Advanced search
Publication Cover
Drug Metabolism Reviews Volume 42, 2010 - Issue 3: Special Issue: Transporter-drug interactions and transporter-mediated toxicity in the liver/hepatocyte
Submit an article Journal homepage
1,059
Views
104
CrossRef citations to date
0
Altmetric
Review Article

ABCC2/Abcc2: a multispecific transporter with dominant excretory functions

Katalin JemnitzChemical Research Center, Institute of Biomolecular Chemistry, HAS, Budapest, Hungary
,
Krisztina Heredi-SzaboSOLVO Biotechnology, Szeged, Hungary
,
Judit JanossySOLVO Biotechnology, Szeged, Hungary
,
Eniko IojaSOLVO Biotechnology, Szeged, Hungary
,
Laszlo VereczkeyChemical Research Center, Institute of Biomolecular Chemistry, HAS, Budapest, Hungary
&
Peter KrajcsiSOLVO Biotechnology, Szeged, HungaryCorrespondence[email protected]
Pages 402-436 | Accepted 17 Nov 2009, Published online: 19 Jan 2010

References

  • Abe, F., Ueyama, J., Kimata, A., Kato, M., Hayashi, T., Nadai, M., et al. (2008). Involvement of multidrug resistance-associated protein 2 (ABCC2/Mrp2) in biliary excretion of micafungin in rats. Life Sci 83:229–235.
  • Akao, T., Sakashita, Y., Hanada, M., Goto, H., Shimada, Y., Terasawa, K. (2004). Enteric excretion of baicalein, a flavone of Scutellariae radix, via glucuronidation in rat: involvement of multidrug resistance-associated protein 2. Pharm Res 21:2120–2126.
  • Akita, H., Suzuki, H., Ito, K., Kinoshita, S., Sato, N., Takikawa, H., et al. (2001a). Characterization of bile acid transport mediated by multidrug resistance associated protein 2 and bile salt export pump. Biochim Biophys Acta 1511:7–16.
  • Akita, H., Suzuki, H., Sugiyama, Y. (2001b). Sinusoidal efflux of taurocholate is enhanced in Mrp2-deficient rat liver. Pharm Res 18:1119–1125.
  • Ambudkar, S. V., Kimchi-Sarfaty, C., Sauna, Z. E., Gottesman, M. M. (2003). P-glycoprotein: from genomics to mechanism. Oncogene 22:7468–7485.
  • Anderson, P. L., Lamba, J., Aquilante, C. L., Schuetz, E., Fletcher, C. V. (2006). Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a pilot study. J Acquir Immune Defic Syndr 42:441–449.
  • Annereau, J. P., Szakacs, G., Tucker, C. J., Arciello, A., Cardarelli, C., Collins, J., et al. (2004). Analysis of ATP-binding cassette transporter expression in drug-selected cell lines by a microarray dedicated to multidrug resistance. Mol Pharmacol 66:1397–1405.
  • Arias, I. M., Johnson, L., Wolfson, S. (1961). Biliary excretion of injected conjugated and unconjugated bilirubin by normal and Gunn rats. Am J Physiol 200:1091–1094.
  • Arts, H. J., Katsaros, D., de Vries E. G., Massobrio, M., Genta, F., Danese, S., et al. (1999). Drug resistance-associated markers P-glycoprotein, multidrug resistance-associated protein 1, multidrug resistance-associated protein 2, and lung resistance protein as prognostic factors in ovarian carcinoma. Clin Cancer Res 5:2798–2805.
  • Asakura, E., Nakayama, H., Sugie, M., Zhao, Y. L., Nadai, M., Kitaichi, K., et al. (2004). Azithromycin reverses anticancer drug resistance and modifies hepatobiliary excretion of doxorubicin in rats. Eur J Pharmacol 484:333–339.
  • Aye, I. L., Paxton, J. W., Evseenko, D. A., Keelan, J. A. (2007). Expression, localization, and activity of ATP-binding cassette (ABC) family of drug transporters in human amnion membranes. Placenta 28:868–877.
  • Bacso, Z., Nagy, H., Goda, K., Bene, L., Fenyvesi, F., Matko, J., et al. (2004). Raft and cytoskeleton associations of an ABC transporter: P-glycoprotein. Cytometry A 61:105–116.
  • Bakos, E., Evers, R., Sinko, E., Varadi, A., Borst, P., Sarkadi, B. (2000). Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions. Mol Pharmacol 57:760–768.
  • Bakos, E., Hegedus, T., Hollo, Z., Welker, E., Tusnady, G. E., Zaman, G. J., et al. (1996). Membrane topology and glycosylation of the human multidrug resistance-associated protein. J Biol Chem 271:12322–12326.
  • Ballatori, N., Hammond, C. L., Cunningham, J. B., Krance, S. M., Marchan, R. (2005). Molecular mechanisms of reduced glutathione transport: role of the MRP/CFTR/ABCC and OATP/SLC21A families of membrane proteins. Toxicol Appl Pharmacol 204:238–255.
  • Ballatori, N., Krance, S. M., Marchan, R., Hammond, C. L. (2009). Plasma membrane glutathione transporters and their roles in cell physiology and pathophysiology. Mol Aspects Med 30:13–28.
  • Ballatori, N., Truong, A. T. (1992). Glutathione as a primary osmotic driving force in hepatic bile formation. Am J Physiol 263:G617–G624.
  • Ballatori, N., Truong, A. T. (1995). Mechanisms of hepatic methylmercury uptake. J Toxicol Environ Health 46:343–353.
  • Ban, D., Kudo, A., Sui, S., Tanaka, S., Nakamura, N., Ito, K., et al. (2009). Decreased Mrp2-dependent bile flow in the post-warm ischemic rat liver. J Surg Res 153:310–316.
  • Bandler, P. E., Westlake, C. J., Grant, C. E., Cole, S. P., Deeley, R. G. (2008). Identification of regions required for apical membrane localization of human multidrug resistance protein 2. Mol Pharmacol 74:9–19.
  • Bart, J., Hollema, H., Groen, H. J., de Vries E. G., Hendrikse, N. H., Sleijfer, D. T., et al. (2004). The distribution of drug-efflux pumps P-gp, BCRP, MRP1, and MRP2 in the normal blood-testis barrier and in primary testicular tumours. Eur J Cancer 40:2064–2070.
  • Bartholome, K., Rius, M., Letschert, K., Keller, D., Timmer, J., Keppler, D. (2007). Data-based mathematical modeling of vectorial transport across double-transfected polarized cells. Drug Metab Dispos 35:1476–1481.
  • Belinsky, M. G., Dawson, P. A., Shchaveleva, I., Bain, L. J., Wang, R., Ling, V., et al. (2005). Analysis of the in vivo functions of Mrp3. Mol Pharmacol 68:160–168.
  • Beuers, U., Denk, G. U., Soroka, C. J., Wimmer, R., Rust, C., Paumgartner, G., et al. (2003). Taurolithocholic acid exerts cholestatic effects via phosphatidylinositol 3-kinase-dependent mechanisms in perfused rat livers and rat hepatocyte couplets. J Biol Chem 278:17810–17818.
  • Bleasby, K., Castle, J. C., Roberts, C. J., Cheng, C., Bailey, W. J., Sina, J. F., et al. (2006). Expression profiles of 50 xenobiotic transporter genes in humans and preclinical species: a resource for investigations into drug disposition. Xenobiotica 36:963–988.
