47:576–584

    Article  CAS  PubMed  Google Scholar 

  • Sandker GW, Slooff MJ, Groothuis GM (1992) Drug transport, viability and morphology of isolated rat hepatocytes preserved for 24 hours in University of Wisconsin solution. Biochem Pharmacol 43:1479–1485

    Article  CAS  PubMed  Google Scholar 

  • Sandker GW, Weert B, Olinga P, Wolters H, Slooff MJ, Meijer DK, Groothuis GM (1994) Characterization of transport in isolated human hepatocytes. A study with the bile acid taurocholic acid, the uncharged ouabain and the organic cations vecuronium and rocuronium. Biochem Pharmacol 47:2193–2200

    Article  CAS  PubMed  Google Scholar 

  • Schonhoff CM, Thankey K, Webster CR, Wakabayashi Y, Wolkoff AW, Anwer MS (2008) Rab4 facilitates cyclic adenosine monophosphate-stimulated bile acid uptake and Na+-taurocholate cotransporting polypeptide translocation. Hepatology 48:1665–1670

    Article  CAS  PubMed  Google Scholar 

  • Schroeder A, Eckhardt U, Stieger B, Tynes R, Schteingart CD, Hofmann AF, Meier PJ, Hagenbuch B (1998) Substrate specificity of the rat liver Na(+)-bile salt cotransporter in Xenopus laevis oocytes and in CHO cells. Am J Physiol 274:G370–G375

    CAS  PubMed  Google Scholar 

  • Schuster D, Laggner C, Langer T (2005) Why drugs fail – a study on side effects in new chemical entities. Curr Pharm Des 11:3545–3559

    Article  CAS  PubMed  Google Scholar 

  • Schwarz LR, Burr R, Schwenk M, Pfaff E, Greim H (1975) Uptake of taurocholic acid into isolated rat-liver cells. Eur J Biochem 55:617–623

    Article  CAS  PubMed  Google Scholar 

  • Seeger MA, van Veen HW (2009) Molecular basis of multidrug transport by ABC transporters. Biochim Biophys Acta 1794:725–737

    CAS  PubMed  Google Scholar 

  • Shitara Y, Li AP, Kato Y, Lu C, Ito K, Itoh T, Sugiyama Y (2003) Function of uptake transporters for taurocholate and estradiol 17beta-d-glucuronide in cryopreserved human hepatocytes. Drug Metab Pharmacokinet 18:33–41

    Article  CAS  PubMed  Google Scholar 

  • Shneider BL, Fox VL, Schwarz KB, Watson CL, Ananthanarayanan M, Thevananther S, Christie DM, Hardikar W, Setchell KD, Mieli-Vergani G, Suchy FJ, Mowat AP (1997) Hepatic basolateral sodium-dependent-bile acid transporter expression in two unusual cases of hypercholanemia and in extrahepatic biliary atresia. Hepatology 25:1176–1183

    Article  CAS  PubMed  Google Scholar 

  • Shoda J, Kano M, Oda K, Kamiya J, Nimura Y, Suzuki H, Sugiyama Y, Miyazaki H, Todoroki T, Stengelin S, Kramer W, Matsuzaki Y, Tanaka N (2001) The expression levels of plasma membrane transporters in the cholestatic liver of patients undergoing biliary drainage and their association with the impairment of biliary secretory function. Am J Gastroenterol 96:3368–3378

    Article  CAS  PubMed  Google Scholar 

  • Sidler Pfandler MA, Hochli M, Inderbitzin D, Meier PJ, Stieger B (2004) Small hepatocytes in culture develop polarized transporter expression and differentiation. J Cell Sci 117:4077–4087

    Article  PubMed  CAS  Google Scholar 

  • Simion FA, Fleischer B, Fleischer S (1984) Subcellular distribution of bile acids, bile salts, and taurocholate binding sites in rat liver. Biochemistry 23:6459–6466

    Article  CAS  PubMed  Google Scholar 

  • Simon FR, Fortune J, Iwahashi M, Gartung C, Wolkoff A, Sutherland E (1996) Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters. Am J Physiol 271:G1043–G1052

