Download PDF
Semin Liver Dis 2002; 22(2): 123-136
DOI: 10.1055/s-2002-30099
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Mechanisms of Hepatic Transport of Drugs: Implications for Cholestatic Drug Reactions

Alan Bohan, James L. Boyer
  • Liver Center, Yale University School of Medicine, New Haven, Connecticut
Further Information

Publication History

Publication Date:
16 May 2002 (online)

    Permissions and Reprints

ABSTRACT

Hepatocellular and canalicular transport proteins are major determinants of the hepatic uptake and biliary excretion of xenobiotics and their metabolites. Recent advances in molecular cloning have resulted in the characterization of many of these transport systems. These advances have enabled the identification of a number of drugs that are substrates for the transporters, and it has facilitated studies of mechanisms of drug-induced cholestasis. This review summarizes the normal function of hepatobiliary transporters and their alteration by drugs or other foreign compounds. Although most of these investigations have been performed in animal models of drug-induced cholestasis, the application to human forms of drug-induced cholestasis is also discussed when possible. One important finding is that genetic polymorphisms can result in changes in drug transporter expression and function that could increase susceptibility to cholestatic drug reactions.

KEYWORDS

Cholestasis - drug-induced cholestasis - hepatocyte transport polypeptides - bile secretion - ABC transporters - genetic polymorphisms - nuclear receptors

REFERENCES

  • 1 Batt A M, Ferrari L. Manifestations of chemically induced liver damage.  Clin Chem . 1995;  41 1882-1887
    PubMedGoogle Scholar
  • 2 Bissell D M, Gores G J, Laskin D L, Hoofnagle J H. Drug-induced liver injury: mechanisms and test systems.  Hepatology . 2001;  33 1009-1013
    CrossrefPubMedGoogle Scholar
  • 3 Trauner M, Meier P J, Boyer J L. Molecular pathogenesis of cholestasis.  N Engl J Med . 1998;  339 1217-1227
    CrossrefPubMedGoogle Scholar
  • 4 Lecureur V, Courtois A, Payen L. Expression and regulation of hepatic drug and bile acid transporters.  Toxicology . 2000;  153 203-219
    CrossrefPubMedGoogle Scholar
  • 5 Lee J, Boyer J L. Molecular alterations in hepatocyte transport mechanisms in acquired cholestatic liver disorders.  Semin Liver Dis . 2000;  20 373-384
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Boyer J L. Molecular pathophysiology of membrane transport function in cholestasis. In: Arias IM, Boyer JL, Chisari FV, et al, eds. The Liver: Biology and Pathobiology, 4th edPhiladelphia: Lippincott Williams & Wilkins 2001: 663-677
    Google Scholar
  • 7 Müller M, Jansen P LM. Molecular aspects of hepatobiliary transport.  Am J Physiol . 1997;  35 G1285-G1303
    PubMedGoogle Scholar
  • 8 King P D, Blitzer B L. Drug-induced cholestasis: pathogenesis and clinical features.  Semin Liver Dis . 1990;  10 316-321
    PubMedGoogle Scholar
  • 9 Seitz S, Kretz-Rommel A, Oude Elferink P J R, Boelsterli U A. Selective protein adduct formation of diclofenac glucuronide is critically dependent on the rat canalicular conjugate export pump (Mrp2).  Chem Res Toxicol . 1998;  11 513-519
    CrossrefPubMedGoogle Scholar
  • 10 Moran D, De Buitrago M J, Fernandez E. Inhibition of biliary glutathione secretion by cyclosporine A in the rat: possible mechanisms and role in the cholestasis induced by the drug.  J Hepatol . 1998;  29 68-77
    CrossrefPubMedGoogle Scholar
  • 11 Rost D, Kartenbeck J, Keppler D. Changes in the localization of the rat canalicular conjugate export pump Mrp2 in phalloidin-induced cholestasis.  Hepatology . 1999;  29 814-821
    CrossrefPubMedGoogle Scholar