  • Bodo, A., Bakos, E., Szeri, F., Varadi, A., Sarkadi, B. (2003). Differential modulation of the human liver conjugate transporters, MRP2 and MRP3, by bile acids and organic anions. J Biol Chem 278:23529–23537.
  • Borst, P, Zelcer, N., van de Wetering, K. (2006a). MRP2 and 3 in health and disease. Cancer Lett 234:51–61.
  • Borst, P., Zelcer, N., van de Wetering, K., Poolman, B. (2006b). On the putative cotransport of drugs by multidrug resistance proteins. FEBS Lett 580:1085–1093.
  • Boyer, J. L., Meier, P. J. (1990). Characterizing mechanisms of hepatic bile acid transport utilizing isolated membrane vesicles. Meth Enzymol 192:517–533.
  • Brand, W., Schutte, M. E., Williamson, G., van Zanden J. J., Cnubben, N. H., Groten, J. P., et al. (2006). Flavonoid-mediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds, and bioactive ingredients. Biomed Pharmacother 60:508–519.
  • Bridges, C. C., Joshee, L., Zalups, R. K. (2008). Multidrug resistance proteins and the renal elimination of inorganic mercury mediated by 2,3-dimercaptopropane-1-sulfonic acid and meso-2,3-dimercaptosuccinic acid. J Pharmacol Exp Ther 324:383–390.
  • Buchler, M., Konig, J., Brom, M., Kartenbeck, J., Spring, H., Horie, T., et al. (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.
  • Callaghan, R., Berridge, G., Ferry, D. R., Higgins, C. F. (1997). The functional purification of P-glycoprotein is dependent on maintenance of a lipid-protein interface. Biochim Biophys Acta 1328:109–124.
  • Chang, C., Ekins, S., Bahadduri, P., Swaan, P. W. (2006). Pharmacophore-based discovery of ligands for drug transporters. Adv Drug Deliv Rev 58:1431–1450.
  • Chen, C., Hennig, G. E., Manautou, J. E. (2003a). Hepatobiliary excretion of acetaminophen glutathione conjugate and its derivatives in transport-deficient (TR−) hyperbilirubinemic rats. Drug Metab Dispos 31:798–804.
  • Chen, C., Scott, D., Hanson, E., Franco, J., Berryman, E., Volberg, M., et al. (2003b). Impact of Mrp2 on the biliary excretion and intestinal absorption of furosemide, probenecid, and methotrexate using Eisai-hyperbilirubinemic rats. Pharm Res 20:31–37.
  • Chen, C., Slitt, A. L., Dieter, M. Z., Tanaka, Y., Scheffer, G. L., Klaassen, C. D. (2005). Upregulation of Mrp4 expression in kidney of Mrp2-deficient TR− rats. Biochem Pharmacol 70:1088–1095.
  • Chen, Z. S., Kawabe, T., Ono, M., Aoki, S., Sumizawa, T., Furukawa, T., et al. (1999). Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter. Mol Pharmacol 56:1219–1228.
  • Choi, J. H., Ahn, B. M., Yi, J., Lee, J. H., Nam, S. W., Chon, C. Y., et al. (2007). MRP2 haplotypes confer differential susceptibility to toxic liver injury. Pharmacogenet Genom 17:403–415.
  • Chu, X. Y., Huskey, S. E., Braun, M. P., Sarkadi, B., Evans, D. C., Evers, R. (2004). Transport of ethinylestradiol glucuronide and ethinylestradiol sulfate by the multidrug resistance proteins, MRP1, MRP2, and MRP3. J Pharmacol Exp Ther 309:156–164.
  • Chu, X. Y., Kato, Y., Niinuma, K., Sudo, K. I., Hakusui, H., Sugiyama, Y. (1997). 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.
  • Chu, X. Y., Strauss, J. R., Mariano, M. A., Li, J., Newton, D. J., Cai, X., et al. (2006). Characterization of mice lacking the multidrug resistance protein, MRP2 (ABCC2). J Pharmacol Exp Ther 317:579–589.
  • Cole, S. P., Bhardwaj, G., Gerlach, J. H., Mackie, J. E., Grant, C. E., Almquist, K. C., et al. (1992). Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258:1650–1654.
  • Contreras, B., Talamantes, F. (1999). Growth hormone (GH) and 17beta-estradiol regulation of the expression of mouse GH receptor and GH-binding protein in cultured mouse hepatocytes. Endocrinology 140:4725–4731.
  • Crocenzi, F. A., Basiglio, C. L., Perez, L. M., Portesio, M. S., Pozzi, E. J., Roma, M. G. (2005). Silibinin prevents cholestasis-associated retrieval of the bile salt export pump, Bsep, in isolated rat hepatocyte couplets: possible involvement of cAMP. Biochem Pharmacol 69:1113–1120.
  • Crocenzi, F. A., Mottino, A. D., Cao, J., Veggi, L. M., Pozzi, E. J., Vore, M., et al. (2003). Estradiol-17beta-D-glucuronide induces endocytic internalization of Bsep in rats. Am J Physiol Gastrointest Liver Physiol 285:G449–G459.
  • Crocenzi, F. A., Sanchez Pozzi, E. J., Pellegrino, J. M., Favre, C. O., Rodriguez Garay, E. A., Mottino, A. D., et al. (2001). Beneficial effects of silymarin on estrogen-induced cholestasis in the rat: a study in vivo and in isolated hepatocyte couplets. Hepatology 34:329–339.
  • Cui, Y., Konig, J., Buchholz, J. K., Spring, H., Leier, I., Keppler, D. (1999). Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol Pharmacol 55:929–937.
  • Cui Y., Konig J., Keppler D. (2001). Vectorial transport by double-transfected cells expressing the human uptake transporter, SLC21A8, and the apical export pump, ABCC2. Mol Pharmacol 60:934–943.
  • Cvetkovic, M., Leake, B., Fromm, M. F., Wilkinson, G. R., Kim, R. B. (1999). OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos 27:866–871.
  • de Waart D. R., Vlaming, M. L., Kunne, C., Schinkel, A. H., Oude Elferink, R. P. (2009). Complex pharmacokinetic behavior of ezetimibe depends on abcc2, abcc3, and abcg2. Drug Metab Dispos 37:1698–1702.
  • Deeley, R. G., Westlake, C., Cole, S. P. (2006). Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol Rev 86:849–899.
  • Dietrich, C. G., de Waart D. R., Ottenhoff, R., Bootsma, A. H., van Gennip A. H., Elferink, R. P. (2001a). Mrp2-deficiency in the rat impairs biliary and intestinal excretion and influences metabolism and disposition of the food-derived carcinogen, 2-amino-1-methyl-6-phenylimidazo. Carcinogenesis 22:805–811.
  • Dietrich, C. G., de Waart D. R., Ottenhoff, R., Schoots, I. G., Elferink, R. P. (2001b). Increased bioavailability of the food-derived carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, in MRP2-deficient rats. Mol Pharmacol 59:974–980.
  • Eckford, P. D., Sharom, F. J. (2009). ABC efflux pump-based resistance to chemotherapy drugs. Chem Rev 109:2989–3011.
  • El-Sheikh, A. A., van den Heuvel J. J., Koenderink, J. B., Russel, F. G. (2007). Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport. J Pharmacol Exp Ther 320:229–235.
