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Membrane Transporters as Drug Targets pp 387–439Cite as

Transporters for Bile Acids and Organic Anions

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Part of the book series: Pharmaceutical Biotechnology ((PBIO,volume 12))

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References

  • Abe, T., Kakyo, M., Sakagami, H., Tokui, T., Nishio, T., Tanemoto, M., Nomura, H., Hebert, S. C., Matsuno, S., Kondo, H., and Yawo, H., 1998, 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. 273:22395–22401.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Akerboom, T. P. M., Narayanaswami, V., Kunst, M., and Sies, H., 1991, ATP-dependent S-(2,4-dinitrophenyl) glutathione transport in canalicular plasma membrane vesicles from rat liver, J. Biol. Chem. 266: 13145–13152.

    Google Scholar 

  • Ananthanarayanan, M., Ng, O.-C., Boyer, J. L., and Suchy, F. J., 1994, Characterization of cloned rat liver Na+-bile acid cotransporter using peptide and fusion protein antibodies, Am. J. Physiol. 267:G637–G643.

    PubMed  CAS  Google Scholar 

  • Angeletti, R. H., Novikoff, P. M., Juvvadi, S. R., Fritschy, J. M., Meier, P. J., and Wolkoff, A. W., 1997, The choroid plexus epithelium is the site of the organic anion transport protein in the brain, Proc. Natl. Acad. Sci. USA 94:283–286.

    Article  PubMed  CAS  Google Scholar 

  • Anwer, M. S., and Hegner, D., 1978, Effect of Na+ on bile acid uptake by isolated rat hepatocytes; evidence for a heterogenous system, Hoppe-Seyler’s Z. Physiol. Chem. 359:181–192.

    PubMed  CAS  Google Scholar 

  • Arrese, M., Ananthananarayanan, M., and Suchy, F., 1998, Hepatobiliary transport: Molecular mechanisms of development and cholestasis, Pediat. Res. 44:141–147.

    PubMed  CAS  Google Scholar 

  • Bergwerk, A. J., Shi, X., Ford, A. C., Kanai, N., Jacquemin, E., Burk, R. D., Bai, S., Novikoff, P. M., Stieger, B., Meier, P. J., Schuster, V. L., and Wolkoff, A., 1996, Immunologic distribution of an organic anion transport protein in rat liver and kidney, Am. J. Physiol. 271: G231–G238.

    PubMed  CAS  Google Scholar 

  • Blitzer, B. L., Ratoosh, S. L., Donovan, C. B., and Boyer, J. L., 1982, Effects of inhibitors of Na+-coupled ion transport on bile acid uptake by isolated rat hepatocytes, Am. J. Physiol. 243: G48–G53.

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  • Borst, P., Kool, M., and Evers, R., 1997, Do cMOAT (MRP2), other MRP homologues, and LRP play a role in MDR? Semin. Cancer Biol. 8:205–213.

    PubMed  CAS  Google Scholar 

  • Bossuyt, X., Müller, M., Hagenbuch, B., and Meier, P. J., 1996a, Polyspecific drug and steroid clearance by an organic anion transporter of mammalian liver, J. Pharmacol. Exp. Ther. 276:891–896.

    PubMed  CAS  Google Scholar 

  • Bossuyt, X., Müller, M., and Meier, P. J., 1996b, Multispecific amphipathic substrate transport by an organic anion transporter of human liver, J. Hepatol. 25: 733–738.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Boyer, J. L., Ng, O.-C., Ananthanarayanan, M., Hofmann, A. F., Schteingart, C. D., Hagenbuch, B., Stieger, B., and Meier, P. J., 1994, Expression and characterization of a functional rat liver Na+bile acid cotransport system in COS-7 cells, Am. J. Physiol. 266:G382–G387.

    PubMed  CAS  Google Scholar 

  • Brown, R., Lomri, N., De Voss, J., Xie, M. H., Hua, T., Lidofsky, S. D., and Scharschmidt, B. F., 1995, Enhanced secretion of glycocholic acid in a specially adapted cell line associated with overexpression of apparently novel ATP-binding cassette proteins, Proc. Natl. Acad. Sci. USA 92:5421–5425.

    PubMed  CAS  Google Scholar 

  • Büchler, M., König, J., Brom, M., Kartenbeck, J., Spring, H., Horie, T., and Keppler, D., 1996, cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats, J. Biol. Chem. 271: 15091–15098.

    PubMed  Google Scholar 

  • Chan, B. S., Satriano, J. A., Pucci, M., and Schuster, V. L., 1998, Mechanism of prostaglandin E2 transport across the plasma membrane of HeLa cells and Xenopus oocytes expressing the prostaglandin transporter “PGI,” J. Biol. Chem. 273:6689–6697.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Chu, X.-Y., Kato, Y., Niinuma, K., Sudo, K., Hakusui, H., and Sugiyama, Y., 1997a, Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats, J. Pharmacol. Exp. Ther. 281:304–314.

    PubMed  CAS  Google Scholar 

  • Chu, X.-Y., Kato, Y., and Sugiyama, Y., 1997b, Multiplicity of biliary excretion mechanisms for irinotecan, CPT-11, and its metabolites in rats, Cancer Res. 57: 1934–1938.

    PubMed  CAS  Google Scholar 

  • Clark, R. F., Cruts, M., Korenblat, K. M., He, C., Talbot, C., Van Broeckhoven, C., and Geate, A. M., 1995, A yeast artificial chromosome contiguity from human chromosome 14q24 spanning the Alzheimer’s disease locus AD3, Hum. Mol. Genet. 8: 1347–1354.

    Google Scholar 

  • Deeley, R. G., and Cole, S. P. C., 1997, Function, evolution and structure of multidrug resistance protein (MRP), Semin. Cancer Biol. 8: 193–204.

    Article  PubMed  CAS  Google Scholar 

  • Deleuze, J.-F., Jacquemin, E., Dubuisson, C., Cresteil, D., Dumont, M., Erlinger, S., Bernard, O., and Hadchouel, M., 1996, Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis, Hepatology 23:904–908.

    PubMed  CAS  Google Scholar 

  • de Vree, J. M., Jacquemin, E., Sturm, E., Cresteil, D., Bosma, P. J., Aten, J., Deleuze, J.-F., Desrochers, M., Burdelski, M., Bernard, O., Oude Elferink, R. P. J., and Hadchouel, M., 1998, Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis, Proc. Natl. Acad. Sci. USA 95:282–287.

    PubMed  Google Scholar 

  • de Vries, M. H., Redegeld, F. A. M., Koster, A. Sj., Noordhoek, J., de Haan, J. G., Oude Elferink, R. P. J., and Jansen, P. L. M., 1989, Hepatic, intestinal and renal transport of 1-naphthol-□-d-glucuronide in mutant rats with hereditary-conjugated hyperbilirubinemia, Naunyn-Schmiedeberg’s Arch. Pharmacol. 340:588–592.

    Google Scholar 

  • Dijkstra, M., Havinga, R., Vonk, R. J., and Kuipers, F., 1996, Bile secretion of cadmium, silver, zinc and copper in the rat: Involvement of various transport systems, Life Sci. 59: 1237–1246.

    Article  PubMed  CAS  Google Scholar 

  • Eckhardt, U., Horz, J. A., Petzinger, E., Stüber, W., Reers, M., Dickneite, G., Daniel, H., Wagener, M., Hagenbuch, B., Stieger, B., and Meier, P. J., 1996, The peptide-based thrombin inhibitor CRC 220 is a new substrate of the basolateral rat liver organic anion-transporting polypeptide, Hepatology 24: 380–384.

    PubMed  CAS  Google Scholar 

  • Elsner, R., and Ziegler, K., 1989, Determination of the apparent functional molecular mass of the hepatocellular sodium-dependent taurocholate transporter by radiaton inactivation, Biochim. Biophys. Acta 983: 113–117.

    PubMed  CAS  Google Scholar 

  • Elsner, R., and Ziegler, K., 1992, Radiation inactivation of multispecific transport systems for bile acids and xenobiotics in basolateral rat liver plasma membrane vesicles, J. Biol. Chem. 267: 9788–9793.