  • 12 Bolder U, Trang N V, Hagey L R. Sulindac is excreted into bile by a canalicular bile salt pump and undergoes a cholehepatic circulation in rats.  Gastroenterology . 1999;  117 962-971
    PubMedGoogle Scholar
  • 13 Stieger B, Fattinger K, Madon J. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver.  Gastroenterology . 2000;  118 422-430
    CrossrefPubMedGoogle Scholar
  • 14 Funk C, Ponelle C, Scheuermann G, Pantze M. Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat.  Mol Pharmacol . 2001;  59 627-635
    PubMedGoogle Scholar
  • 15 Yasumiba S, Tazuma S, Ochi H. Cyclosporin A reduces canalicular membrane fluidity and regulates transporter function in rats.  Biochem J . 2001;  354 591-596
    CrossrefPubMedGoogle Scholar
  • 16 Fattinger K, Funk C, Pantze M. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions.  Clin Pharmacol Ther . 2001;  69 223-231
    CrossrefPubMedGoogle Scholar
  • 17 Iverson S L, Uetrecht J P. Identification of a reactive metabolite of terbinafine: insights into terbinafine-induced hepatotoxicity.  Chem Res Toxicol . 2001;  14 175-181
    CrossrefPubMedGoogle Scholar
  • 18 Lakehal F, Dansette P M, Becquemont L. Indirect cytotoxicity of flucloxacillin toward human biliary epithelium via metabolite formation in hepatocytes.  Chem Res Toxicol . 2001;  14 694-701
    PubMedGoogle Scholar
  • 19 Boehme M, Buchler M, Muller M, Keppler D. Differential inhibition by cyclosporins of primary-active ATP-dependent transporters in the hepatocyte canalicular membrane.  FEBS Lett . 1993;  333 193-196
    CrossrefPubMedGoogle Scholar
  • 20 Bohme M, Jedlitschky G, Leier I. ATP-dependent export pumps and their inhibition by cyclosporins.  Adv Enzyme Regul . 1994;  34 371-380
    PubMedGoogle Scholar
  • 21 Smith L L. Key challenges for toxicologists in the 21st century.  Trends Pharmacol Sci . 2001;  22 281-285
    CrossrefPubMedGoogle Scholar
  • 22 Fielden M R, Zacharewski T R. Challenges and limitations of gene expression profiling in mechanistic and predictive toxicology.  Toxicol Sci . 2001;  60 6-10
    CrossrefPubMedGoogle Scholar
  • 23 Lovett R A. Toxicogenomics. Toxicologists brace for genomics revolution.  Science . 2000;  289 536-537
    CrossrefPubMedGoogle Scholar
  • 24 Fredrickson H L, Perkins E J, Bridges T S. Towards environmental toxicogenomics-development of a flow-through, high-density DNA hybridization array and its application to ecotoxicity assessment.  Sci Total Environ . 2001;  274 137-149
    CrossrefPubMedGoogle Scholar
  • 25 Medlin J. Array of hope for gene technology.  Environ Health Perspect . 2001;  109 A34-A37
    PubMedGoogle Scholar
  • 26 Pennie W D, Woodyatt N J, Aldridge T C, Orphanides G. Application of genomics to the definition of the molecular basis for toxicity.  Toxicol Lett . 2001;  120 353-358
    CrossrefPubMedGoogle Scholar
  • 27 Burchiel S W, Knall C M, Davis J W. Analysis of genetic and epigenetic mechanisms of toxicity: potential roles of toxicogenomics and proteomics in toxicology.  Toxicol Sci . 2001;  59 193-195
    CrossrefPubMedGoogle Scholar
  • 28 Nuwaysir E F, Bittner M, Trent J. Microarrays and toxicology: the advent of toxicogenomics.  Mol Carcinog . 1999;  24 153-159
    CrossrefPubMedGoogle Scholar
  • 29 Boyer J L, Nathanson M H. Bile formation. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff's Diseases of the Liver, 8th ed Philadelphia: Lippincott-Raven 1999: 119-146
    Google Scholar
  • 30 Fitz J G, Scharschmidt B F. Regulation of transmembrane electrical potential gradient in rat hepatocytes in situ.  Am J Physiol . 1987;  252 G56-G64
    PubMedGoogle Scholar
  • 31 Graf J, Henderson R M, Krumpholz B, Boyer J L. Cell membrane and transepithelial voltages and resistances in isolated rat hepatocyte couplets.  J Membr Biol . 1987;  95 241-254
    PubMedGoogle Scholar