  • Elferink, M. G., Bosma, T., Lolkema, J. S., Gleiszner, M., Driessen, A. J., Konings, W. N. (1995). Thermostability of respiratory terminal oxidases in the lipid environment. Biochim Biophys Acta 1230:31–37.
  • Elferink, R. P., Ottenhoff, R., Liefting, W., de Haan J., Jansen P. L. (1989). Hepatobiliary transport of glutathione and glutathione conjugate in rats with hereditary hyperbilirubinemia. J Clin Invest 84:476–483.
  • Evers, R., de Haas M., Sparidans, R., Beijnen, J., Wielinga, P. R., Lankelma, J., et al. (2000). Vinblastine and sulfinpyrazone export by the multidrug resistance protein, MRP2, is associated with glutathione export. Br J Cancer 83:375–383.
  • Evers, R., Kool, M., van Deemter L., Janssen, H., Calafat, J., Oomen, L. C., et al. (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.
  • Faneyte, I. F., Kristel, P. M., van de Vijver, M. J. (2004). Multidrug resistance–associated genes MRP1, MRP2, and MRP3 in primary and anthracycline exposed breast cancer. Anticancer Res 24:2931–2939.
  • Fernandez, S. B., Hollo, Z., Kern, A., Bakos, E., Fischer, P. A., Borst, P., Evers, R. (2002). Role of the N-terminal transmembrane region of the multidrug resistance protein MRP2 in routing to the apical membrane in MDCKII cells. J Biol Chem 277:31048–31055.
  • Folmer, Y., Schneider, M., Blum, H. E., Hafkemeyer, P. (2007). Reversal of drug resistance of hepatocellular carcinoma cells by adenoviral delivery of anti-ABCC2 antisense constructs. Cancer Gene Ther 14:875–884.
  • Fukumoto, K., Kikuchi, S., Itoh, N., Tamura, A., Hata, M., Yamagishi, H., et al. (2007). Effects of genetic backgrounds on hyperbilirubinemia in radixin-deficient mice due to different expression levels of Mrp3. Biochim Biophys Acta 1772:298–306.
  • Gao, M., Loe, D. W., Grant, C. E., Cole, S. P., Deeley, R. G. (1996). Reconstitution of ATP-dependent leukotriene C4 transport by coexpression of both half-molecules of human multidrug resistance protein in insect cells. J Biol Chem 271:27782–27787.
  • Gaugg, M., Haslmayer, P., Jager, W., Thalhammer, T. (2001). Influence of hypotonic stress on the biliary excretion of doxorubicin in Wistar and TR− rats. Anticancer Res 21:2745–2751.
  • Gavrilova, O., Geyer, J., Petzinger, E. (2007). In vivo relevance of Mrp2-mediated biliary excretion of the Amanita mushroom toxin, demethylphalloin. Biochim Biophys Acta 1768:2070–2077.
  • Gerk, P. M., Li, W., Vore, M. (2004). Estradiol-3-glucuronide is transported by multidrug resistance-associated protein 2 but does not activate the allosteric site bound by estradiol 17-glucuronide. Drug Metab Dispos 32:1139–1145.
  • Gerk, P. M., Vore, M. (2002). Regulation of expression of the multidrug resistance–associated protein 2 (MRP2) and its role in drug disposition. J Pharmacol Exp Ther 302:407–415.
  • Ghibellini, G., Vasist, L. S., Leslie, E. M., Heizer, W. D., Kowalsky, R. J., Calvo, B. F., et al. (2007). In vitro–in vivo correlation of hepatobiliary drug clearance in humans. Clin Pharmacol Ther 81:406–413.
  • Gimpl, G., Klein, U., Reilander, H., Fahrenholz, F. (1995). Expression of the human oxytocin receptor in baculovirus-infected insect cells: high-affinity binding is induced by a cholesterol-cyclodextrin complex. Biochemistry 34:13794–13801.
  • Glaeser, H., Bailey, D. G., Dresser, G. K., Gregor, J. C., Schwarz, U. I., McGrath, J. S., et al. (2007). Intestinal drug transporter expression and the impact of grapefruit juice in humans. Clin Pharmacol Ther 81:362–370.
  • Glavinas, H., Kis, E., Pal, A., Kovacs, R., Jani, M., Vagi, E., et al. (2007). ABCG2 (breast cancer resistance protein/mitoxantrone resistance-associated protein) ATPase assay: a useful tool to detect drug-transporter interactions. Drug Metab Dispos 35:1533–1542.
  • Glavinas, H., Mehn, D., Jani, M., Oosterhuis, B., Heredi-Szabo, K., Krajcsi, P. (2008). Utilization of membrane vesicle preparations to study drug-ABC transporter interactions. Exp Opin Drug Metab Toxicol 4:721–732.
  • Glynne, P. A., Evans, T. J. (2002). Role of the PDZ scaffolding protein in tubule cells in maintenance of polarised function. Exp Nephrol 10:307–312.
  • Goto, S., Iida, T., Cho, S., Oka, M., Kohno, S., Kondo, T. (1999). Overexpression of glutathione S-transferase pi enhances the adduct formation of cisplatin with glutathione in human cancer cells. Free Radic Res 31:549–558.
  • Gotoh, Y., Suzuki, H., Kinoshita, S., Hirohashi, T., Kato, Y., Sugiyama, Y. (2000). Involvement of an organic anion transporter (canalicular multispecific organic anion transporter/multidrug resistance-associated protein 2) in gastrointestinal secretion of glutathione conjugates in rats. J Pharmacol Exp Ther 292:433–439.
  • Grant, C. E., Kurz, E. U., Cole, S. P., Deeley, R. G. (1997). Analysis of the intron-exon organization of the human multidrug-resistance protein gene (MRP) and alternative splicing of its mRNA. Genomics 45:368–378.
  • Guminski, A. D., Balleine, R. L., Chiew, Y. E., Webster, L. R., Tapner, M., Farrell, G. C., et al. (2006). MRP2 (ABCC2) and cisplatin sensitivity in hepatocytes and human ovarian carcinoma. Gynecol Oncol 100:239–246.
  • Hagenauer, B., Maier-Salamon, A., Thalhammer, T., Zollner, P., Senderowicz, A., Jager, W. (2004). Metabolism of UCN-01 in isolated perfused rat liver: role of Mrp2 in the biliary excretion of glucuronides. Oncol Rep 11:1069–1075.
  • Hagmann, W., Schubert, J., Konig, J., Keppler, D. (2002). Reconstitution of transport-active multidrug resistance protein 2 (MRP2; ABCC2) in proteoliposomes. Biol Chem 383:1001–1009.
  • Han, J. Y., Lim, H. S., Yoo, Y. K., Shin, E. S., Park, Y. H., Lee, S. Y., et al. (2007). Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small-cell lung cancer. Cancer 110:138–147.
  • Han, Y. H., Kato, Y., Haramura, M., Ohta, M., Matsuoka, H., Sugiyama, Y. (2001). Physicochemical parameters responsible for the affinity of methotrexate analogs for rat canalicular multispecific organic anion transporter (cMOAT/MRP2). Pharm Res 18:579–586.
  • Harpole, D. H., Jr., Moore, M. B., Herndon, J. E., 2nd, Aloia, T., D’,Amico, T. A., Sporn, T., et al. (2001). The prognostic value of molecular marker analysis in patients treated with trimodality therapy for esophageal cancer. Clin Cancer Res 7:562–569.