    PubMed  CAS  Google Scholar 

  • Evers, R., Kool, M., van Deemter, L., Janssen, H., Calafat, J., Oomen, L. C. J. M., Paulusma, C. C., Oude Elferink, R. P. J., Baas, F., Schinkel, A. H., and Borst, P., 1998, Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA, J. Clin. Invest. 101: 1310–1319.

    PubMed  CAS  Google Scholar 

  • Fernandez-Checa, J. C., Takikawa, H., Horie, T., Ookhtens, M., and Kaplowitz, N., 1992, Canalicular transport of reduced glutathione in normal and mutant Eisai hyperbilirubinemic rats, J. Biol. Chem. 267: 1667–1673.

    PubMed  CAS  Google Scholar 

  • Friesema, E. C. H., Docter, R., Moerings, E. P. C. M., Stieger, B., Hagenbuch, B., Meier, P. J., Krenning, E. P., Hennemann, G., and Visser, T. J., 1999, Identification of thyroid hormone transporters, Biochem. Biophys. Res. Commun. 254: 497–501.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Gyurasics, A., Koszorüs, L., Varga, F., and Gregus, Z., 1992, Increased biliary excretion of glutathione is generated by the glutathione-dependent hepatobiliary transport of antimony and bismuth, Biochem. Pharmacol. 44: 1275–1281.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Hagenbuch, B., Scharschmidt, B. F., and Meier, P. J., 1996, Effect of antisense oligonucleotides on the expression of hepatocellular bile acid and organic anion uptake systems in Xenopus laevis oocytes, Biochem. J. 316: 901–904.

    PubMed  CAS  Google Scholar 

  • Higgins, C. F., 1992, ABC transporters: From microorganisms to man, Annu. Rev. Cell Biol. 8:67–113.

    Article  PubMed  CAS  Google Scholar 

  • Hipfner, D. R., Almquist, K. C., Leslie, E. M., Gerlach, J. H., Grant, C. E., Deeley, R. G., and Cole, S. P. C., 1997, Membrane topology of the multidrug resistance protein (MRP), J. Biol. Chem. 272: 23623–23630.

    Article  PubMed  CAS  Google Scholar 

  • Hirohashi, T., Ogawa, K., Suzuki, H., Ito, K., Kume, K., Shimizu, T., and Sugiyama, Y., 1997, Molecular characterization of canalicular multispecific organic anion transporter and its related proteins expressed in rat liver, Pharmaceut. Res. 14: S458–S459.

    Google Scholar 

  • Hirohashi, T., Suzuki, H., Ito, K., Kume, K., Shimizu, T., and Sugiyama, Y., 1998, Hepatic expression of multidrug resistance-associated protein (MRP)-like proteins maintained in Eisai hyperbilirubinemic rats (EHBR), Mol. Pharmacol. 53: 1068–1075.

    PubMed  CAS  Google Scholar 

  • Hirohashi, T., Suzuki, H., and Sugiyama, Y., 1999, Characterization of transport properties of cloned rat MRP3, J. Biol. Chem., 274: 15181–15185.

    Article  PubMed  CAS  Google Scholar 

  • Honscha, W., Schulz, K., Müller, D., and Petzinger, E., 1993, Two different mRNAs from rat liver code for the transport of bumetanide and taurocholate in Xenopus laevis oocytes, Eur. J. Pharmacol. 246: 227–232.

    PubMed  CAS  Google Scholar 

  • Huber, M., Guhlmann, A., Jansen, P. L. M., and Kepper, D., 1987, Hereditary defect of hepatobiliary cysteinyl leukotriene elimination in mutant rats with defective hepatic anion excretion, Hepatology 7:224–228.

    PubMed  CAS  Google Scholar 

  • Imawaka, H., and Sugiyama, Y., 1998, Kinetic study of the hepatobiliary transport of a new prostaglandin receptor agonist, J. Pharmacol. Exp. Ther. 284:949–957.

    PubMed  CAS  Google Scholar 

  • Ishigami, M., Tokui, T., Komai, T., Tsukahara, K., Yamazaki, M., and Sugiyama, Y., 1995, Evaluation of the uptake of pravastatin by perfused rat liver and primary cultured rat hepatocytes, Pharmaceut. Res. 12: 1741–1745.

    Article  CAS  Google Scholar 

  • Ishikawa, T., Müller, M., Klünemann, C., Schaub, T., and Keppler, D., 1990, ATP-dependent primary active transport of cysteinyl leukotrienes across liver canalicular membrane: Role of the ATP-dependent transport system for glutathione S-conjugates, J. Biol. Chem. 265: 19279–19286.

    PubMed  CAS  Google Scholar 

  • Ishizuka, H., Konno, K., Naganuma, H., Sasahara, K., Kawahara, Y., Niinuma, K., Suzuki, H., and Sugiyama, Y., 1997, Temocaprilat, a novel angiotensin-converting enzyme inhibitor, is excreted in bile via an ATP-dependent active transporter (cMOAT) that is deficient in Eisai hyperbilirubinemic mutant rats (EHBR), J. Pharmacol. Exp. Ther. 280: 1304–1311.

    PubMed  CAS  Google Scholar 

  • Ishizuka, H., Konno, K., Naganuma, H., Nishimura, K., Kouzuki, H., Suzuki, H., Stieger, B., Meier, P. J., and Sugiyama, Y., 1998a, Transport of temocaprilat into rat hepatocytes: Role of organic anion transporting protein (oatp), J. Pharmacol. Exp. Ther. 287:37–42.

    PubMed  CAS  Google Scholar 

  • Ishizuka, H., Suzuki, H., and Sugiyama, Y., 1998b, Species differences in the transport activity of cMOAT determined in vivo and in vitro, Hepatology 28: 424A.

    Google Scholar 

  • Ito, K., Suzuki, H., Hirohashi, T., Kume, K., Shimizu, T., and Sugiyama, Y., 1996, Expression of a putative ATP-binding cassette region, homologous to that in multidrug resistance associated protein (MRP), is hereditarily defective in Eisai hyperbilirubinemic rats (EHBR), Int. Hepatol. Commun. 4: 292–299.

    Google Scholar 

  • Ito, K., Suzuki, H., Hirohashi, T., Kume, K., Shimizu, T., and Sugiyama, Y., 1997, Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR, Am. J. Physiol. 272: G16–G22.

    PubMed  CAS  Google Scholar 

  • Ito, K., Iwatsubo, T., Kanamitsu, S., Nakajima, Y., and Sugiyama, Y., 1998a, Quantitative prediction of in vivo drug clearance and drug interactions from in vitro data on metabolism, together with binding and transport, Annu. Rev. Pharmaol. Toxicol. 38: 461–499.

    CAS  Google Scholar 

  • Ito, K., Iwatsubo, T., Kanamitsu, S., Ueda, K., Suzuki, H., and Sugiyama, Y., 1998b, Prediction of pharmacokinetic alterations caused by drug-drug interactions; focusing on metabolic intreaction in the liver, Pharmacol. Rev. 50: 387–411.

    PubMed  CAS  Google Scholar 

  • Ito, K., Suzuki, H., Hirohashi, T., Kume, K., Shimizu, T., and Sugiyama, Y., 1998c, Functional analysis of a canalicular multispecific organic anion transporter cloned from rat liver, J. Biol. Chem. 273: 1684–1688.

    PubMed  CAS  Google Scholar 

  • Iwatsubo, T., Hirota, N., Ooie, T., Suzuki, H., and Sugiyama, Y., 1996, Prediction of in vivo drug disposition from in vitro data based on physiological pharmacokinetics, Biopharmaceut. Drug Disposit. 17:273–310.

    CAS  Google Scholar 

  • Iwatsubo, T., Horita, N., Ooie, T., Suzuki, H., Shimada, N., Chiba, K., Ishizaki, T., Green, C. E., Tyson, C. A., and Sugiyama, Y., 1997, Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data, Pharmacol. Ther. 73: 147–171.

    Article  PubMed  CAS  Google Scholar 

  • Jacquemin, E., Hagenbuch, B., Stieger, B., Wolkoff, A. W., and Meier, P. J., 1994, Expression cloning of a rat liver Na+-independent organic anion transporter, Proc. Natl. Acad. Sci. USA 91:133–137.