    CAS  PubMed  Google Scholar 

  • Slitt AL, Allen K, Morrone J, Aleksunes LM, Chen C, Maher JM, Manautou JE, Cherrington NJ, Klaassen CD (2007) Regulation of transporter expression in mouse liver, kidney, and intestine during extrahepatic cholestasis. Biochim Biophys Acta 1768:637–647

    Article  CAS  PubMed  Google Scholar 

  • Small DM (2003) Role of ABC transporters in secretion of cholesterol from liver into bile. Proc Natl Acad Sci U S A 100:4–6

    Article  CAS  PubMed  Google Scholar 

  • Smith DA, Schmid EF (2006) Drug withdrawals and the lessons within. Curr Opin Drug Discov Devel 9:38–46

    CAS  PubMed  Google Scholar 

  • Snow KL, Moseley RH (2007) Effect of thiazolidinediones on bile acid transport in rat liver. Life Sci 80:732–740

    Article  CAS  PubMed  Google Scholar 

  • Sokol RJ, Devereaux M, Dahl R, Gumpricht E (2006) “Let there be bile” – understanding hepatic injury in cholestasis. J Pediatr Gastroenterol Nutr 43(Suppl 1):S4–S9

    PubMed  Google Scholar 

  • Souza RF, Krishnan K, Spechler SJ (2008) Acid, bile, and CDX: the ABCs of making Barrett’s metaplasia. Am J Physiol Gastrointest Liver Physiol 295:G211–G218

    Article  CAS  PubMed  Google Scholar 

  • Stacey NH, Kotecka B (1988) Inhibition of taurocholate and ouabain transport in isolated rat hepatocytes by cyclosporin A. Gastroenterology 95:780–786

    CAS  PubMed  Google Scholar 

  • Stieger B (2009) Recent insights into the function and regulation of the bile salt export pump (ABCB11). Curr Opin Lipidol 20:176–181

    Article  CAS  PubMed  Google Scholar 

  • Stieger B (2010) Role of the bile salt export pump, BSEP, in acquired forms of cholestasis. Drug Metab Rev 42:437–445

    Article  CAS  PubMed  Google Scholar 

  • Stieger B, Meier PJ (2001) Adenosine triphosphate dependent bile salt transport. In: Matern S, Boyer JL, Keppler D, Meier-Abt PJ (eds) Hepatobiliary transport: from bench to bedside. Kluwer Academic, Dordrecht, pp 54–59

    Google Scholar 

  • Stieger B, O'Neill B, Meier PJ (1992) ATP-dependent bile-salt transport in canalicular rat liver plasma-membrane vesicles. Biochem J 284(Pt 1):67–74

    CAS  PubMed  Google Scholar 

  • Stieger B, Hagenbuch B, Landmann L, Hochli M, Schroeder A, Meier PJ (1994) In situ localization of the hepatocytic Na+/Taurocholate cotransporting polypeptide in rat liver. Gastroenterology 107:1781–1787

    CAS  PubMed  Google Scholar 

  • Stieger B, Zhang J, O'Neill B, Sjovall J, Meier PJ (1997) Differential interaction of bile acids from patients with inborn errors of bile acid synthesis with hepatocellular bile acid transporters. Eur J Biochem 244:39–44

    Article  CAS  PubMed  Google Scholar 

  • Stieger B, Fattinger K, Madon J, Kullak-Ublick GA, Meier PJ (2000) Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 118:422–430

    Article  CAS  PubMed  Google Scholar 

  • Stieger B, Meier Y, Meier PJ (2007) The bile salt export pump. Pflugers Arch 453:611–620

    Article  CAS  PubMed  Google Scholar 

  • Stolz A, Takikawa H, Ookhtens M, Kaplowitz N (1989) The role of cytoplasmic proteins in hepatic bile acid transport. Annu Rev Physiol 51:161–176

    Article  CAS  PubMed  Google Scholar 

  • St-Pierre MV, Stallmach T, Freimoser GA, Dufour JF, Serrano MA, Marin JJ, Sugiyama Y, Meier PJ (2004) Temporal expression profiles of organic anion transport proteins in placenta and fetal liver of the rat. Am J Physiol Regul Integr Comp Physiol 287:R1505–R1516