  • Harris, M. J., Kuwano, M., Webb, M., Board, P. G. (2001). Identification of the apical membrane-targeting signal of the multidrug resistance-associated protein 2 (MRP2/MOAT). J Biol Chem 276:20876–20881.
  • Hashimoto, K., Uchiumi, T., Konno, T., Ebihara, T., Nakamura, T., Wada, M., et al. (2002). Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome. Hepatology 36:1236–1245.
  • Hayes, J. H., Soroka, C. J., Rios-Velez, L., Boyer, J. L. (1999). Hepatic sequestration and modulation of the canalicular transport of the organic cation, daunorubicin, in the rat. Hepatology 29:483–493.
  • Hegedus, T., Sessler, T., Scott, R., Thelin, W., Bakos, E., Varadi, A., et al. (2003). C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins. Biochem Biophys Res Commun 302:454–461.
  • Heredi-Szabo, K., Glavinas, H., Kis, E., Mehn, D., Bathori, G., Veres, Z., et al. (2009). Multidrug resistance protein 2-mediated estradiol-17beta-D-glucuronide transport potentiation: in vitro–in vivo correlation and species specificity. Drug Metab Dispos 37:794–801.
  • Heredi-Szabo, K., Kis, E., Molnar, E., Gyorfi, A., Krajcsi, P. (2008). Characterization of 5(6)-carboxy-2,’7’-dichlorofluorescein transport by MRP2 and utilization of this substrate as a fluorescent surrogate for LTC4. J Biomol Screen 13:295–301.
  • Hesselink, D. A., van Hest R. M., Mathot, R. A., Bonthuis, F., Weimar, W., de Bruin R. W., et al. (2005). Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transpl 5:987–994.
  • Hinoshita, E., Uchiumi, T., Taguchi, K., Kinukawa, N., Tsuneyoshi, M., Maehara, Y., et al. (2000). Increased expression of an ATP-binding cassette superfamily transporter, multidrug resistance protein 2, in human colorectal carcinomas. Clin Cancer Res 6:2401–2407.
  • Hirohashi, T., Suzuki, H., Ito, K., Ogawa, K., Kume, K., Shimizu, T., et al. (1998). Hepatic expression of multidrug resistance–associated protein-like proteins maintained in Eisai-hyperbilirubinemic rats. Mol Pharmacol 53:1068–1075.
  • Hirohashi, T., Suzuki, H., Sugiyama, Y. (1999). Characterization of the transport properties of cloned rat multidrug resistance–associated protein 3 (MRP3). J Biol Chem 274:15181–15185.
  • Hirono, S., Nakagome, I., Imai, R., Maeda, K., Kusuhara, H., Sugiyama, Y. (2005). Estimation of the three-dimensional pharmacophore of ligands for rat multidrug-resistance–associated protein 2 using ligand-based drug design techniques. Pharm Res 22:260–269.
  • Hirouchi, M., Suzuki, H., Itoda, M., Ozawa, S., Sawada, J., Ieiri, I., et al. (2004). Characterization of the cellular localization, expression level, and function of SNP variants of MRP2/ABCC2. Pharm Res 21:742–748.
  • Hirouchi, M., Suzuki, H., Sugiyama, Y. (2005). Treatment of hyperbilirubinemia in Eisai-hyperbilirubinemic rat by transfecting human MRP2/ABCC2 gene. Pharm Res 22:661–666.
  • Hoeflich, K. P., Ikura, M. (2004). Radixin: cytoskeletal adopter and signaling protein. Int J Biochem Cell Biol 36:2131–2136.
  • Hoffmann, K., Gastens, A. M., Volk, H. A., Loscher, W. (2006). Expression of the multidrug transporter MRP2 in the blood-brain barrier after pilocarpine-induced seizures in rats. Epilepsy Res 69:1–14.
  • Hoffmaster, K. A., Zamek-Gliszczynski, M. J., Pollack, G. M., Brouwer, K. L. (2005). Multiple transport systems mediate the hepatic uptake and biliary excretion of the metabolically stable opioid peptide, [D-penicillamine2,5]enkephalin. Drug Metab Dispos 33:287–293.
  • Hooijberg, J. H., Broxterman, H. J., Kool, M., Assaraf, Y. G., Peters, G. J., Noordhuis, P., et al. (1999). Antifolate resistance mediated by the multidrug resistance proteins, MRP1 and MRP2. Cancer Res 59:2532–2535.
  • Horikawa, M., Kato, Y., Tyson, C. A., Sugiyama, Y. (2002). The potential for an interaction between MRP2 (ABCC2) and various therapeutic agents: probenecid as a candidate inhibitor of the biliary excretion of irinotecan metabolites. Drug Metab Pharmacokinet 17:23–33.
  • Hosokawa, S., Tagaya, O., Mikami, T., Nozaki, Y., Kawaguchi, A., Yamatsu, K., et al. (1992). A new rat mutant with chronic conjugated hyperbilirubinemia and renal glomerular lesions. Lab Anim Sci 42:27–34.
  • Huang, L., Hoffman, T., Vore, M. (1998). Adenosine triphosphate-dependent transport of estradiol-17beta(beta-D-glucuronide) in membrane vesicles by MDR1 expressed in insect cells. Hepatology 28:1371–1377.
  • Huang, L., Smit, J. W., Meijer, D. K., Vore, M. (2000). Mrp2 is essential for estradiol-17beta(beta-D-glucuronide)-induced cholestasis in rats. Hepatology 32:66–72.
  • Huber, M., Guhlmann, A., Jansen, P. L., Keppler, D. (1987). Hereditary defect of hepatobiliary cysteinyl leukotriene elimination in mutant rats with defective hepatic anion excretion. Hepatology 7:224–228.
  • Huisman, M. T., Chhatta, A. A., van Tellingen O., Beijnen, J. H., Schinkel, A. H. (2005). MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. Int J Cancer 116:824–829.
  • Huisman, M. T., Smit, J. W., Crommentuyn, K. M., Zelcer, N., Wiltshire, H. R., Beijnen, J. H., et al. (2002). Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs. Aids 16:2295–2301.
  • Hulot, J. S., Villard, E., Maguy, A., Morel, V., Mir, L., Tostivint, I., et al. (2005). A mutation in the drug transporter gene, ABCC2, associated with impaired methotrexate elimination. Pharmacogenet Genom 15:277–285.
  • Inagaki, N., Gonoi, T., Clement, J. P., Wang, C. Z., Aguilar-Bryan, L., Bryan, J., et al. (1996). A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels. Neuron 16:1011–1017.
  • Inagaki, N., Gonoi, T., Clement, J. P., Namba, N., Inazawa, J., Gonzalez, G., et al. (1995). Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 270:1166–1170.
  • Inoue, H., Tsuruta, A., Kudo, S., Ishii, T., Fukushima, Y., Iwano, H., et al. (2005). Bisphenol A glucuronidation and excretion in liver of pregnant and nonpregnant female rats. Drug Metab Dispos 33:55–59.
  • Ishiguro, N., Maeda, K., Saito, A., Kishimoto, W., Matsushima, S., Ebner, T., et al. (2008). Establishment of a set of double transfectants coexpressing organic anion-transporting polypeptide 1B3 and hepatic efflux transporters for the characterization of the hepatobiliary transport of telmisartan acylglucuronide. Drug Metab Dispos 36:796–805.