    PubMed  CAS  Google Scholar 

  • Jansen, P. L. M., Groothuis, G. M. M., Peters, W. H. M., and Meijer, D. F. M., 1987, Selective hepatobiliary transport defect for organic anions and neutral steroids in mutant rats with hereditary-conjugated hyperbilirubinemia, Hepatology 7:71–76.

    PubMed  CAS  Google Scholar 

  • Jansen, P. L. M., van Klinken, J.-W., van Gelder, M., Ottenhoff, R., and Oude Elferink, R. P. J., 1993, Preserved organic anion transport in mutant TR- rats with a hepatobiliary secretion defect, Am. J. Physiol. 265:G445–G452.

    PubMed  CAS  Google Scholar 

  • Jedlitschky, G., Leier, I., Buchholz, U., Center, M., and Keppler, D., 1994, ATP-dependent transport of glutathione-S-conjugates by the multidrug resistance-associated protein, Cancer Res. 54:4833–4836.

    PubMed  CAS  Google Scholar 

  • Jedlitschky, G., Leier, I., Buchholz, U., Barnouin, K., Kurz, G., and Keppler, D., 1996, Transport of glutathione, glucuronate, and sulfate conjugates by the MRP gene-encoded conjugate export pump, Cancer Res. 56:988–994.

    PubMed  CAS  Google Scholar 

  • Jedlitschky, G., Leier, I., Buchholz, U., Hummel-Eisenbeiss, J., Burchell, B., and Keppler, D., 1997, ATP-dependent transport of bilirubin glucuronides by the multidrug resistance protein MRP1 and its hepatocyte canalicular isoform MRP2, Biochem. J. 327:305–310.

    PubMed  CAS  Google Scholar 

  • Kamimoto, Y., Gatmaitan, Z., Hsu, J., and Arias, I. M., 1989, The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles, J. Biol. Chem. 264:11693–11698.

    PubMed  CAS  Google Scholar 

  • Kanai, N., Lu, R., Satriano, J. A., Bao, Y., Wolkoff, A., and Schuster, V. L., 1995, Identification and characterization of a prostaglandin transporter, Science 268:866–869.

    PubMed  CAS  Google Scholar 

  • Kanai, N., Lu, R., Bao, Y., Wolkoff, A. W., Vore, M., and Shuster, V. L., 1996, Estradiol 17□-d-glucuronide is a high-affinity substrate for oatp organic anion transporter, Am. J. Physiol. 270:F326–F331.

    PubMed  CAS  Google Scholar 

  • Karpen, S. J., Sun, A.-Q., Kudish, B., Hagenbuch, B., Meier, P. J., Ananthanarayanan, M., and Suchy, F. J., 1996, Multiple factors regulate the rat liver basolateral sodium-dependent bile acid cotransporter gene promoter, J. Biol. Chem. 271:1521l–15221.

    Google Scholar 

  • Kartenbeck, J., Leuschner, U., Mayer, R., and Keppler, D., 1996, Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome, Hepatology 23:1061–1066.

    PubMed  CAS  Google Scholar 

  • Kast, C., Stieger, B., Winterhalter, K. H., and Meier, P. J., 1994, Hepatocellular transport of bile acids: Evidence for distinct subcellular localizations of electrogenic and ATP-dependent taurocholate transport in rat hepatocytes, J. Biol. Chem. 269:5179–5186.

    PubMed  CAS  Google Scholar 

  • Kauffmann, H. M., and Schrenk, D., 1998, Sequence analysis and functional characterization of the 52-flanking region of the rat multidrug resistance protein 2 (MRP2) gene, Biochem. Biophys. Res. Commun. 245:325–331.

    Article  PubMed  CAS  Google Scholar 

  • Kauffmann, H. M., Keppler, D., Kartenbeck, J., and Schrenk, D., 1997, Induction of cMrp/cMoat gene expression by cisplatin, 2-acethylaminofluorene, or cycloheximide in rat hepatocytes, Hepatology 26:980–985.

    PubMed  CAS  Google Scholar 

  • Kauffmann, H. M., Keppler, D., Grant, T. W., and Schrenk, D., 1998, Induction of hepatic mrp2 (cmrp/cmoat) gene expression in nonhuman primates treated with rifampicin or tamoxifen, Arch. Toxicol. 72:763–768.

    Article  PubMed  CAS  Google Scholar 

  • Keppler, D., and Kartenbeck, J., 1996, The canalicular conjugate export pump encoded by the cmrp/cmoat gene, Prog. Liver Dis. 14:55–67.

    PubMed  CAS  Google Scholar 

  • Keppler, D., and König, J., 1997, Expression and localization of the conjugated export pump encoded by the MRP2 (cMRP/cMOAT) gene in liver, FASEB J. 11:509–516.

    PubMed  CAS  Google Scholar 

  • Kinoshita, S., Suzuki, H., Ito, K., Kume, K., Shimizu, T., and Sugiyama, Y., 1998, Transfected rat cMOAT is functionally expressed on the apical membrane in Madin-Darby canine kidney (MDCK) cells, Pharmaceut. Res. 15:1851–1856.

    Article  CAS  Google Scholar 

  • Kitamura, T., Jansen, P., Hardenbrook, C., Kamimoto, Y., Gatmaitan, Z., and Arias, I. M., 1990, Defective ATP-dependent bile canalicular transport of organic anions in mutant (TR-) rats with conjugated hyperbilirubinemia, Proc. Natl. Acad. Sci. USA 87:3557–3561.

    PubMed  CAS  Google Scholar 

  • Kiuchi, Y., Suzuki, H., Hirohashi, T., Tyson, C. A., and Sugiyama, Y., 1998, cDNA cloning and inducible expression of human multidrug resistance associated protein 3 (MRP3), FEBS Lett. 433:149–152.

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi, K., Sogame, Y., Hara, H., and Hayashi, K., 1990, Mechanism of glutathione S-conjugate transport in canalicular and basolateral rat liver plasma membrane, J. Biol. Chem. 265:7737–7741.

    PubMed  CAS  Google Scholar 

  • Kobayashi, K., Komatsu, S., Nishi, T., Hara, H., and Hayashi, K., 1991, ATP-dependent transpor for glucuronides in canalicular plasma membrane vesicles, Biochem. Biophys. Res. Commun. 176:622–626.

    Article  PubMed  CAS  Google Scholar 

  • Koepsell, H., 1998, Organic cation transporters in intestine, kidney, liver and brain, Annu. Rev. Physiol. 60:243–266.

    Article  PubMed  CAS  Google Scholar 

  • Koga, T., Shimada, Y., Kuroda, M., Tsujita, Y., Hasegawa, K., and Yamazaki, M., 1990, Tissue-selective inhibition of cholesterol synthesis in vivo by pravastatin sodium, a 3-hydroxymethylglutaryl coenzyme A reductase inhibitor, Biochim. Biophys. Acta 1045:115–120.

    PubMed  CAS  Google Scholar 

  • Koike, K., Kawabe, T., Tanaka, T., Toh, S., Uchiumi, T., Wada, M., Akiyama, S., Ono, M., and Kuwano, M., 1997, A canalicular multispecific organic anion transporter (cMOAT) antisense cDNA enhances drug sensitivity in human hepatic cancer cells, Cancer Res. 57:5475–5479.

    PubMed  CAS  Google Scholar 

  • König, J., Cui, Y., Leier, I., and Keppler, D., 1998, Localization and functional characterization of the apical multidrug resistance protein, MRP2, permanently expressed in transfected human and canine cells, Hepatology, 28:427A.

    Google Scholar 

  • König, J., Rost, D., Cui, Y., and Keppler, D., 1999, Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane, Hepatology 29:1156–1163.

    PubMed  Google Scholar 

  • Kontaxi, M., Eckhardt, U., Hagenbuch, B., Stieger, B., Meier, P. J., and Petzinger, E., 1996, Uptake of the mycotoxin ochratoxin A in liver cells occurs via the cloned organic anion transporting polypeptide, J. Pharmacol. Exp. Ther. 279:1507–1513.

    PubMed  CAS  Google Scholar 

  • Kool, M., de Haas, M., Scheffer, G. L., Scheper, R. J., van Eijk, M. J. T., Juijn, J. A., Baas, F., and Borst, P., 1997, Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines, Cancer Res. 57:3537–3547.