    CAS  PubMed  Google Scholar 

  • Strautnieks SS, Bull LN, Knisely AS, Kocoshis SA, Dahl N, Arnell H, Sokal E, Dahan K, Childs S, Ling V, Tanner MS, Kagalwalla AF, Nemeth A, Pawlowska J, Baker A, Mieli-Vergani G, Freimer NB, Gardiner RM, Thompson RJ (1998) A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet 20:233–238

    Article  CAS  PubMed  Google Scholar 

  • Strautnieks SS, Byrne JA, Pawlikowska L, Cebecauerova D, Rayner A, Dutton L, Meier Y, Antoniou A, Stieger B, Arnell H, Ozcay F, Al-Hussaini HF, Bassas AF, Verkade HJ, Fischler B, Nemeth A, Kotalova R, Shneider BL, Cielecka-Kuszyk J, McClean P, Whitington PF, Sokal E, Jirsa M, Wali SH, Jankowska I, Pawlowska J, Mieli-Vergani G, Knisely AS, Bull LN, Thompson RJ (2008) Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology 134:1203–1214

    Article  CAS  PubMed  Google Scholar 

  • Suchy FJ, Balistreri WF, Heubi JE, Searcy JE, Levin RS (1981) Physiologic cholestasis: elevation of the primary serum bile acid concentrations in normal infants. Gastroenterology 80:1037–1041

    CAS  PubMed  Google Scholar 

  • Suchy FJ, Balistreri WF, Hung J, Miller P, Garfield SA (1983) Intracellular bile acid transport in rat liver as visualized by electron microscope autoradiography using a bile acid analogue. Am J Physiol 245:G681–G689

    CAS  PubMed  Google Scholar 

  • Suchy FJ, Bucuvalas JC, Goodrich AL, Moyer MS, Blitzer BL (1986) Taurocholate transport and Na+-K+-ATPase activity in fetal and neonatal rat liver plasma membrane vesicles. Am J Physiol 251:G665–G673

    CAS  PubMed  Google Scholar 

  • Suchy FJ, Bucuvalas JC, Novak DA (1987) Determinants of bile formation during development: ontogeny of hepatic bile acid metabolism and transport. Semin Liver Dis 7:77–84

    Article  CAS  PubMed  Google Scholar 

  • Sun AQ, Arrese MA, Zeng L, Swaby I, Zhou MM, Suchy FJ (2001a) The rat liver Na(+)/bile acid cotransporter. Importance of the cytoplasmic tail to function and plasma membrane targeting. J Biol Chem 276:6825–6833

    Article  CAS  PubMed  Google Scholar 

  • Sun AQ, Swaby I, Xu S, Suchy FJ (2001b) Cell-specific basolateral membrane sorting of the human liver Na(+)-dependent bile acid cotransporter. Am J Physiol Gastrointest Liver Physiol 280:G1305–G1313

    CAS  PubMed  Google Scholar 

  • Sundaram SS, Bove KE, Lovell MA, Sokol RJ (2008) Mechanisms of disease: inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol 5:456–468

    Article  CAS  PubMed  Google Scholar 

  • Suzuki H, Sugiyama Y (2000) Transport of drugs across the hepatic sinusoidal membrane: sinusoidal drug influx and efflux in the liver. Semin Liver Dis 20:251–263

    Article  CAS  PubMed  Google Scholar 

  • Takada T, Weiss HM, Kretz O, Gross G, Sugiyama Y (2004) Hepatic transport of PKI166, an epidermal growth factor receptor kinase inhibitor of the pyrrolo-pyrimidine class, and its main metabolite, ACU154. Drug Metab Dispos 32:1272–1278

    Article  CAS  PubMed  Google Scholar 

  • Takahashi A, Hasegawa M, Sumazaki R, Suzuki M, Toki F, Suehiro T, Onigata K, Tomomasa T, Suzuki T, Matsui A, Morikawa A, Kuwano H (2007) Gradual improvement of liver function after administration of ursodeoxycholic acid in an infant with a novel ABCB11 gene mutation with phenotypic continuum between BRIC2 and PFIC2. Eur J Gastroenterol Hepatol 19:942–946