  • Ishikawa, T., Muller, M., Klunemann, C., Schaub, T., 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.
  • Itagaki, S., Sugawara, M., Kobayashi, M., Miyazaki, K., Iseki, K. (2003). Mechanism of active secretion of phenolsulfonphthalein in the liver via Mrp2 (abcc2), an organic anion transporter. Drug Metab Pharmacokinet 18:238–244.
  • Ito, K., Oleschuk, C. J., Westlake, C., Vasa, M. Z., Deeley, R. G., Cole, S. P. (2001a). Mutation of Trp1254 in the multispecific organic anion transporter, multidrug resistance protein 2 (MRP2) (ABCC2), alters substrate specificity and results in loss of methotrexate transport activity. J Biol Chem 276:38108–38114.
  • Ito, K., Suzuki, H., Hirohashi, T., Kume, K., Shimizu, T., Sugiyama, Y. (1997). Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR. Am J Physiol 272:G16–G22.
  • Ito, K., Suzuki, H., Hirohashi, T., Kume, K., Shimizu, T., Sugiyama, Y. (1998). Functional analysis of a canalicular multispecific organic anion transporter cloned from rat liver. J Biol Chem 273:1684–1688.
  • Ito, K., Suzuki, H., Sugiyama, Y. (2001b). Charged amino acids in the transmembrane domains are involved in the determination of the substrate specificity of rat Mrp2. Mol Pharmacol 59:1077–1085.
  • Ito, K., Suzuki, H., Sugiyama, Y. (2001c). Single amino acid substitution of rat MRP2 results in acquired transport activity for taurocholate. Am J Physiol Gastrointest Liver Physiol 281:G1034–G1043.
  • Itoh, Y., Tamai, M., Yokogawa, K., Nomura, M., Moritani, S., Suzuki, H., et al. (2002). Involvement of multidrug resistance–associated protein 2 in in vivo cisplatin resistance of rat hepatoma AH66 cells. Anticancer Res 22:1649–1653.
  • Jager, W., Gehring, E., Hagenauer, B., Aust, S., Senderowicz, A., Thalhammer, T. (2003). Biliary excretion of flavopiridol and its glucuronides in the isolated perfused rat liver: role of multidrug resistance protein 2 (Mrp2). Life Sci 73:2841–2854.
  • Jain, R., Agarwal, S., Mandava, N. K., Sheng, Y., Mitra, A. K. (2008). Interaction of dipeptide prodrugs of saquinavir with multidrug resistance protein-2 (MRP-2): evasion of MRP-2 mediated efflux. Int J Pharm 362:44–51.
  • Jansen, P. L., Peters, W. H., Lamers, W. H. (1985). Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport. Hepatology 5:573–579.
  • Jedlitschky, G., Keppler, D. (2002). Transport of leukotriene C4 and structurally related conjugates. Vitam Horm 64:153–184.
  • Jedlitschky, G., Leier, I., Buchholz, U., Hummel-Eisenbeiss, J., Burchell, B., Keppler, D. (1997). ATP-dependent transport of bilirubin glucuronides by the multidrug resistance protein, MRP1, and its hepatocyte, canalicular isoform MRP2. Biochem J 327(Pt 1):305–310.
  • Ji, B., Ito, K., Suzuki, H., Sugiyama, Y., Horie, T. (2002). Multidrug resistance–associated protein2 (MRP2) plays an important role in the biliary excretion of glutathione conjugates of 4-hydroxynonenal. Free Radic Biol Med 33:370–378.
  • Johnson, B. M., Zhang, P., Schuetz, J. D., Brouwer, K. L. (2006). Characterization of transport protein expression in multidrug resistance–associated protein (Mrp) 2-deficient rats. Drug Metab Dispos 34:556–562.
  • Kamata, S., Kishimoto, T., Kobayashi, S., Miyazaki, M. (2008). Expression and localization of ATP-binding cassette (ABC) family of drug transporters in gastric hepatoid adenocarcinomas. Histopathology 52:747–754.
  • Kamisako, T., Leier, I., Cui, Y., Konig, J., Buchholz, U., Hummel-Eisenbeiss, J., et al. (1999). Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2. Hepatology 30:485–490.
  • Kato, Y., Takahara, S., Kato, S., Kubo, Y., Sai, Y., Tamai, I., et al. (2008). Involvement of multidrug resistance–associated protein 2 (Abcc2) in molecular weight-dependent biliary excretion of beta-lactam antibiotics. Drug Metab Dispos 36:1088–1096.
  • Kawabata, Y., Kamada, E., Furuta, S., Takei, M., Kurimoto, T., Okudaira, K., Nishigaki, R. (2004). ATP-dependent transport of a novel thromboxane A2 receptor antagonist, [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335), and its xenobiotic taurine conjugate (Z-335-Tau) by rat bile canalicular membrane vesicles. Pharm Res 21:467–475.
  • Kawabe, T., Chen, Z. S., Wada, M., Uchiumi, T., Ono, M., Akiyama, S., et al. (1999). Enhanced transport of anticancer agents and leukotriene C4 by the human canalicular multispecific organic anion transporter (cMOAT/MRP2). FEBS Lett 456:327–331.
  • Keitel, V., Kartenbeck, J., Nies, A. T., Spring, H., Brom, M., Keppler, D. (2000). Impaired protein maturation of the conjugate export pump, multidrug resistance protein 2, as a consequence of a deletion mutation in Dubin-Johnson syndrome. Hepatology 32:1317–1328.
  • Keitel, V., Nies, A. T., Brom, M., Hummel-Eisenbeiss, J., Spring, H., Keppler, D. (2003). A common Dubin-Johnson syndrome mutation impairs protein maturation and transport activity of MRP2 (ABCC2). Am J Physiol Gastrointest Liver Physiol 284:G165–G174.
  • Keppler, D. (2005). Uptake and efflux transporters for conjugates in human hepatocytes. Meth Enzymol 400:531–542.
  • Keppler, D., Konig, J. (2000). Hepatic secretion of conjugated drugs and endogenous substances. Semin Liver Dis 20:265–272.
  • Kikuchi, S., Hata, M., Fukumoto, K., Yamane, Y., Matsui, T., Tamura, A., et al. (2002). Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes. Nat Genet 31:320–325.
  • Kim, M. S., Liu, D. Q., Strauss, J. R., Capodanno, I., Yao, Z., Fenyk-Melody, J. E., et al. (2003). Metabolism and disposition of gemfibrozil in Wistar and multidrug resistance–associated protein 2-deficient TR− rats. Xenobiotica 33:1027–1042.
  • Kimura, Y., Kioka, N., Kato, H., Matsuo, M., Ueda, K. (2007). Modulation of drug-stimulated ATPase activity of human MDR1/P-glycoprotein by cholesterol. Biochem J 401:597–605.
  • Kis, E., Ioja, E., Nagy, T., Szente, L., Heredi-Szabo, K., Krajcsi, P. (2009a). Effect of membrane cholesterol on BSEP/Bsep activity: species specificity studies for substrates and inhibitors. Drug Metab Dispos 37:1878–1886.
  • Kis, E., Rajnai, Z., Ioja, E., Heredi-Szabo, K., Nagy, T., Mehn, D., et al. (2009b). Mouse Bsep ATPase assay: a nonradioactive tool for assessment of the cholestatic potential of drugs. J Biomol Screen 14:10–15.