    PubMed  CAS  Google Scholar 

  • Kool, M., van der Linden, M., de Haas, M., Scheffer, G. L., de Vree, J. M. L., Smith, A. J., Jansen, G., Peters, G. J., Ponne, N., Scheper, R. J., Oude Elferink, R. P. J., Baas, F., and Borst, P., 1999, MRP3, an organic anion transporter able to transport anti-cancer drugs, Proc. Natl. Acad. Sci. (USA) 96:6914–6919.

    CAS  Google Scholar 

  • Kouzuki, H., Suzuki, H., Ohashi, R., Ito, K., and 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.

    PubMed  CAS  Google Scholar 

  • Kouzuki, H., Suzuki, H., Ohashi, R., Ito, K., and Sugiyama, Y., 1999, Contribution of organic anion transporting polypeptide to the uptake of ligands into rat hepatocytes, J. Pharmacol. Exp. Ther. 288:627–634.

    PubMed  CAS  Google Scholar 

  • Kramer, W., and Wess, G., 1996, Bile acid transport systems as pharmaceutical targets, Eur. J. Clin. Invest. 26:715–732.

    PubMed  CAS  Google Scholar 

  • Kramer, W., Wess, G., Schubert, G., Bickel, M., Girbig, F., Gutjahr, U., Kowalewski, S., Baringhaus, K.-H., Enhsen, A., Glombik, H., Müllner, S., Neckermann, G., Schulz, S., and Petzinger, E., 1992, Liver-specific drug targeting by coupling to bile acids, J. Biol. Chem. 267:18598–18604.

    PubMed  CAS  Google Scholar 

  • Kuipers, F., Enserink, M., Havinga, R., van der Steen, A. B. M., Hardonk, M. J., Fevery, J., and Vonk, R. J., 1988, Separate transport systems for biliary secretion of sulfated and unsulfated bile acids in the rat, J. Clin. Invest. 81:1593–1599.

    PubMed  CAS  Google Scholar 

  • Kuipers, F., Radominska, A., Zimniak, P., Little, J. M., Havinga, R., Vonk, R. J., and Lester, R., 1989, Defective biliary secretion of bile acid 3-O-glucuronides in rats with hereditary conjugated hyperbilirubinemia, J. Lipid Res. 30:1835–1845.

    PubMed  CAS  Google Scholar 

  • Kullak-Ublick, G.-A., Hagenbuch, B., Stieger, B., Wolkoff, A. W., and Meier, P. J., 1994, Functional characterization of the basolateral rat liver organic anion transporting polypeptide, Hepatology 20:411–416.

    Article  PubMed  CAS  Google Scholar 

  • Kullak-Ublick, G.-A., Hagenbuch, B., Stieger, B., Schteingart, C. D., Hofmann, A. F., Wolkoff, A. W., and Meier, P. J., 1995, Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver, Gastroenterology 109:1274–1282.

    PubMed  CAS  Google Scholar 

  • Kullak-Ublick, G.-A., Beuers, U., Meier, P. J., Domdey, H., and Paumgartner, G., 1996a, Assignment of the human organic anion transporting polypeptide (OATP) gene to chromosome 12p12 by fluorescence in situ hybridization, J. Hepatol. 25:985–987.

    Article  PubMed  CAS  Google Scholar 

  • Kullak-Ublick, G.-A., Beuers, U., and Paumgartner, G., 1996b, Molecular and functional characterization of bile acid transport in human hepatoblastoma JepG2 cells, Hepatology 23:1053–1060.

    PubMed  CAS  Google Scholar 

  • Kullak-Ublick, G.-A., Beuers, U., Fahney, C., Hagenbuch, B., Meier, P. J., and Paumgartner, G., 1997a, Identification and functional characterization of the promoter region of the human organic anion transporting polypeptide gene, Hepatology 26:991–997.

    PubMed  CAS  Google Scholar 

  • Kullak-Ublick, G.-A., Glasa, J., Böker, C., Oswald, M., Grützner, U., Hagenbuch, B., Stieger, B., Meier, P. J., Beuers, U., Kramer, W., Wess, G., and Paumgartner, G., 1997b, Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas, Gastroenterology 113:1295–1305.

    PubMed  CAS  Google Scholar 

  • Kullak-Ublick, G.-A., Fisch, T., Oswald, M., Hagenbuch, B., Meier, P. J., Beuers, U., and Paumgartner, G., 1998, Dehydroepiandrosterone sulfate (DHEAS): Identification of a carrier protein in human liver and brain, FEBS Lett. 424:173–176.

    Article  PubMed  CAS  Google Scholar 

  • Kusuhara, H., Suzuki, H., and Sugiyama, Y., 1998, The role of P-glycoprotein and canalicular multispecific organic anion transporter (cMOAT) in the hepatobiliary excretion of drugs, J. Pharmaceut. Sci. 87:1025–1040.

    Article  CAS  Google Scholar 

  • Kusuhara, H., Sekine, T., Utsunomiya-Tate, N. Tsuda, M., Kojima, R., Cha, S. H., Sugiyama, Y., Kanai, Y., and Endou, H., 1999, Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain, J. Biol. Chem. 274:13675–13680.

    Article  PubMed  CAS  Google Scholar 

  • Lautier, D., Canitrot, Y., Deeley, R. G., and Cole, S. P. C., 1996, Multidrug resistance mediated by the multidrug resistance protein (MRP) gene, Biochem. Pharmacol. 52:967–977.

    Article  PubMed  CAS  Google Scholar 

  • Leier, I., Jedlitschky, G., Buchholz, U., Cole, S. P. C., Deeley, R. G., and Keppler, D., 1994, The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates, J. Biol. Chem. 269:27807–27810.

    PubMed  CAS  Google Scholar 

  • Li, L., Lee, T. K., Meier, P. J., and Ballatori, N., 1998, Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp-1, the hepatic sinusoidal organic solute transporter, J. Biol. Chem. 273:16184–16191.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Loe, D. W., Almquist, K. C., Cole, S. P. C., and Deeley, R. G., 1996a, ATP-dependent 17□-estradiol 17-(□-d-glucuronide) transport by multidrug resistance eprotein (MRP), J. Biol. Chem. 271:9683–9689.

    Article  PubMed  CAS  Google Scholar 

  • Loe, D. W., Almquist, K. C., Deeley, R. G., and Cole, S. P. C., 1996b, Multidrug resistance protein (MRP)-mediated transport of leukotriene C4 and chemotherapeutic agents in membrane vesicles, J. Biol. Chem. 271:9675–9682.

    Article  PubMed  CAS  Google Scholar 

  • Loe, D. W., Deeley, R. G., and Cole, S. P. C., 1996c, Biology of the multidrug resistance-associated protein, MRP, Eur. J. Cancer 32A:945–957.

    PubMed  CAS  Google Scholar 

  • Lowenthal, D. T., Irvin, J. D., Merrill, D., Saris, S., Ulm, E., Goldstein, S., Hichens, M., Klein, L., Till, A., and Harris, K., 1985, The effect of renal function on enalapril kinetics, Clin. Pharmacol. Ther. 38:661–666.

    PubMed  CAS  Google Scholar 

  • Lu, R., Kanai, N., Bao, Y., and Schuster, V. L., 1996, Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA (hPGT), J. Clin. Invest. 98:1142–1149.

    PubMed  CAS  Google Scholar 

  • Luther, T. T., Hammerman, P., Rahmaoui, C. M., Lee, P. P., Sela-Herman, S., Matula, G. S., Ananthanarayanan, M., Suchy, F. J., Cavalieri, R. R., Lomri, N., and Scharschmidt, B. F., 1997, Evidence for an ATP-dependent bile acid transport protein other than the canalicular liver ecto-ATPase in rats, Gastroenterology 113:249–254.

    Article  PubMed  CAS  Google Scholar 

  • Madon, J., Eckhardt, U., Gerloff, T., Stieger, B., and Meier, P. J., 1997, Functional expression of the rat liver canalicular isoform of the multidrug resistance-associated protein, FEBS Lett. 406:75–78.

    Article  PubMed  CAS  Google Scholar 

  • Madon, J., Hagenbuch, B., Gerloff, T., Landmann, L., Meier, P. J., and Stieger, B., 1998, Identificatino of a novel multidrug resistance-associated protein (mrp6) at the lateral plasma membrane of rat hepatocytes, Hepatology 28:400A.