    Article  PubMed  Google Scholar 

  • Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K (2008) Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 7:678–693

    Article  CAS  PubMed  Google Scholar 

  • Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, Macchiarulo A, Yamamoto H, Mataki C, Pruzanski M, Pellicciari R, Auwerx J, Schoonjans K (2009) TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 10:167–177

    Article  CAS  PubMed  Google Scholar 

  • Thompson R, Strautnieks S (2000) Inherited disorders of transport in the liver. Curr Opin Genet Dev 10:310–313

    Article  CAS  PubMed  Google Scholar 

  • Tomer G, Ananthanarayanan M, Weymann A, Balasubramanian N, Suchy FJ (2003) Differential developmental regulation of rat liver canalicular membrane transporters Bsep and Mrp2. Pediatr Res 53:288–294

    CAS  PubMed  Google Scholar 

  • Torchia EC, Shapiro RJ, Agellon LB (1996) Reconstitution of bile acid transport in the rat hepatoma McArdle RH-7777 cell line. Hepatology 24:206–211

    Article  CAS  PubMed  Google Scholar 

  • Torok M, Gutmann H, Fricker G, Drewe J (1999) Sister of P-glycoprotein expression in different tissues. Biochem Pharmacol 57:833–835

    Article  CAS  PubMed  Google Scholar 

  • Trauner M, Boyer JL (2003) Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 83:633–671

    CAS  PubMed  Google Scholar 

  • Trauner M, Meier PJ, Boyer JL (1999) Molecular regulation of hepatocellular transport systems in cholestasis. J Hepatol 31:165–178

    Article  CAS  PubMed  Google Scholar 

  • Treepongkaruna S, Gaensan A, Pienvichit P, Luksan O, Knisely AS, Sornmayura P, Jirsa M (2009) Novel ABCB11 mutations in a Thai infant with progressive familial intrahepatic cholestasis. World J Gastroenterol 15:4339–4342

    Article  CAS  PubMed  Google Scholar 

  • Treiber A, Schneiter R, Hausler S, Stieger B (2007) 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 35:1400–1407

    Article  CAS  PubMed  Google Scholar 

  • Vallejo M, Briz O, Serrano MA, Monte MJ, Marin JJ (2006) Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy. J Hepatol 44:1150–1157

    Article  CAS  PubMed  Google Scholar 

  • Vallejo M, Castro MA, Medarde M, Macias RI, Romero MR, El-Mir MY, Monte MJ, Briz O, Serrano MA, Marin JJ (2007) Novel bile acid derivatives (BANBs) with cytostatic activity obtained by conjugation of their side chain with nitrogenated bases. Biochem Pharmacol 73:1394–1404

    Article  CAS  PubMed  Google Scholar 

  • Van der Borght S, Libbrecht L, Katoonizadeh A, Aerts R, Nevens F, Verslype C, Roskams TA (2007) Nuclear beta-catenin staining and absence of steatosis are indicators of hepatocellular adenomas with an increased risk of malignancy. Histopathology 51:855–856

    Article  PubMed  Google Scholar 

  • Van Dyke RW, Stephens JE, Scharschmidt BF (1982) Bile acid transport in cultured rat hepatocytes. Am J Physiol 243:G484–G492

    PubMed  Google Scholar 

  • van Mil SW, van der Woerd WL, van der Brugge G, Sturm E, Jansen PL, Bull LN, van den Berg IE, Berger R, Houwen RH, Klomp LW (2004) Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology 127:379–384

    Article  PubMed  CAS  Google Scholar 

  • Visser WE, Wong WS, van Mullem AA, Friesema EC, Geyer J, Visser TJ (2009) Study of the transport of thyroid hormone by transporters of the SLC10 family. Mol Cell Endocrinol 315:138–145

    PubMed  Google Scholar 

  • von Dippe P, Amoui M, Alves C, Levy D (1993) Na(+)-dependent bile acid transport by hepatocytes is mediated by a protein similar to microsomal epoxide hydrolase. Am J Physiol 264:G528–G534

    Google Scholar 

  • Vore M (1987) Estrogen cholestasis. Membranes, metabolites, or receptors? Gastroenterology 93:643–649