  • Kitamura, S., Maeda, K., Wang, Y., Sugiyama, Y. (2008). Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos 36:2014–2023.
  • Kitamura, T., Alroy, J., Gatmaitan, Z., Inoue, M., Mikami, T., Jansen, P., et al. (1992). Defective biliary excretion of epinephrine metabolites in mutant (TR−) rats: relation to the pathogenesis of black liver in the Dubin-Johnson syndrome and Corriedale sheep with an analogous excretory defect. Hepatology 15:1154–1159.
  • Kivisto, K. T., Grisk, O., Hofmann, U., Meissner, K., Moritz, K. U., Ritter, C., et al. (2005). Disposition of oral and intravenous pravastatin in MRP2-deficient TR− rats. Drug Metab Dispos 33:1593–1596.
  • Kobayashi, M., Saitoh, H., Tadano, K., Takahashi, Y., Hirano, T. (2004). Cyclosporin A, but not tacrolimus, inhibits the biliary excretion of mycophenolic acid, glucuronide, possibly mediated by multidrug resistance–associated protein 2 in rats. J Pharmacol Exp Ther 309:1029–1035.
  • Kocher, O., Pal, R., Roberts, M., Cirovic, C., Gilchrist, A. (2003). Targeted disruption of the PDZK1 gene by homologous recombination. Mol Cell Biol 23:1175–1180.
  • Koh, A. S., Simmons-Willis, T. A., Pritchard, J. B., Grassl, S. M., Ballatori, N. (2002). Identification of a mechanism by which the methylmercury antidotes N-acetylcysteine and dimercaptopropanesulfonate enhance urinary metal excretion: transport by the renal organic anion transporter-1. Mol Pharmacol 62:921–926.
  • Koike, K., Kawabe, T., Tanaka, T., Toh, S., Uchiumi, T., Wada, M., et al. (1997). A canalicular multispecific organic anion transporter (cMOAT), antisense cDNA, enhances drug sensitivity in human hepatic cancer cells. Cancer Res 57:5475–5479.
  • Kojima, H., Sakurai, S., Uemura, M., Kitamura, K., Kanno, H., Nakai, Y., et al. (2008). Disturbed colocalization of multidrug resistance protein 2 and radixin in human cholestatic liver diseases. J Gastroenterol Hepatol 23:e120–e128.
  • Konig, J., Nies, A. T., Cui, Y., Keppler, D. (2003). MRP2, the apical export pump for anionic conjugates. In:Holland, B., Cole, S. P., Kuchler, K., Higgins, C. F. (Eds.), ABC proteins, from bacteria to man ( pp 423–444). London: Academic Press.
  • Konig, J., Nies, A. T., Cui, Y., Keppler, D. (2003). MRP2, the apical export pump for anionic conjugates. London: Academic Press.
  • Konig, J., Nies, A. T., Cui, Y., Leier, I., Keppler, D. (1999). Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta 1461:377–394.
  • Konno, T., Ebihara, T., Hisaeda, K., Uchiumi, T., Nakamura, T., Shirakusa, T., et al. (2003). Identification of domains participating in the substrate specificity and subcellular localization of the multidrug resistance proteins, MRP1 and MRP2. J Biol Chem 278:22908–22917.
  • Kono, Y., Yang, S., Roberts, E. A. (1997). Extended primary culture of human hepatocytes in a collagen gel sandwich system. In Vitro Cell Dev Biol Anim 33:467–472.
  • Kopplow, K., Letschert, K., Konig, J., Walter, B., Keppler, D. (2005). Human hepatobiliary transport of organic anions analyzed by quadruple-transfected cells. Mol Pharmacol 68:1031–1038.
  • Kouzuki, H., Suzuki, H., Sugiyama, Y. (2000). Pharmacokinetic study of the hepatobiliary transport of indomethacin. Pharm Res 17:432–438.
  • Kremer, J. M., Hamilton, R. A. (1995). The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses, but not at 7.5 mg. J Rheumatol 22:2072–2077.
  • Kruh, G. D., Belinsky, M. G. (2003). The MRP family of drug efflux pumps. Oncogene 22:7537–7552.
  • Kuipers, F., Enserink, M., Havinga, R., van der Steen A. B., Hardonk, M. J., Fevery, J., et al. (1988). Separate transport systems for biliary secretion of sulfated and unsulfated bile acids in the rat. J Clin Invest 81:1593–1599.
  • Kuipers, F., Radominska, A., Zimniak, P., Little, J. M., Havinga, R., Vonk, R. J., et al. (1989). Defective biliary secretion of bile acid 3-O-glucuronides in rats with hereditary conjugated hyperbilirubinemia. J Lipid Res 30:1835–1845.
  • Kuroda, M., Kobayashi, Y., Tanaka, Y., Itani, T., Mifuji, R., Araki, J., et al. (2004). Increased hepatic and renal expressions of multidrug resistance–associated protein 3 in Eisai-hyperbilirubinuria rats. J Gastroenterol Hepatol 19:146–153.
  • Lagas, J. S., van der Kruijssen, C. M., van de Wetering K., Beijnen, J. H., Schinkel, A. H. (2009). Transport of diclofenac by breast cancer resistance protein (ABCG2) and stimulation of multidrug resistance protein 2 (ABCC2)-mediated drug transport by diclofenac and benzbromarone. Drug Metab Dispos 37:129–136.
  • Lagas, J. S., Vlaming, M. L., van Tellingen O., Wagenaar, E., Jansen, R. S., Rosing, H., et al. (2006). Multidrug resistance protein 2 is an important determinant of paclitaxel pharmacokinetics. Clin Cancer Res 12:6125–6132.
  • Lai, Y., Xing, L., Poda, G. I., Hu, Y. (2007). Structure-activity relationships for interaction with multidrug resistance protein 2 (ABCC2/MRP2): the role of torsion angle for a series of biphenyl-substituted heterocycles. Drug Metab Dispos 35:937–945.
  • Lau, Y. Y., Sapidou, E., Cui, X., White, R. E., Cheng, K. C. (2002). Development of a novel in vitro model to predict hepatic clearance using fresh, cryopreserved, and sandwich-cultured hepatocytes. Drug Metab Dispos 30:1446–1454.
  • Laupeze, B., Amiot, L., Drenou, B., Bernard, M., Branger, B., Grosset, J. M., et al. (2002). High multidrug resistance protein activity in acute myeloid leukaemias is associated with poor response to chemotherapy and reduced patient survival. Br J Haematol 116:834–838.
  • LeCluyse, E. L., Audus, K. L., Hochman, J. H. (1994). Formation of extensive canalicular networks by rat hepatocytes cultured in collagen-sandwich configuration. Am J Physiol 266:C1764–C1774.
  • Lecureux, L., Dieter, M. Z., Nelson, D. M., Watson, L., Wong, H., Gemzik, B., et al. (2009). Hepatobiliary disposition of thyroid hormone in Mrp2-deficient TR− rats: reduced biliary excretion of thyroxine glucuronide does not prevent xenobiotic-induced hypothyroidism. Toxicol Sci 108:482–491.
  • Lee, J. K., Leslie, E. M., Zamek-Gliszczynski, M. J., Brouwer, K. L. (2008). Modulation of trabectedin (ET-743) hepatobiliary disposition by multidrug resistance–associated proteins (Mrps) may prevent hepatotoxicity. Toxicol Appl Pharmacol 228:17–23.