  • 32 Hagenbuch B, Meier P J. Sinusoidal (basolateral) bile salt uptake systems of hepatocytes.  Semin Liver Dis . 1996;  16 129-136
    PubMedGoogle Scholar
  • 33 Hagenbuch B, Stieger B, Foguet M. Functional expression cloning and characterization of the hepatocyte Na+/bile acid cotransport system.  Proc Natl Acad Sci USA . 1991;  88 10629-10633
    PubMedGoogle Scholar
  • 34 Ananthanarayanan M, Ng O C, Boyer J L, Suchy F J. Characterization of cloned rat liver Na+-bile acid cotransporter using peptide and fusion protein antibodies.  Am J Physiol . 1994;  267 G637-G643
    PubMedGoogle Scholar
  • 35 Konig J, Nies A T, Cui Y. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance.  Biochim Biophys Acta . 1999;  1461 377-394
    PubMedGoogle Scholar
  • 36 Oude Elferink P J R, Tytgat G NJ, Groen A K. The role of mdr2 P-glycoprotein in hepatobiliary lipid transport.  FASEB J . 1997;  11 19-28
    PubMedGoogle Scholar
  • 37 Keppler D, Konig J. Expression and localization of the conjugate export pump encoded by the MRP2 (cMRP/cMOAT) gene in liver.  FASEB J . 1997;  11 509-516
    PubMedGoogle Scholar
  • 38 Gerloff T, Stieger B, Hagenbuch B. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver.  J Biol Chem . 1998;  273 10046-10050
    CrossrefPubMedGoogle Scholar
  • 39 Kullak-Ublick G A, Hagenbuch B, Stieger B. Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver.  Gastroenterology . 1995;  109 1274-1282
    PubMedGoogle Scholar
  • 40 Noe B, Hagenbuch B, Stieger B, Meier P J. Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain.  Proc Natl Acad Sci USA . 1997;  94 10346-10350
    CrossrefPubMedGoogle Scholar
  • 41 Abe T, Kakyo M, Sakagami H. Molecular characterization and tissue distribution of a new organic anion transporter subtype (oatp3) that transports thyroid hormones and taurocholate and comparison with oatp2.  J Biol Chem . 1998;  273 22395-22401
    CrossrefPubMedGoogle Scholar
  • 42 Jacquemin E, Hagenbuch B, Stieger B. Expression cloning of a rat liver Na+-independent organic anion transporter.  Proc Natl Acad Sci USA . 1994;  91 133-137
    PubMedGoogle Scholar
  • 43 Kullak-Ublick G A, Ismair M G, Stieger B. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver.  Gastroenterology . 2001;  120 525-533
    PubMedGoogle Scholar
  • 44 Kullak-Ublick G A, Beuers U, Meier P J. Assignment of the human organic anion transporting polypeptide (OATP) gene to chromosome 12p12 by fluorescence in situ hybridization.  J Hepatol . 1996;  25 985-987
    CrossrefPubMedGoogle Scholar
  • 45 Cattori V, Hagenbuch B, Hagenbuch N. Identification of organic anion transporting polypeptide 4 (Oatp4) as a major full-length isoform of the liver-specific transporter-1 (rlst-1) in rat liver.  FEBS Lett . 2000;  474 242-245
    CrossrefPubMedGoogle Scholar
  • 46 Abe T, Kakyo M, Tokui T. Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1.  J Biol Chem . 1999;  274 17159-17163
    CrossrefPubMedGoogle Scholar
  • 47 Kakyo M, Unno M, Tokui T. Molecular characterization and functional regulation of a novel rat liver-specific organic anion transporter rlst-1.  Gastroenterology . 1999;  117 770-775
    PubMedGoogle Scholar
  • 48 Hagenbuch N, Reichel C, Stieger B. Effect of phenobarbital on the expression of bile salt and organic anion transporters of rat liver.  J Hepatol . 2001;  34 881-887
    PubMedGoogle Scholar
  • 49 Rausch-Derra L C, Hartley D P, Meier P J, Klaassen C D. Differential effects of microsomal enzyme-inducing chemicals on the hepatic expression of rat organic anion transporters, OATP1 and OATP2.  Hepatology . 2001;  33 1469-1478
    CrossrefPubMedGoogle Scholar
  • 50 Bramow S, Ott P, Thomsen N F. Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (rapamycin).  Pharmacol Toxicol . 2001;  89 133-139