    CAS  PubMed  Google Scholar 

  • Vos TA, Hooiveld GJ, Koning H, Childs S, Meijer DK, Moshage H, Jansen PL, Muller M (1998) Up-regulation of the multidrug resistance genes, Mrp1 and Mdr1b, and down-regulation of the organic anion transporter, Mrp2, and the bile salt transporter, Spgp, in endotoxemic rat liver. Hepatology 28:1637–1644

    Article  CAS  PubMed  Google Scholar 

  • Vos TA, Ros JE, Havinga R, Moshage H, Kuipers F, Jansen PL, Muller M (1999) Regulation of hepatic transport systems involved in bile secretion during liver regeneration in rats. Hepatology 29:1833–1839

    Article  CAS  PubMed  Google Scholar 

  • Wagner M, Zollner G, Trauner M (2009) New molecular insights into the mechanisms of cholestasis. J Hepatol 51:565–580

    Article  CAS  PubMed  Google Scholar 

  • Wakabayashi Y, Lippincott-Schwartz J, Arias IM (2004) Intracellular trafficking of bile salt export pump (ABCB11) in polarized hepatic cells: constitutive cycling between the canalicular membrane and rab11-positive endosomes. Mol Biol Cell 15:3485–3496

    Article  CAS  PubMed  Google Scholar 

  • Wakabayashi Y, Kipp H, Arias IM (2006) Transporters on demand: intracellular reservoirs and cycling of bile canalicular ABC transporters. J Biol Chem 281:27669–27673

    Article  CAS  PubMed  Google Scholar 

  • Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le Roux CW (2009) A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis. Clin Gastroenterol Hepatol 7:1189–1194

    Google Scholar 

  • Wang R, Salem M, Yousef IM, Tuchweber B, Lam P, Childs SJ, Helgason CD, Ackerley C, Phillips MJ, Ling V (2001) Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis. Proc Natl Acad Sci USA 98:2011–2016

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Soroka CJ, Boyer JL (2002) The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II. J Clin Invest 110:965–972

    CAS  PubMed  Google Scholar 

  • Wang R, Lam P, Liu L, Forrest D, Yousef IM, Mignault D, Phillips MJ, Ling V (2003) Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein. Hepatology 38:1489–1499

    CAS  PubMed  Google Scholar 

  • Wang L, Dong H, Soroka CJ, Wei N, Boyer JL, Hochstrasser M (2008a) Degradation of the bile salt export pump at endoplasmic reticulum in progressive familial intrahepatic cholestasis type II. Hepatology 48:1558–1569

    Article  CAS  PubMed  Google Scholar 

  • Wang YD, Chen WD, Moore DD, Huang W (2008b) FXR: a metabolic regulator and cell protector. Cell Res 18:1087–1095

    Article  CAS  PubMed  Google Scholar 

  • Wang R, Chen HL, Liu L, Sheps JA, Phillips MJ, Ling V (2009) Compensatory role of P-glycoproteins in knockout mice lacking the bile salt export pump. Hepatology 50:948–956

    Article  CAS  PubMed  Google Scholar 

  • Wasmuth HE, Glantz A, Keppeler H, Simon E, Bartz C, Rath W, Mattsson LA, Marschall HU, Lammert F (2007) Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene. Gut 56:265–270

    Article  CAS  PubMed  Google Scholar 

  • Weinman SA (1997) Electrogenicity of Na(+)-coupled bile acid transporters. Yale J Biol Med 70:331–340

    CAS  PubMed  Google Scholar 

  • Weinman SA, Maglova LM (1994) Free concentrations of intracellular fluorescent anions determined by cytoplasmic dialysis of isolated hepatocytes. Am J Physiol 267:G922–G931

    CAS  PubMed  Google Scholar 

  • Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14, 000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678

    Article  CAS  Google Scholar 

  • Wolters H, Kuipers F, Slooff MJ, Vonk RJ (1992) Adenosine triphosphate-dependent taurocholate transport in human liver plasma membranes. J Clin Invest 90:2321–2326

    Article  CAS  PubMed  Google Scholar 

  • Wolters H, Elzinga BM, Baller JF, Boverhof R, Schwarz M, Stieger B, Verkade HJ, Kuipers F (2002) Effects of bile salt flux variations on the expression of hepatic bile salt transporters in vivo in mice. J Hepatol 37:556–563