    Google Scholar 

  • Marin, J. J. G., Herrera, M. C., Palomero, M. F., Macias, R. I. R., Monte, M. J., El-Mir, M. Y., and Villanueva, G. R., 1998, Rat liver transport and biotransformation of a cytostatic complex of bis-cholylglycinate and platinum (II), J. Hepatol. 28:417–425.

    PubMed  CAS  Google Scholar 

  • Masuda, M., Iizuka, Y., Yamazaki, M., Nishigaki, R., Kato, Y., Niinuma, N., Suzuki, H., and Sugiyma, Y., 1997, Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter (cMOAT) in rats, Cancer Res. 57:3506–3510.

    PubMed  CAS  Google Scholar 

  • Masuda, S., Ibaramoto, K., Takeuchi, A., Satito, H., Hashimoto, Y., and Inui, K., 1999, Cloning and functional characterization of a new multispecific organic anion transporter, OAT-K2, in rat kidney, Mol. Pharmacol. 55:743–752.

    PubMed  CAS  Google Scholar 

  • Meier, P. J., 1995, Molecular mechanisms of hepatic bile salt transport from sinusoidal blood into bile, Am. J. Physiol. 269:G801–G812.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Miyauchi, S., Sawada, Y., Iga, T., Hanano, M., and Sugiyama, Y., 1993, Comparison of the hepatic uptake clearances of fifteen drugs with a wide range of membrane permeabilities in isolated rat hepatocytes and perfused rat livers, Pharmaceut. Res. 10:434–440.

    Article  CAS  Google Scholar 

  • Mukhopadhayay, S., Ananthanarayanan, M., Stieger, B., Meier, P. J., Suchy, F. J., and Anwer, M. S., 1997, CAMP increases liver Na+-taurocholate cotransport by translocating transporter to plasma membranes, Am. J. Physiol. 273:G842–G848.

    PubMed  CAS  Google Scholar 

  • Müller, M., and Jansen, P. L. M., 1997, Molecular aspects of hepatobiliary transport, Am. J. Phyisol. 272:Gl285–G1303.

    Google Scholar 

  • Müller, J., and Jansen, P. L. M., 1998, The secretory function of the liver: New aspects of hepatobiliary transport, J. Hepatol. 28:344–354.

    PubMed  Google Scholar 

  • Müller, M., Ishikawa, T., Berger, U., Klüneman, C., Lucka, L., Schreyer, A., Kannicht, C., Reutter, W., Kurz, G., and Kepper, 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.

    PubMed  Google Scholar 

  • Müller, M., Meijer, C., Zaman, G. J. R., Borst, P., Scheper, R. J., Mulder, N. H., De Vries, E. G. E., and Jansen, P. L. M., 1994, Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport, Proc. Natl. Acad. Sci. USA 91:13033–13037.

    PubMed  Google Scholar 

  • Nakamura, T., Hisaka, A., Sawasaki, Y., Suzuki, Y., Fukami, T., Ishikawa, K., Yano, M., and Sugiyama, Y., 1996, Carrier-mediated active transport of BQ-123, a peptidic endothelin antagonist, into rat hepatocytes, J. Pharmacol. Exp. Ther. 278:564–572.

    PubMed  CAS  Google Scholar 

  • Nies, A. T., Cartz, T., Brom, M., Leier, I., and Keppler, D., 1998, Expression of the apical conjugate export pump, Mrp2, in the polarized hepatoma cell line, WIF-B, Hepatology 28:1332–1340.

    Article  PubMed  CAS  Google Scholar 

  • Niinuma, K., Takenaka, O., Horie, T., Kobayashi, K., Kato, Y., Suzuki, H., and Sugiyama, Y., 1997, Kinetic analysis of the primary active transport of conjugated metabolites across the bile canalicular membrane: Comparative study between DNP-SG (S-(2,4-dinitrophenyl)-glutathione) and E3040-glucuronide, J. Pharmacol. Exp. Ther. 282:866–872.

    PubMed  CAS  Google Scholar 

  • Niinuma, K., Kato, Y., Suzuki, H., Tyson, C. A., Weizer, V., Dabbs, J. E., Froelich, R., Green, C. E., and Sugiyama, Y., 1999, Primary active transport of organic anions on bile canalicular membrane in humans, Am. J. Physiol. 276:G1153–G1164.

    PubMed  CAS  Google Scholar 

  • Nishida, T., Gatmaitan, Z., Che, M., and Arias, I. M., 1991, Rat liver canalicular membrane vesicles contain an ATP-dependent bile acid transport system, Proc. Natl. Acad. Sci. USA 88:6590–6594.

    PubMed  CAS  Google Scholar 

  • Nishida, T., Gatmaitan, Z., Roy-Chowdhury, J., and Arias, I. M., 1992a, Two distinct mechanisms for bilirubin glucuronide transport by rat bile canalicular membrane vesicles: Demonstration of defective ATP-dependent transport in rats (TR-) with inherited conjugated hyperbilirubinemia, J. Clin. Invest. 90:2130–2135.

    PubMed  CAS  Google Scholar 

  • Nishida, T., Hardenbrook, C., Gatmaitan, Z., and Arias, I. M., 1992b, ATP-dependent organic anion transport system in normal and TR- rat liver canalicular membranes, Am. J. Physiol. 262:G629–G635.

    PubMed  CAS  Google Scholar 

  • Nishida, T., Che, M., Gatmaitan, Z., and Arias, I. M., 1995, Structure-specific inhibition by bile acids of adenosine triphosphate-dependent taurocholate transport in rat canalicular membrane vesicles, Hepatology 21:1058–1062.

    Article  PubMed  CAS  Google Scholar 

  • Noé, B., Hagenbuch, B., Stieger, B., and Meier, P. J., 1997, Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain, Proc. Natl. Acad. Sci. USA 94:10346–10350.

    PubMed  Google Scholar 

  • Oguchi, H., Miyasaka, M., Koiwai, T., Tokunaga, S., Hara, K., Sato, K., Yoshie, T., Shioya, H., and Furuta, S., 1993, Pharmacokinetics of temocapril and enalapril in patients with arious degrees of renal insufficiency, Clin. Pharmacokinet. 24:421–427.

    Article  PubMed  CAS  Google Scholar 

  • Ortiz, D. F., St. Pierre, M. V., Abdulmessih, A., and Arias, I. M., 1997, A yeast ATP-binding cassette-type protein mediating ATP-dependent bile acid transport, J. Biol. Chem. 272:15358–15365.

    PubMed  CAS  Google Scholar 

  • Ortiz, D. F., Li, S. H., Iyer, R., Zhang, X. M., Novikoff, P., and Arias, I. M., 1999, MRP3 a new ATP-binding cassette protein localized to the canalicular domain of the hepatocyte, Am. J. Physiol. 276:G1493–G1500.

    PubMed  CAS  Google Scholar 

  • Oude Elferink, R. P. J., and Jansen, P. L. M., 1994, The role of the canalicular multispecific organic anion transporter in the disposal of endo-and xenobiotics, Pharmacol. Ther. 64:77–97.

    Article  PubMed  CAS  Google Scholar 

  • Oude Elferink, R. P. J., De Haan, J., Lambert, K. J., Hagey, L. R., Hofmann, A. F., and Jansen, P. L. M., 1989a, Selective hepatobiliary transport of nordeoxycholate side chain conjugates in mutant rats with a canalicular transport defect, Hepatology 9:861–865.

    PubMed  CAS  Google Scholar 

  • Oude Elferink, R. P. J., Ottenhoff, R., Liefting, W., de Haan, J., and Jansen, P., 1989b, Hepatobiliary transport of glutathione and glutathione conjugate in rats with hereditary hyperbilirubinemia, J. Clin. Invest. 84:476–483.

    Google Scholar 

  • Oude Elferink, R. P. J., Ottenhoff, R., Liefting, W. G. M., Schoemaker, B., Groen, A. K., and Jansen, P. L. M., 1990, ATP-dependent efflux of GSSG and GS-conjugate from isolated rat hepatocytes, Am. J. Physiol. 258:G699–G706.