    CrossrefPubMedGoogle Scholar
  • 51 Tirona R G, Leake B F, Merino G, Kim R B. Polymorphisms in OATP-C. Identification of multiple allelic variants associated with altered transport activity among European- and African-Americans.  J Biol Chem . 2001;  276 35669-35675
    CrossrefPubMedGoogle Scholar
  • 52 van Montfoort E J, Muller M, Groothuis G M. Comparison of ``type I'' and ``type II'' organic cation transport by organic cation transporters and organic anion-transporting polypeptides.  J Pharmacol Exp Ther . 2001;  298 110-115
    PubMedGoogle Scholar
  • 53 Kekuda R, Prasad P D, Wu X. Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta.  J Biol Chem . 1998;  273 15971-15979
    CrossrefPubMedGoogle Scholar
  • 54 Okuda M, Urakami Y, Saito H, Inui K. Molecular mechanisms of organic cation transport in OCT2-expressing Xenopus oocytes.  Biochim Biophys Acta . 1999;  1417 224-231
    PubMedGoogle Scholar
  • 55 Urakami Y, Okuda M, Masuda S. Functional characteristics and membrane localization of rat multispecific organic cation transporters, OCTI and OCT2, mediating tubular secretion of cationic drugs.  J Pharmacol Exp Ther . 1998;  287 800-805
    PubMedGoogle Scholar
  • 56 Zhang L, Schaner M E, Giacomini K M. Functional characterization of an organic cation transporter (hOCTI) in a transiently transfected human cell line (HeLa).  J Pharmacol Exp Ther . 1998;  286 354-361
    PubMedGoogle Scholar
  • 57 Grundemann D, Gorboulev V, Gambaryan S. Drug excretion mediated by a new prototype of polyspecific transporter.  Nature . 1994;  372 549-552
    CrossrefPubMedGoogle Scholar
  • 58 Gorboulev V, Ulzheimer J C, Akhoundova A. Cloning and characterization of two human polyspecific organic cation transporters.  DNA Cell Biol . 1997;  16 871-881
    PubMedGoogle Scholar
  • 59 Denison M S, Whitlock J PJ. Xenobiotic-inducible transcription of cytochrome P450 genes.  J Biol Chem . 1995;  270 18175-18178
    CrossrefPubMedGoogle Scholar
  • 60 Vickers A, Sinclair J, Sollinger M. Multiple cytochrome P-450s involved in the metabolism of terbinafine suggest a limited potential for drug-drug interactions.  Drug Metab Dispos . 1999;  27 1029-1038
    PubMedGoogle Scholar
  • 61 Sueyoshi T, Negishi M. Phenobarbital response elements of cytochrome P450 genes and nuclear receptors.  Annu Rev Pharmacol Toxicol . 2001;  41 123-143
    CrossrefPubMedGoogle Scholar
  • 62 Staudinger J L, Goodwin B, Jones S A. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.  Proc Natl Acad Sci USA . 2001;  98 3369-3374
    CrossrefPubMedGoogle Scholar
  • 63 Xie W, Radominska-Pandya A, Shi Y. An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids.  Proc Natl Acad Sci USA . 2001;  98 3375-3380
    Google Scholar
  • 64 Kast H R, Goodwin B, Tarr P T. Regulation of multidrug resistance-associated protein 2 (MRP2; ABCC2) by nuclear receptors PXR, FXR and CAR.  J Biol Chem . 2002;  277 2908-2915
    CrossrefPubMedGoogle Scholar
  • 65 Gottesman M M, Hrycyna C A, Schoenlein P V. Genetic analysis of the multidrug transporter.  Annu Rev Genet . 1995;  29 607-649
    CrossrefPubMedGoogle Scholar
  • 66 Borst P, Schinkel A H. What have we learnt thus far from mice with disrupted P-glycoprotein genes?.  Eur J Cancer . 1996;  32A 985-990
    PubMedGoogle Scholar
  • 67 Schinkel A H, Smit J JM, vanTellingen M O. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs.  Cell . 1994;  77 491-502
    CrossrefPubMedGoogle Scholar
  • 68 Schinkel A H, Mayer U, Wagenaar E. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins.  Proc Natl Acad Sci USA . 1997;  94 4028-4033
    CrossrefPubMedGoogle Scholar
  • 69 Schinkel A H, Wagenaar E, van Deemter L. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A.  J Clin Invest . 1995;  96 1698-1705