    Article  CAS  PubMed  Google Scholar 

  • Yabuuchi H, Tanaka K, Maeda M, Takemura M, Oka M, Ohashi R, Tamai I (2008) Cloning of the dog bile salt export pump (BSEP; ABCB11) and functional comparison with the human and rat proteins. Biopharm Drug Dispos 29:441–448

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi K, Murai T, Yabuuchi H, Kurosawa T (2009) Measurement of the transport activities of bile salt export pump using LC-MS. Anal Sci 25:1155–1158

    Article  CAS  PubMed  Google Scholar 

  • Zahner D, Eckhardt U, Petzinger E (2003) Transport of taurocholate by mutants of negatively charged amino acids, cysteines, and threonines of the rat liver sodium-dependent taurocholate cotransporting polypeptide Ntcp. Eur J Biochem 270:1117–1127

    Article  CAS  PubMed  Google Scholar 

  • Zaja R, Munic V, Klobucar RS, Ambriovic-Ristov A, Smital T (2008) Cloning and molecular characterization of apical efflux transporters (ABCB1, ABCB11 and ABCC2) in rainbow trout (Oncorhynchus mykiss) hepatocytes. Aquat Toxicol 90:322–332

    Article  CAS  PubMed  Google Scholar 

  • Zhou SF (2008) Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 38:802–832

    Article  CAS  PubMed  Google Scholar 

  • Zhu QS, Xing W, Qian B, von Dippe P, Shneider BL, Fox VL, Levy D (2003) Inhibition of human m-epoxide hydrolase gene expression in a case of hypercholanemia. Biochim Biophys Acta 1638:208–216

    CAS  PubMed  Google Scholar 

  • Zimmerli B, Valantinas J, Meier PJ (1989) Multispecificity of Na+-dependent taurocholate uptake in basolateral (sinusoidal) rat liver plasma membrane vesicles. J Pharmacol Exp Ther 250:301–308

    CAS  PubMed  Google Scholar 

  • Zinchuk VS, Okada T, Akimaru K, Seguchi H (2002) Asynchronous expression and colocalization of Bsep and Mrp2 during development of rat liver. Am J Physiol Gastrointest Liver Physiol 282:G540–G548

    CAS  PubMed  Google Scholar 

  • Zinchuk V, Zinchuk O, Okada T (2005) Experimental LPS-induced cholestasis alters subcellular distribution and affects colocalization of Mrp2 and Bsep proteins: a quantitative colocalization study. Microsc Res Tech 67:65–70

    Article  PubMed  Google Scholar 

  • Zinchuk V, Zinchuk O, Akimaru K, Moriya F, Okada T (2007) Ethanol consumption alters expression and colocalization of bile salt export pump and multidrug resistance protein 2 in the rat. Histochem Cell Biol 127:503–512

    Article  CAS  PubMed  Google Scholar 

  • Zollner G, Fickert P, Zenz R, Fuchsbichler A, Stumptner C, Kenner L, Ferenci P, Stauber RE, Krejs GJ, Denk H, Zatloukal K, Trauner M (2001) Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 33:633–646

    Article  CAS  PubMed  Google Scholar 

  • Zollner G, Fickert P, Silbert D, Fuchsbichler A, Marschall HU, Zatloukal K, Denk H, Trauner M (2003) Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 38:717–727

    Article  CAS  PubMed  Google Scholar 

  • Zollner G, Wagner M, Fickert P, Silbert D, Fuchsbichler A, Zatloukal K, Denk H, Trauner M (2005) Hepatobiliary transporter expression in human hepatocellular carcinoma. Liver Int 25:367–379

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

Bruno Stieger is supported by Grant #3100A0-112524/1 from the Swiss National Science Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bruno Stieger .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Berlin Heidelberg

About this chapter

Cite this chapter

Stieger, B. (2011). The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation. In: Fromm, M., Kim, R. (eds) Drug Transporters. Handbook of Experimental Pharmacology, vol 201. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-14541-4_5

Download citation

Publish with us

Policies and ethics