    PubMed  CAS  Google Scholar 

  • Oude Elferink, R. P. J., Bakker, C. T. M., Roelofsen, H., Middelkoop, E., Ottenhoff, R., Heijn, M., and Jansen, P. L. M., 1993, Accumulation of organic anion in intracellular vesicles of cultured rat hepatocytes is mediated by the canalicular multispecific organic anion transporter, Hepatology 17:434–444.

    Article  PubMed  CAS  Google Scholar 

  • Oude Elferink, R. P. J., Meijer, D. K. F., Kuipers, F., Jansen, P. L. M., Groen, A. K., and Groothuis, G. M. M., 1995, Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport, Biochim. Biophys. Acta 1241:215–268.

    PubMed  Google Scholar 

  • Oude Elferink, R. P. J., Tytgat, G. N. J., and Groen, A. K., 1997, The role of mdr2 P-gly-coprotein in hepatobiliary lipid transport, FASEB J. 11:19–28.

    Google Scholar 

  • Oude Elferink, R. P. J., and van Berge Henegouwen, G. P., 1998, Cracking the genetic code for benign recurrent and progressive familial intrahepatic cholestasis, J. Hepatol. 29:317–320.

    Article  PubMed  CAS  Google Scholar 

  • Paulusma, C. C., and Oude Elferink, R. P. J., 1997, The canalicular multispecific organic anion transporter and conjugated hyperbilirubinemia in rat and man, J. Mol. Med. 75:420–428.

    Article  PubMed  CAS  Google Scholar 

  • Paulusma, C. C., Bosma, P. J., Zaman, G. J., Bakker, C. T., Otter, M., Scheffer, G. L., Scheper, R. J., Borst, P., and Oude Elferink, R. P., 1996, Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene, Science 271:1126–1128.

    PubMed  CAS  Google Scholar 

  • Paulusma, C. C., Kool, M., Bosma, P. J., Scheffer, G. L., Ter Borg, F., Scheper, R. J., Tytgat, G. N. J., Borst, P., Baas, F. and Oude Elferink, R. P. J., 1997, A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome, Hepatology, 25:1539–1542.

    Article  PubMed  CAS  Google Scholar 

  • Petzinger, E., 1994, Transport of organic anions in the liver: An update on bile acid, fatty acid, monocarboxylate, anionic amino acid, cholephilic organic anion, and anionic drug transport, Rev. Physiol. Biochem. Pharmacol. 123:47–211.

    PubMed  CAS  Google Scholar 

  • Petzinger, E., Müller, N., Föllmann, W., Deutscher, J., and Kinne, R. K. H., 1989, Uptake of bumetanide into isolated rat hepatocytes and primary liver cell cultures, Am. J. Physiol. 256:G78–G86.

    PubMed  CAS  Google Scholar 

  • Petzinger, E., Blumrichi, M., Brühl, B., Eckhardt, U., Föllmann, W., Honscha, W., Horz, J. A., Müller, N., Nickau, L., Ottallah-Kolac, M., Platte, H.-D., Schenk, A., Schuh, K., Schulz, K., and Schulz, S., 1996, What we have learned about bumetanide and the concept of multispecific bile acid/drug transporters from the liver, J. Hepatol. 24(Suppl. 1): 42–49.

    PubMed  CAS  Google Scholar 

  • Polhuijs, M., Kuipers, F., Vonk, R. J., and Mulder, G. J., 1989, Stereoselectivity of glutathione conjugation: Blood elimination of alpha-bromoisovalerylurea enantiomers and biliary excretion of the conjugates in unanesthetized normal or congenitally jaundiced rats, J. Pharmacol. Exp. Ther. 249:874–878.

    PubMed  CAS  Google Scholar 

  • Roelofsen, H., Soroka, C. J., Keppler, D., and Boyer, J. L., 1998, Cyclic AMP stimulates sorting of the canalicular organic anion transporter (Mrp2/cMOAT) to the apical domain in hepatocyte couplets, J. Cell Sci. 111:1137–1145.

    PubMed  CAS  Google Scholar 

  • Saito, H., Masuda, S., and Inui, K., 1996, Cloning and functional characterization of a novel rat organic anion transporter mediating basolateral uptake of methotrexate in the kidney, J. Biol. Chem. 271:20719–20725.

    PubMed  CAS  Google Scholar 

  • Sasabe, H., Kato, Y., Tsuji, A., and Sugiyama, Y., 1998a, Stereoselective hepatobiliary transport of the quinolone antibiotic grepafloxacin and its glucuronide in the rat, J. Pharmacol. Exp. Ther. 284:661–668.

    PubMed  CAS  Google Scholar 

  • Sasabe, H., Tsuji, A., and Sugiyama, Y., 1998b, Carrier-mediated mechanism for the biliary excretion of the quinolone antibiotic grepafloxacin and its glucuronide in rats, J. Pharmacol. Exp. Ther. 284:1033–1039.

    PubMed  CAS  Google Scholar 

  • Sasabe, H., Terasaki, T., Tsuji, A., and Sugiyama, Y., 1997, Carrier-mediated hepatic uptake of quinolone antibiotics in the rat, J. Pharmacol. Exp. Ther. 282:162–171.

    PubMed  CAS  Google Scholar 

  • Sathirakul, K., Suzuki, H., Yamada, T., Hanano, M., and Sugiyama, Y., 1993a, Multiple transport systems for organic anions across the bile canalicular membrane, J. Pharmacol. Exp. Ther. 268:65–73.

    Google Scholar 

  • Sathirakul, K., Suzuki, H., Yasuda, K., Hanano, M., Tagaya, O., Horie, T., and Sugiyama, Y., 1993b, Kinetic analysis of hepatobiliary transport of organic anions in Eisai hyperbilirubinemic mutant rats, J. Pharmacol. Exp. Ther. 265:1301–1312.

    PubMed  CAS  Google Scholar 

  • Satlin, L. M., Amin, V., and Wolkoff, A. W., 1997, Organic anion transporting polypeptide mediates organic anion/HCO3- exchange, J. Biol. Chem. 272:26340–26345.

    Article  PubMed  CAS  Google Scholar 

  • Schaub, T. P., Kartenbeck, J., König, J., Vogel, O., Witzgall, R., Kriz, W., and Keppler, D., 1997, Expression of the conjugate export pump encoded by the mrp2 in the apical membrane of kidney proximal tubules, J. Am. Soc. Neprhol. 8:1213–1221.

    CAS  Google Scholar 

  • Schinkel, A. H., Mayer, U., Wagenaar, E., Mol, C. A. A. M., van Deemter, L., Smit, J. J. M., van der Valk, M. A., Voordouw, A. C., Spits, H., van Tellingen, O., Zijlmans, J. M. J. M., Fibbe, W. E., and Borst, P., 1997, Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins, Proc. Natl. Acad. Sci. USA 94:4028–4033.

    Article  PubMed  CAS  Google Scholar 

  • Schmidt, J. V., and Bradfield, C. A., 1996, Ah receptor signaling pathways, Annu. Rev. Cell Dev. Biol. 12:55–89.

    Article  PubMed  CAS  Google Scholar 

  • Schroeder, A., Eckhardt, U., Stieger, B., Tynes, R., Schteingart, C. D., Hofmann, A. F., Meier, P. J., and 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.

    PubMed  CAS  Google Scholar 

  • Scott, W. A., 1990, Hydrophilicity and the differential pharmacology of pravastatin, in: Lipid Management: Pravastatin and the Differential Pharmacology of HMG-CoA Reductase Inhibitors (C. Wood, ed.), Round Table Series No. 16, Royal Soc. Med. Service, London, pp. 17–25.

    Google Scholar 

  • Sekine, T., Watanabe, N., Hosoyamada, M., Kanai, Y., and Endou, H., 1997, Expression cloning and characterization of a novel multispecific organic anion transporter, J. Biol. Chem. 272:18526–18529.

    PubMed  CAS  Google Scholar 

  • Sekine, T., Cha, S. H., Tsuda, M., Apiwattanakul, N., Nakajima, N., Kanai, Y., and Endou, H., 1998, Identification of multispecific organic anion transporter 2 expressed predominantly in the liver, FEBS Lett. 429:179–182.

    Article  PubMed  CAS  Google Scholar 

  • Shi, X., Bai, S., Ford, A. C., Burk, R. D., Jacquemin, E., Hagenbuch, B., Meier, P. J., and Wolkoff, A. W., 1995, Stable inducible expression of a functional rat liver organic anion transport protein in HeLa cells, J. Biol. Chem. 270:25591–25595.