    PubMedGoogle Scholar
  • 70 Gigliozzi A, Fraioli F, Sundaram P. Molecular identification and functional characterization of mdr1a in rat cholangiocytes.  Gastroenterology . 2000;  119 1113-1122
    PubMedGoogle Scholar
  • 71 Ros J E, Schuetz J D, Geuken M. Induction of Mdr1b expression by tumor necrosis factor-alpha in rat liver cells is independent of p53 but requires NF-kappaB signaling.  Hepatology . 2001;  33 1425-1431
    CrossrefPubMedGoogle Scholar
  • 72 Hoffmeyer S, Burk O, von Richter O. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.  Proc Natl Acad Sci USA . 2000;  97 3473-3478
    CrossrefPubMedGoogle Scholar
  • 73 Deleuze J F, Jacquemin E, Dubuisson C. Defect on multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis.  Hepatology . 1996;  23 904-908
    CrossrefPubMedGoogle Scholar
  • 74 deVree J ML, Jacquemin E, Sturm E. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis (abstract).  Proc Natl Acad Sci USA . 1998;  95 282-287
    CrossrefPubMedGoogle Scholar
  • 75 Jacquemin E, De Vree M J, Cresteil D. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood.  Gastroenterology . 2001;  120 1448-1458
    CrossrefPubMedGoogle Scholar
  • 76 Jacquemin E, Cresteil D, Manouvrier S. Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy.  Lancet . 1999;  353 210-211
    CrossrefPubMedGoogle Scholar
  • 77 Rosmorduc O, Hermelin B, Poupon R. Mdr3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis.  Gastroenterology . 2001;  120 1459-1467
    CrossrefPubMedGoogle Scholar
  • 78 Childs S, Yeh R L, Georges E, Ling V. Identification of a sister gene to p-glycoprotein.  Cancer Res . 1995;  55 2029-2034
    PubMedGoogle Scholar
  • 79 Strautnieks S S, Bull L, Knisely A S. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis.  Nat Genet . 1998;  20 233-238
    CrossrefPubMedGoogle Scholar
  • 80 Childs S, Yeh R L, Hui D, Ling V. Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein.  Cancer Res . 1998;  58 4160-4167
    PubMedGoogle Scholar
  • 81 Lecureur V, Sun D, Hargrove P. Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein.  Mol Pharmacol . 2000;  57 24-35
    PubMedGoogle Scholar
  • 82 Hipfner D R, Deeley R G, Cole S PC. Structural, mechanistic and clinical aspects of MRP1.  Biochim Biophys Acta . 1999;  1461 359-376
    PubMedGoogle Scholar
  • 83 Kool M, De Haas L G, Scheffer G L. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologs of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines.  Cancer Res . 1997;  57 3537-3547
    PubMedGoogle Scholar
  • 84 Kiuchi Y, Suzuki H, Hirohashi T. cDNA cloning and inducible expression of human multidrug resistance associated protein 3 (MRP3).  FEBS Lett . 1998;  433 149-152
    CrossrefPubMedGoogle Scholar
  • 85 Wijnholds J, Mol C A, van Deemter L. Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs.  Proc Natl Acad Sci USA . 2000;  97 7476-7481
    CrossrefPubMedGoogle Scholar
  • 86 Fernandez-Checa J C, Takikawa H, Horie T. Canalicular transport of reduced glutathione in normal and mutant Eisai hyperbilirubinemic rats.  J Biol Chem . 1992;  267 1667-1673
    PubMedGoogle Scholar
  • 87 Kool M, van der Linden M, deHaas M. MRP3, an organic anion transporter able to transport anti-cancer drugs.  Proc Natl Acad Sci USA . 1999;  96 6914-6919
    CrossrefPubMedGoogle Scholar
  • 88 Soroka C J, Lee J M, Azzaroli F, Boyer J L. Cellular localization and up-regulation of multidrug resistance-associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver.  Hepatology . 2001;  33 783-791
    CrossrefPubMedGoogle Scholar
  • 89 Donner M G, Keppler D. Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver.  Hepatology . 2001;  34 351-359
    CrossrefPubMedGoogle Scholar