  • Leier, I., Hummel-Eisenbeiss, J., Cui, Y., Keppler, D. (2000). ATP-dependent para-aminohippurate transport by apical multidrug resistance protein MRP2. Kidney Int 57:1636–1642.
  • Leier, I., Jedlitschky, G., Buchholz, U., Center, M., Cole, S. P., Deeley, R. G., et al. (1996). ATP-dependent glutathione disulphide transport mediated by the MRP gene-encoded conjugate export pump. Biochem J 314(Pt 2):433–437.
  • Lengyel, G., Veres, Z., Tugyi, R., Vereczkey, L., Molnar, T., Glavinas, H., et al. (2008). Modulation of sinusoidal and canalicular elimination of bilirubin-glucuronides by rifampicin and other cholestatic drugs in a sandwich culture of rat hepatocytes. Hepatol Res 38:300–309.
  • Leslie, E. M., Deeley, R. G., Cole, S. P. (2005). Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 204:216–237.
  • Leslie, E. M., Ito, K., Upadhyaya, P., Hecht, S. S., Deeley, R. G., Cole, S. P. (2001). Transport of the beta-O-glucuronide conjugate of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by multidrug resistance protein 1 (MRP1). Requirement for glutathione or a non-sulfur-containing analog. J Biol Chem 276:27846–27854.
  • Letourneau, I. J., Slot, A. J., Deeley, R. G., Cole, S. P. (2007). Mutational analysis of a highly conserved proline residue in MRP1, MRP2, and MRP3 reveals a partially conserved function. Drug Metab Dispos 35:1372–1379.
  • Leyers, S., Hacker, H. G., Wiendlocha, J., Gutschow, M., Wiese, M. (2008). A 4-aminobenzoic acid derivative as novel lead for selective inhibitors of multidrug resistance–associated proteins. Bioorg Med Chem Lett 18:4761–4763.
  • Li, H., Jin, H. E., Kim, W., Han, Y. H., Kim, D. D., Chung, S. J., et al. (2008). Involvement of P-glycoprotein, multidrug resistance protein 2, and breast cancer resistance protein in the transport of belotecan and topotecan in Caco-2 and MDCKII cells. Pharm Res 25:2601–2612.
  • Lischka, K., Starke, D., Failing, K., Herling, A., Kramer, W., Petzinger, E. (2003). Hepatobiliary elimination of bile-acid–modified oligodeoxynucleotides in Wistar and TR− rats: evidence for mrp2 as carrier for oligodeoxynucleotides. Biochem Pharmacol 66:565–577.
  • Liu, L., Cui, Y., Chung, A. Y., Shitara, Y., Sugiyama, Y., Keppler, D., et al. (2006). Vectorial transport of enalapril by Oatp1a1/Mrp2 and OATP1B1 and OATP1B3/MRP2 in rat and human livers. J Pharmacol Exp Ther 318:395–402.
  • Liu, Y., Binz, J., Numerick, M. J., Dennis, S., Luo, G., Desai, B., et al. (2003). Hepatoprotection by the farnesoid X receptor agonist, GW4064, in rat models of intra- and extrahepatic cholestasis. J Clin Invest 112:1678–1687.
  • Lou, H., Ookhtens, M., Stolz, A., Kaplowitz, N. (2003). Chelerythrine stimulates GSH transport by rat Mrp2 (Abcc2) expressed in canine kidney cells. Am J Physiol Gastrointest Liver Physiol 285:G1335–1344.
  • Luciani, F., Molinari, A., Lozupone, F., Calcabrini, A., Lugini, L., Stringaro, A., et al. (2002). P-glycoprotein-actin association through ERM family proteins: a role in P-glycoprotein function in human cells of lymphoid origin. Blood 99:641–648.
  • Luo, G., Garner, C. E., Xiong, H., Hu, H., Richards, L. E., Brouwer, K. L. et al. (2007). Effect of DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrr olidin-1-yl}-N-hydroxy-4-methylpentanamide], a human tumor necrosis factor alpha-converting enzyme inhibitor, on the disposition of methotrexate: a transporter-based drug-drug interaction case study. Drug Metab Dispos 35:835–840.
  • Ma, J. J., Chen, B. L., Xin, X. Y. (2009). Inhibition of multidrug resistance of ovarian carcinoma by small-interfering RNA targeting to MRP2 gene. Arch Gynecol Obstet 279:149–157.
  • Machida, I., Wakusawa, S., Sanae, F., Hayashi, H., Kusakabe, A., Ninomiya, H., et al. (2005). Mutational analysis of the MRP2 gene and long-term follow-up of Dubin-Johnson syndrome in Japan. J Gastroenterol 40:366–370.
  • Madejczyk, M. S., Aremu, D. A., Simmons-Willis, T. A., Clarkson, T. W., Ballatori, N. (2007). Accelerated urinary excretion of methylmercury following administration of its antidote, N-acetylcysteine, requires Mrp2/Abcc2, the apical multidrug resistance–associated protein. J Pharmacol Exp Ther 322:378–384.
  • Madon, J., Eckhardt, U., Gerloff, T., Stieger, B., Meier, P. J. (1997). Functional expression of the rat liver canalicular isoform of the multidrug resistance–associated protein. FEBS Lett 406:75–78.
  • Maglova, L. M., Jackson, A. M., Meng, X. J., Carruth, M. W., Schteingart, C. D., Ton-Nu, H. T., et al. (1995). Transport characteristics of three fluorescent conjugated bile acid analogs in isolated rat hepatocytes and couplets. Hepatology 22:637–647.
  • Maier-Salamon, A., Hagenauer, B., Reznicek, G., Szekeres, T., Thalhammer, T., Jager, W., et al. (2008). Metabolism and disposition of resveratrol in the isolated perfused rat liver: role of Mrp2 in the biliary excretion of glucuronides. J Pharm Sci 97:1615–1628.
  • Maier-Salamon, A., Trauner, G., Hiltscher, R., Reznicek, G., Kopp, B., Thalhammer, T., et al.(2009). Hepatic metabolism and biliary excretion of valerenic acid in isolated perfused rat livers: role of Mrp2 (Abcc2). J Pharm Sci 98:3839–3849.
  • Mannermaa, E., Vellonen, K. S., Urtti, A. (2006). Drug transport in corneal epithelium and blood-retina barrier: emerging role of transporters in ocular pharmacokinetics. Adv Drug Deliv Rev 58:1136–1163.
  • Marchetti, S., Oostendorp, R. L., Pluim, D., van Eijndhoven M., van Tellingen, O., Schinkel, A. H., et al. (2007). In vitro transport of gimatecan (7-t-butoxyiminomethylcamptothecin) by breast cancer resistance protein, P-glycoprotein, and multidrug resistance protein 2. Mol Cancer Ther 6:3307–3313.
  • Marin, J. J., Macias, R. I., Briz, O., Perez, M. J., Serrano, M. A. (2005). Molecular bases of the excretion of fetal bile acids and pigments through the fetal liver-placenta-maternal liver pathway. Ann Hepatol 4:70–76.
  • Masereeuw, R., Notenboom, S., Smeets, P. H., Wouterse, A. C., Russel, F. G. (2003). Impaired renal secretion of substrates for multidrug resistance protein 2 in mutant transport-deficient (TR−) rats. J Am Soc Nephrol 14:2741–2749.