    PubMed  CAS  Google Scholar 

  • Shimamura, H., Suzuki, H., Hanano, M., Suzuki, A., Tagaya, O., Horie, T., and Sugiyama, Y., 1994, Multiple systems for the biliary excretion of organic anions in rats: Liquiritigenin conjugates as model compounds, J. Pharmacol. Exp. Ther. 271:370–378.

    PubMed  CAS  Google Scholar 

  • Shimamura, H., Suzuki, H., Tagaya, O., Horie, T., and Sugiyama, Y., 1996, Biliary excretion of glycyrrhizin in rats: Kinetic basis for the multiplicity in the bile canalicular transport of organic anions, Pharmaceut. Res. 13:1833–1837.

    Article  CAS  Google Scholar 

  • Shin, H.-C., Kato, Y., Yamada, T., Niinuma, K., Hisaka, A., and Sugiyama, Y., 1997, Hepatobiliary transport mechanism for the cyclopentapeptide endothelin antagonist BQ-123, Am. J. Physiol. 272:G979–G986.

    PubMed  CAS  Google Scholar 

  • Shneider, B., and Moyer, M. S., 1993, Characterization of endogenous carrier-mediated taurocholate efflux from Xenopus laevis oocytes, J. Biol. Chem. 268:6985–6988.

    PubMed  CAS  Google Scholar 

  • Sica, D. A., 1992, Kinetics of angiotensin-converting enzyme inhibitor in renal failure, J. Cardiovasc. Pharmacol. 20(Suppl. 10):S13–S20.

    PubMed  CAS  Google Scholar 

  • Smit, J. J., Schinkel, A. H., Oude Elferink, R. P., Groen, A. K., Wagenaar, E., van Deemter, L., Mol, C. A., Ottenhoff, R., van der Lugt, N. M., van Roon, M. A., van der Valk, M. A., Offenhaus, G. J. A., Berns, A. J. M., and Borst, P., 1993, Homozygous distruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver diseases Cell 75:45l–462.

    Article  Google Scholar 

  • Stephan, Z. F., Yurachek, E. C., Sharif, R., Wasrary, J. M., Steele, R. E., and Howes, C., 1992, Reduction of cardiovascular and thyroxine-suppressing activities of L-T3 by liver targeting with cholic acid, Biochem. Pharmacol. 43:1969–1974.

    Article  PubMed  CAS  Google Scholar 

  • Stieger, B., and Meier, P. J., 1998, Bile acid and xenobiotic transporters in liver, Curr. Opin. Cell Biol. 10:462–467.

    Article  PubMed  CAS  Google Scholar 

  • Stieger, B., O’Neill, B., and Meier, P. J., 1992, ATP-dependent bile-salt transport in canalicular rat plasma-membrane vesicles, Biochem. J. 284:67–74.

    PubMed  CAS  Google Scholar 

  • Stieger, B., Hagenbuch, B., Landmann, L., Höchli, M., Schroeder, A., and Meier, P. J., 1994, In situ localization of the hepatocytic Na+/taurocholate cotransporting polypeptide in rat liver, Gastroenterology 107:1781–1787.

    PubMed  CAS  Google Scholar 

  • Strautnieks, S. S., Bull, L. N., Knisely, A. S., Kocoshis, S. A., Dahl, N., Arnell, H., Sokal, E., Dahan, K., Childs, S., Ling, V., Tanner, M. S., Kagalwalla, A. F., Nemeth, A., Pawlowska, J., Baker, A., Mieli-Vergani, G., Freimer, N. B., Gardiner, R. M., and Thompson, R. J., 1998, A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis, Nature Genet. 20:233–238.

    PubMed  CAS  Google Scholar 

  • Suchy, F. J., 1993, Hepatocellular transport of bile acids, Semin. Liver Dis. 13:235–247.

    Article  PubMed  CAS  Google Scholar 

  • Suchy, F. J., Sippel, C. J., and Ananthanarayanan, M., 1997, Bile acid transport across the hepatocyte canalicular membrane, FASEB J. 11:199–205.

    PubMed  CAS  Google Scholar 

  • Sugiyama, Y., Kato, Y., and Chu, X.-Y., 1998, Multiplicity of biliary excretion mechanisms for the camptothecin derivative irinotecan (CPT-11), its metabolite SN-38, and its glucuronide: Role of canalicular multispecific organic anion transporter and P-glycoprotein, Cancer Chemother. Pharmacol. 42(Suppl):544–549.

    Google Scholar 

  • Suzuki, H., and Sugiyama, Y., 1998, Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/MRP2, Semin. Liver Dis. 18:359–376.

    PubMed  CAS  Google Scholar 

  • Sweet, D. H., Wolff, N. A., and Pritchard, J. B., 1997, Expression cloning and characterization of ROAT1: The basolateral organic anion transporter in rat kidney, J. Biol. Chem. 272:30088–30095.

    Article  PubMed  CAS  Google Scholar 

  • Takenaka, O., Horie, T., Suzuki, H., Kobayashi, K., and Sugiyama, Y., 1995]a, Kinetic analysis of hepatobiliary transport for conjugative metabolites in the perfused liver of mutant rats (EHBR) with hereditary conjugative hyperbilirubinemia, Pharmaceut. Res.} 12}:1746–1

    Article  CAS  Google Scholar 

  • Takenaka, O., Horie, T., Suzuki, H., and Sugiyama, Y., 1995b, The biliary excretion systems for conjugative metabolites: Comparison of glucuronide and sulfate in Eisai hyperbilirubinemic rats (EHBR), J. Pharmacol. Exp. Ther. 274:1362–1369.

    PubMed  CAS  Google Scholar 

  • Takenaka, O., Horie, T., Suzuki, H., and Sugiyama, Y., 1997, Carrier-mediated active transport of the glucuronide and sulfate of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole (E3040) into rat liver. Quantitative comparison of permeability in isolated hepatocytes, perfused liver and liver in vivo, J. Pharmacol. Exp. Ther. 280:948–958.

    PubMed  CAS  Google Scholar 

  • Takikawa, H., Sano, N., Narita, T., Uchida, Y., Yamanaka, M., Horie, T., Mikami T., and Tagaya, O., 1991, Biliary excretion of bile acid conjugates in a hyperbilirubinemic mutant Sprague-Dawley rat, Hepatology 14:352–360.

    Article  PubMed  CAS  Google Scholar 

  • Takikawa, H., Yamazaki, R., Sano, N., and Yamanaka, M., 1996, Biliary excretion of estradiol-17□-glucuronide in the rat, Hepatology 23:607–613.

    PubMed  CAS  Google Scholar 

  • Taniguchi, K., Wada, M., Kohno, K., Nakamura, T., Kawabe, T., Kawakami, M., Kagotani, K., Okumura, K., Akiyama, S., and Kuwano, M., 1996, A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation, Cancer Res. 56:4124–4129.

    PubMed  CAS  Google Scholar 

  • Terasaki, T., Mizuguchi, H., Itoho, C., Tamai, I., Lemaire, M., and Tsuji, A., 1995, Hepatic uptake of octreotide, a long-acting somatostatin analogue, via a bile acid transport system, Pharmaceut. Res. 12:12–17.

    Article  CAS  Google Scholar 

  • Toh, S., Wada, M., Uhciumi, T., Inokuchi, A., Makino, Y., Horie, Y., Adachi, Y., Sakisaka, S., and Kuwano, M., 1999, Genomic structure of the canalicular multispecific organic anion transporte r(MRP2/cMOAT) gene and mutations in the ATP-binding cassette region in Dubin-Johnson syndrome, Am. J. Hum. Genet. 64:739–746.

    Article  PubMed  CAS  Google Scholar 

  • Torchia, E. C., Shapiro, R. J., and Agellon, L. B., 1996, Reconstitution of bile acid transport in the rat hepatoma McArdle RH-7777 cell line, Hepatology 24:206–211.

    PubMed  CAS  Google Scholar 

  • Trauner, M., Meier, P. J., and Boyer, J. L., 1998, Molecular pathogenesis of cholestasis, N. Engl. J. Med. 339:1217–1227.