  • 90 Ito K, Suzuki H, Sugiyama Y. Charged amino acids in the transmembrane domains are involved in the determination of the substrate specificity of rat Mrp2.  Mol Pharmacol . 2001;  59 1077-1085
    PubMedGoogle Scholar
  • 91 Ito K, Suzuki H, Sugiyama Y. Single amino acid substitution of rat MRP2 results in acquired transport activity for taurocholate.  Am J Physiol . 2001;  281 G1034-G1043
    PubMedGoogle Scholar
  • 92 Hooijberg J H, Broxterman H J, Kool M. Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2.  Cancer Res . 1999;  59 2532-2535
    PubMedGoogle Scholar
  • 93 Ballatori N, Truong A T. Glutathione as a primary osmotic driving force in hepatic bile formation.  Am J Physiol . 1992;  263 G617-G624
    PubMedGoogle Scholar
  • 94 Paulusma C C, van Geer M, Heijn M. The canalicular multispecific organic anion transporter mediates transport of reduced glutathione.  Hepatology . 1997;  26 292A
    PubMedGoogle Scholar
  • 95 Ballatori N, Dutczak W J. Identification and characterization of high and low affinity transport systems for reduced glutathione in liver cell canalicular membranes.  J Biol Chem . 1994;  269 19731-19737
    PubMedGoogle Scholar
  • 96 Oude Elferink P J R, Ottenhoff R, Liefting W. Hepatobiliary transport of glutathione and glutathione conjugate in rats with hereditary hyperbilirubinemia.  J Clin Invest . 1989;  84 478-483
    PubMedGoogle Scholar
  • 97 Ishizuka H, Konno K, Shiina T. Species differences in the transport activity for organic anions across the bile canalicular membrane.  J Pharmacol Exp Ther . 1999;  290 1324-1330
    PubMedGoogle Scholar
  • 98 Roelofsen H, Soroka C J, Boyer J L. Cyclic AMP stimulates sorting of the canalicular multispecific organic anion transporter into the transcytotic bile secretory pathway in hepatocyte couplets.  Hepatology . 1994;  20 174A
    PubMedGoogle Scholar
  • 99 Kubitz R, Huth C, Schmitt M. Protein kinase C- dependent distribution of the multidrug resistance protein 2 from the canalicular to the basolateral membrane in human HepG2 cells.  Hepatology . 2001;  34 340-350
    CrossrefPubMedGoogle Scholar
  • 100 Beuers U, Bilzer M, Chittattu A. Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver.  Hepatology . 2001;  33 1206-1216
    CrossrefPubMedGoogle Scholar
  • 101 Fickert P, Zollner G, Fuchsbichler A. Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver.  Gastroenterology . 2001;  121 170-183
    CrossrefPubMedGoogle Scholar
  • 102 Paulusma C C, Kool M, Bosma P J. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome.  Hepatology . 1997;  25 1539-1542
    CrossrefPubMedGoogle Scholar
  • 103 Hirohashi T, Suzuki H, Ito K. Hepatic expression of multidrug resistance-associated protein-like proteins maintained in Eisai hyperbilirubinemic rats.  Mol Pharmacol . 1998;  53 1068-1075
    PubMedGoogle Scholar
  • 104 Ogawa K, Suzuki H, Hirohashi T. Characterization of inducible nature of MRP3 in rat liver.  Am J Physiol . 2000;  278 G438-G446
    PubMedGoogle Scholar
  • 105 Cohn J A, Strong T V, Picciotto M R. Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells.  Gastroenterology . 1993;  105 1857-1864
    CrossrefPubMedGoogle Scholar
  • 106 Alpini G, Glaser S S, Rodgers R. Functional expression of the apical Na+-dependent bile acid transporter in large but not small rat cholangiocytes.  Gastroenterology . 1997;  113 1734-1740
    PubMedGoogle Scholar
  • 107 Lazaridis K N, Pham L, Tietz P. Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter.  J Clin Invest . 1997;  100 2714-2721
    PubMedGoogle Scholar
  • 108 Martinez-Anso E, Castillo J E, Diez J. Immunohistochemical detection of chloride/bicarbonate anion exchangers in human liver.  Hepatology . 1994;  19 1400-1406
    CrossrefPubMedGoogle Scholar
  • 109 Haussinger D, Schliess F. Osmotic induction of signaling cascades: role in regulation of cell function.  Biochem Biophys Res Commun . 1999;  255 551-555
    CrossrefPubMedGoogle Scholar
  • 110 Haussinger D, Hallbrucker C, Saha N. Cell volume and bile acid excretion.  Biochem J . 1992;  288 681-690
    PubMedGoogle Scholar
  • 111 Bruck R, Haddad P, Graf J, Boyer J L. Regulatory volume decrease stimulates bile flow, bile acid excretion, and exocytosis in isolated perfused rat liver.  Am J Physiol . 1992;  262 G806-G812
    PubMedGoogle Scholar
  • 112 Nemchausky B A, Layden T J, Boyer J L. Effects of chronic choleretic infusions of bile acids on the membrane of the bile canaliculus.  Lab Invest . 1977;  36 259-267
    PubMedGoogle Scholar
  • 113 Gartung C, Ananthanarayanan M, Rahman M A. Down-regulation of expression and function of the rat liver Na+/bile acid cotransporter in extrahepatic cholestasis.  Gastroenterology . 1996;  110 199-209
    PubMedGoogle Scholar
  • 114 Stravitz R T, Vlahevic Z R, Russell T L. Regulation of sterol 27-hydroxylase and its role in the regulation of acidic pathway of bile acid biosynthesis in primary cultures of rat hepatocytes.  J Steroid Biochem Mol Biol . 1996;  57 337-347
    CrossrefPubMedGoogle Scholar
  • 115 Meier P J, Eckhardt U, Schroeder A. Substrate specificity of sinusoidal bile acid and organic anion uptake systems in rat and human liver.  Hepatology . 1997;  26 1667-1677
    PubMedGoogle Scholar
  • 116 Mukhopadhayay S, Ananthanarayanan M, Stieger B. cAMP increases liver Na+-taurocholate cotransport by translocating transporter to plasma membranes.  Am J Physiol . 1997;  273 G842-G848
    PubMedGoogle Scholar
  • 117 Mukhopadhyay S, Webster C RL, Anwer M S. Role of protein phosphatases in cyclic AMP-mediated stimulation of hepatic Na+/taurocholate cotransport.  J Biol Chem . 1998;  273 30039-30045
    CrossrefPubMedGoogle Scholar
  • 118 Haussinger D, Schmitt M, Weiergraber O, Kubitz R. Short-term regulation of canalicular transport.  Semin Liver Dis . 2000;  20 307-321
    Article in Thieme ConnectPubMedGoogle Scholar
  • 119 Haussinger D, Saha N, Hallbrucker C. Involvement of microtubules in the swelling-induced stimulation of transcellular taurocholate transport in perfused rat liver.  Biochem J . 1993;  291 355-360
    PubMedGoogle Scholar
  • 120 Benedetti A, Strazzabosco M, Ng O C, Boyer J L. Regulation of activity and apical targeting of the Cl-/HCO3 - exchanger in rat hepatocytes.  Proc Natl Acad Sci USA . 1994;  91 792-796
    PubMedGoogle Scholar
  • 121 Boyer J L, Soroka C J. Vesicle targeting to the apical domain regulates bile excretory function in isolated rat hepatocyte couplets.  Gastroenterology . 1995;  109 1600-1611
    PubMedGoogle Scholar
  • 122 Lu T T, Repa J J, Mangelsdorf D J. Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism.  J Biol Chem . 2001;  276 37735-37738
    PubMedGoogle Scholar
  • 123 Janowski B A, Willy P J, Devi T R. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha.  Nature . 1996;  383 728-731
    CrossrefPubMedGoogle Scholar
  • 124 Parks D J, Blanchard S G, Bledsoe R K. Bile acids: natural ligands for an orphan nuclear receptor.  Science . 1999;  284 1365-1368
    CrossrefPubMedGoogle Scholar
  • 125 Makishima M, Okamoto A Y, Repa J J. Identification of a nuclear receptor for bile acids.  Science . 1999;  284 1362-1365
    CrossrefPubMedGoogle Scholar
  • 126 Wang H, Chen J, Hollister K. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.  Mol Cell . 1999;  3 543-553
    PubMedGoogle Scholar
  • 127 Sinal C J, Tohkin M, Miyata M. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis.  Cell . 2000;  102 731-744
    CrossrefPubMedGoogle Scholar
  • 128 Tu H, Okamoto A Y, Shan B. FXR, a bile acid receptor and biological sensor.  Trends Cardiovasc Med . 2000;  10 30-35
    CrossrefPubMedGoogle Scholar