    Article  PubMed  CAS  Google Scholar 

  • Tsuji, A., Terasaki, T., Takanosu, T., Tamai, I., and Nakashima, E., 1986, Uptake of benzylpenicillin, cefpiramide, and cefazolin by freshly prepared rat hepatocytes, Biochem. Pharmacol. 35:1151–158.

    Google Scholar 

  • Tsujita, Y., Juroda, M., Shimada, Y., Tanzawa, K., Arai, M., Kaneko, I., Tanaka, M., Masuda, H., Tarumi, C., Watanabe, Y., and Fujii, S., 1986, CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: Tissue-selective inhibition of sterol synthesis and hypolipodemic effect on various animal species, Biochim. Biophys. Acta 877:50–60.

    PubMed  CAS  Google Scholar 

  • van Aubel, R. A. M. H., van Kuijck, M. A., Koenderink, J. B., Deen, P. M. T., van OS, C. H., and Russel, F. G. M., 1998, Adenosine triphosphate-dependent transport of anionic conjugates by the rabbit multidrug resistance-associated protein Mrp2 expressed in insect cells, Mol. Pharmacol. 53:1062–1067.

    PubMed  Google Scholar 

  • van Montfoort, J. E., Hagenbuch, B., Muller, M., Meijer, D. K. F., and Meier, P. J., 1998, Transport of organic cations by the rat organic anion transporting polypeptides oatp1, oatp2 and the human OATP, Hepatology 28:506A.

    Google Scholar 

  • Verkade, H. J., Wolbers, M. J., Havinga, R. Uges, D. R. A., Vonk, R. J., and Kuipers, F., 1990, The uncoupling of biliary lipid from bile acid secretion by organic anions in the rat, Gastroenterology 99:1485–1492.

    PubMed  CAS  Google Scholar 

  • von Dippe, P., and Levy, D., 1990, Expression of the bile acid transport protein during liver development and in hepatoma cells, J. Biol. Chem. 265:5942–5945.

    Google Scholar 

  • von Dippe, P., Amoui, M., Stellwagen, R. H., and Levy, D., 1996, The functional expression of sodium-dependent bile acid transport in Madin-Darby canine kidney cells transfected with the cDNA for microsomal epoxide hydrolase, J. Biol. Chem. 271:18176–18180.

    Google Scholar 

  • Vore, M., Hoffman, T., and Gosland, M., 1996, ATP-dependent transport of □-estradiol 17-(□-d-glucuronide) in rat canalicular membrane vesicles, Am. J. Physiol. 271:G791–G798.

    PubMed  CAS  Google Scholar 

  • Wada, M., Toh, S., Taniguchi, K., Nakamura, T., Uchiumi, T., Kohno, K., Yoshida, I., Kimura, A., Sakisaka, S., Adachi, Y., and Kuwano, M., 1998, Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome, Human Mol. Genet. 7:203–207.

    CAS  Google Scholar 

  • Watanabe, T., Miyauchi, S., Sawada, Y., Iga, T., Hanano, M., Inaba, M., and Sugiyama, Y., 1992, Kinetic analysis of hepatobiliary transport of vincristine in perfused rat liver: Possible roles of P-glycoprotein in biliary excretion of vincristine, J. Hepatol. 16:77–88.

    Google Scholar 

  • Watanabe, T., Suzuki, H., Sawada, Y., Naito, M., Tsuruo, T., Inaba, M., Hanano, M., and Sugiyama, Y., 1995, Induction of hepatic P-glycoprotein enhances biliary excretion of vincristine in rats, J. Hepatol. 23:440–448.

    Article  PubMed  CAS  Google Scholar 

  • Wolters, H., Kuipers, F. Slooff, M. J. H., and Vonk, R. J., 1992, Adenosine triphosphate-de-pendent taurocholate transport in human liver plasma membranes, J. Clin. Invest. 90:2321–2326.

    Article  PubMed  CAS  Google Scholar 

  • Yamada, T., Niinuma, K., Lemaire, M., Terasaki, T., and Sugiyama, Y., 1997a, Mechanism of the tissue distribution and biliary excretion of the cyclic peptide octreotide, J. Pharmacol. Exp. Ther. 279:1357–1364.

    Google Scholar 

  • Yamada, T., Niinuma, K., Lemaire, M., Terasaki, T., and Sugiyama, Y., 1997b, Carrier-mediated hepatic uptake of the cationic cyclopeptide, octreotide, in rats: Comparison between in vivo and in vitro, Drug Metab. Dispos. 25:536–543.

    PubMed  CAS  Google Scholar 

  • Yamazaki, M., Suzuki, H., Sugiyama, Y., Iga, T., and Hanano, M., 1992a, Uptake of organic anions by isolated rat hepatocytes: A classification in terms of ATP-dependency, J. Hepatol. 14:41–47.

    PubMed  CAS  Google Scholar 

  • Yamazaki, M., Suzuki, H., Sugiyama, Y., Iga, T., and Hanano, M., 1992b, Utilization of ATP-depleted cells in the analysis of taurocholate uptake by isolated rat hepatocytes, J. Hepatol. 14:54–63.

    PubMed  CAS  Google Scholar 

  • Yamazaki, M., Suzuki, H., Hanano, M., and Sugiyama, Y., 1993a, Different relationships between cellular ATP and hepatic uptake among taurocholate, cholate, and organic anions, Am. J. Physiol. 264:G693–G701.

    PubMed  CAS  Google Scholar 

  • Yamazaki, M., Suzuki, H., Hanano, M., Tokui, T., Komai, T., and Sugiyama, Y., 1993b, Na+-independent multispecific anion transporter mediates active transport of pravastatin into rat liver, Am. J. Physiol. 264:G36–G44.

    PubMed  CAS  Google Scholar 

  • Yamazaki, M., Akiyama, S., Nishigaki, R., and Sugiyama, Y., 1996a, Uptake is the rate-limiting step in the overall hepatic elimination of pravastatin at steady-state in rats, Pharmaceut. Res. 13:1559–1564.

    CAS  Google Scholar 

  • Yamazaki, M., Kobayashi, K., and Sugiyama, Y., 1996b, Primary active transport of pravastatin across the liver canalicular membrane in normal and mutant Eisai hyperbilirubinemic rats, Biopharmaceut. Drug Dispos. 17:607–621.

    CAS  Google Scholar 

  • Yamazaki, M., Suzuki, H., and Sugiyama, Y., 1996c, Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics, Pharmaceut. Res. 13:497–513.

    CAS  Google Scholar 

  • Yamazaki, M., Tokui, T., Ishigami, M., and Sugiyama, Y., 1996d, Tissue-selective uptake of pravastatin in rats: Contribution of a specific carrier-mediated uptake system, Biopharmaceut. Drug Dispos. 17:775–789.

    CAS  Google Scholar 

  • Yamazaki, M., Akiyama, S., Niinuma, K., Nishigaki, R., and Sugiyama, Y., 1997, Biliary excretion of pravastatin in rats: Contribution of the excretion pathway mediated by canalicular multispecific organic anion transporter (cMOAT), Drug Metab. Disposit. 25:1123–1129.

    CAS  Google Scholar 

  • Zhang, L., Dresser, M. J., Gray, A. T., Yost, S. C., Terashita, S., and Giacomini, K. M., 1997, Cloning and functional expression of a human liver organic cation transporter, Mol. Pharmacol. 51:913–921.

    PubMed  CAS  Google Scholar 

  • Zhang, L., Brett, C. M., and Giacomini, K. M., 1998, Role of organic cation transporters in drug absorption and elimination, Annu. Rev. Pharmacol. Toxicol. 38:431–460.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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  1. Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Hiroshi Suzuki & Yuichi Sugiyama

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  1. Hiroshi Suzuki
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  1. University of Michigan, Ann Arbor, Michigan

    Gordon L. Amidon

  2. University of California, San Francisco, San Francisco, California

    Wolfgang Sadée

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Suzuki, H., Sugiyama, Y. (2002). Transporters for Bile Acids and Organic Anions. In: Amidon, G.L., Sadée, W. (eds) Membrane Transporters as Drug Targets. Pharmaceutical Biotechnology, vol 12. Springer, Boston, MA. https://doi.org/10.1007/0-306-46812-3_14

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  • DOI: https://doi.org/10.1007/0-306-46812-3_14

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