  • 129 Bertolotti M, Carulli L, Concari M. Suppression of bile acid synthesis, but not of hepatic cholesterol 7alpha-hydroxylase expression, by obstructive cholestasis in humans.  Hepatology . 2001;  34 234-242
    CrossrefPubMedGoogle Scholar
  • 130 Gupta S, Todd S R, Pandak W M. Regulation of multidrug resistance 2 P-glycoprotein expression by bile salts in rats and in primary cultures of rat hepatocytes.  Hepatology . 2000;  32 341-347
    CrossrefPubMedGoogle Scholar
  • 131 Zollner G, Fickert P, Zenz R. Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases.  Hepatology . 2001;  33 633-646
    CrossrefPubMedGoogle Scholar
  • 132 Boehme M, Mueller M, Leier I. Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in rat liver.  Gastroenterology . 1994;  107 255-265
    PubMedGoogle Scholar
  • 133 Carrella M, Feldman D, Cogoi S. Enhancement of mdr2 gene transcription mediates the biliary transfer of phosphatidylcholine supplied by an increased biosynthesis in the pravastatin-treated rat.  Hepatology . 1999;  29 1825-1832
    CrossrefPubMedGoogle Scholar
  • 134 Shibuya A, Watanabe M, Fujita Y. An autopsy case of troglitazone-induced fulminant hepatitis.  Diabetes Care . 1998;  21 2140-2143
    CrossrefPubMedGoogle Scholar
  • 135 Gitlin N, Julie N L, Spurr C L. Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone.  Ann Intern Med . 1998;  129 36-38
    CrossrefPubMedGoogle Scholar
  • 136 Talwalkar J A, Soetikno R E, Carr-Locke D L, Berg C L. Severe cholestasis related to itraconazole for the treatment of onychomycosis.  Am J Gastroenterol . 1999;  94 3632-3633
    CrossrefPubMedGoogle Scholar
  • 137 Gregus Z, Gyurasics A. Role of glutathione in the biliary excretion of the arsenical drugs trimelarsan and melarsoprol.  Biochem Pharmacol . 2000;  11 1375-1385
    PubMedGoogle Scholar
  • 138 Apiwattanakul N, Sekine T, Chairoungdua A. Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes.  Mol Pharmacol . 1999;  55 847-854
    PubMedGoogle Scholar
  • 139 Hsiang B, Zhu Y, Wang Z. A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters.  J Biol Chem . 1999;  274 37161-37168
    CrossrefPubMedGoogle Scholar
  • 140 Ismair M G, Stieger B, Cattori V. Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides oatp4 and oatp8 of rat and human liver.  Gastroenterology . 2001;  121 1185-1190
    PubMedGoogle Scholar
  • 141 Pang K S, Wang P J, Chung A YK, Wolkoff A W. The modified dipeptide, enalapril, an angiotensin-converting enzyme inhibitor, is transported by the rat liver organic anion transport protein.  Hepatology . 1998;  28 1341-1346
    CrossrefPubMedGoogle Scholar
  • 142 Ishizuka H, Konno K, Naganuma H. Transport of temocaprilat into rat hepatocytes: role of organic anion transporting polypeptide.  J Pharmacol Exp Ther . 1998;  287 37-42
    PubMedGoogle Scholar
  • 143 Reichel C, Gao B, Van Montfoort J. Localization and function of the organic anion-transporting polypeptide oatp2 in rat liver.  Gastroenterology . 1999;  117 688-695
    PubMedGoogle Scholar
  • 144 Morita N, Kusuhara H, Sekine T. Functional characterization of rat organic anion transporter 2 in LLC-PK1 cells.  J Pharmacol Exp Ther . 2001;  298 1179-1184
    PubMedGoogle Scholar
  • 145 Cui Y, Konig J, Buchholz J K. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells.  Mol Pharmacol . 1999;  55 929-937
    PubMedGoogle Scholar
  • 146 Masuda M, I'izuka Y, Yamazaki M. Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats.  Cancer Res . 1997;  57 3506-3510
    PubMedGoogle Scholar
  • 147 Kauffmann H-M, Keppler D, Kartenbeck J, Schrenk D. Induction of cMrp/cMoat gene expression by cisplatin, 2-acetylaminofluorene, or cycloheximide in rat hepatocytes.  Hepatology . 1997;  26 980-985
    PubMedGoogle Scholar
      >