  • Masuda, M., I’Izuka, Y., Yamazaki, M., Nishigaki, R., Kato, Y., Ni’inuma, K., et al. (1997). Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats. Cancer Res 57:3506–3510.
  • Materna, V., Liedert, B., Thomale, J., Lage, H. (2005). Protection of platinum-DNA adduct formation and reversal of cisplatin resistance by anti-MRP2 hammerhead ribozymes in human cancer cells. Int J Cancer 115:393–402.
  • Matsson, P., Englund, G., Ahlin, G., Bergstrom, C. A., Norinder, U., Artursson, P. (2007). A global drug inhibition pattern for the human ATP-binding cassette transporter breast cancer resistance protein (ABCG2). J Pharmacol Exp Ther 323:19–30.
  • Matsson, P., Pedersen, J. M., Norinder, U., Bergstrom, C. A., Artursson, P. (2009). Identification of novel-specific and general inhibitors of the three major human ATP-binding cassette transporters, P-gp, BCRP, and MRP2, among registered drugs. Pharm Res 26:1816–1831.
  • Matsumoto, Y., Tamiya, T., Nagao, S. (2005). Resistance to topoisomerase II inhibitors in human glioma cell lines overexpressing multidrug resistant–associated protein (MRP) 2. J Med Invest 52:41–48.
  • Mayer, R., Kartenbeck, J., Buchler, M., Jedlitschky, G., Leier, I., Keppler, D. (1995). Expression of the MRP gene-encoded conjugate export pump in liver and its selective absence from the canalicular membrane in transport-deficient mutant hepatocytes. J Cell Biol 131:137–150.
  • McDonagh, A. F., Lightner, D. A., Boiadjiev, S. E., Brower, J. O., Norona, W. S. (2002). Hepatobiliary excretion of dipyrrinone sulfonates in Mrp2-deficient (TR(-) rats. Bioorg Med Chem Lett 12:2483–2486.
  • Mesa, V. A., De Vos, R., Fevery, J. (1997). Elevation of the serum bilirubin diconjugate fraction provides an early marker for cholestasis in the rat. J Hepatol 27:912–916.
  • Mikami, T., Nozaki, T., Tagaya, O., Hosokawa, S., Nakura, T., Mori, H., et al. (1986). The characters of a new mutant in rats with hyperbilirubinuria syndrome. Cong Anom 26:250–251.
  • Milkiewicz, P., Chilton, A. P., Hubscher, S. G., Elias, E. (2003). Antidepressant-induced cholestasis: hepatocellular redistribution of multidrug resistant protein (MRP2). Gut 52:300–303.
  • Mills, C. O., Milkiewicz, P., Muller, M., Roma, M. G., Havinga, R., Coleman, R., et al. (1999). Different pathways of canalicular secretion of sulfated and nonsulfated fluorescent bile acids: a study in isolated hepatocyte couplets and TR− rats. J Hepatol 31:678–684.
  • Miranda, S. R., Lee, J. K., Brouwer, K. L., Wen, Z., Smith, P. C., et al. (2008). Hepatic metabolism and biliary excretion of silymarin flavonolignans in isolated perfused rat livers: role of multidrug resistance–associated protein 2 (Abcc2). Drug Metab Dispos 36:2219–2226.
  • Mitaka, T., Sato, F., Mizuguchi, T., Yokono, T., Mochizuki, Y. (1999). Reconstruction of hepatic organoid by rat small hepatocytes and hepatic nonparenchymal cells. Hepatology 29:111–125.
  • Miura, M., Satoh, S., Inoue, K., Kagaya, H., Saito, M., Inoue, T., et al. (2007). Influence of SLCO1B1, 1B3, 2B1, and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol 63:1161–1169.
  • Miura, M., Satoh, S., Inoue, K., Saito, M., Habuchi, T., Suzuki, T. (2009). Telmisartan pharmacokinetics in Japanese renal transplant recipients. Clin Chim Acta 399:83–87.
  • Mor-Cohen, R., Zivelin, A., Rosenberg, N., Shani, M., Muallem, S., Seligsohn, U. (2001). Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome. J Biol Chem 276:36923–36930.
  • Morikawa, A., Goto, Y., Suzuki, H., Hirohashi, T., Sugiyama, Y. (2000). Biliary excretion of 17beta-estradiol 17beta-D-glucuronide is predominantly mediated by cMOAT/MRP2. Pharm Res 17:546–552.
  • Mottino, A. D., Hoffman, T., Jennes, L., Vore, M. (2000). Expression and localization of multidrug resistant protein mrp2 in rat small intestine. J Pharmacol Exp Ther 293:717–723.
  • Naba, H., Kuwayama, C., Kakinuma, C., Ohnishi, S., Ogihara, T. (2004). Eisai-hyperbilirubinemic rat (EHBR) as an animal model affording high drug exposure in toxicity studies on organic anions. Drug Metab Pharmacokinet 19:339–351.
  • Naesens, M., Kuypers, D. R., Verbeke, K., Vanrenterghem, Y. (2006). Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation 82:1074–1084.
  • Nakagomi-Hagihara, R., Nakai, D., Kawai, K., Yoshigae, Y., Tokui, T., Abe, T., et al. (2006). OATP1B1, OATP1B3, and mrp2 are involved in hepatobiliary transport of olmesartan, a novel angiotensin II blocker. Drug Metab Dispos 34:862–869.
  • Naruhashi, K., Tamai, I., Inoue, N., Muraoka, H., Sai, Y., Suzuki, N., et al. (2002). Involvement of multidrug resistance–associated protein 2 in intestinal secretion of grepafloxacin in rats. Antimicrob Agents Chemother 46:344–349.
  • Nezasa, K., Tian, X., Zamek-Gliszczynski, M. J., Patel, N. J., Raub, T. J., Brouwer, K. L. (2006). Altered hepatobiliary disposition of 5 (and 6)-carboxy-2’,7’-dichlorofluorescein in Abcg2 (Bcrp1) and Abcc2 (Mrp2) knockout mice. Drug Metab Dispos 34:718–723.
  • Ng, C., Xiao, Y. D., Lum, B. L., Han, Y. H. (2005). Quantitative structure-activity relationships of methotrexate and methotrexate analogues transported by the rat-multispecific resistance-associated protein 2 (rMrp2). Eur J Pharm Sci 26:405–413.
  • Niemi, M., Arnold, K. A., Backman, J. T., Pasanen, M. K., Godtel-Armbrust, U., Wojnowski, L., et al. (2006). Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance–associated protein 2 expression and pravastatin pharmacokinetics. Pharmacogenet Genom 16:801–808.
  • Nies, A. T., Cantz, T., Brom, M., Leier, I., Keppler, D. (1998). Expression of the apical conjugate export pump, Mrp2, in the polarized hepatoma cell line, WIF-B. Hepatology 28:1332–1340.
  • Nies, A. T., Jedlitschky, G., Konig, J., Herold-Mende, C., Steiner, H. H., Schmitt, H. P., et al. (2004). Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain. Neuroscience 129:349–360.
  • Nies, A.T., Keppler, D. (2007). The apical conjugate efflux pump, ABCC2 (MRP2). Pflug Arch 453:643–659.
  • Nies, A. T., Konig, J., Cui, Y., Brom, M., Spring, H., Keppler, D. (2002). Structural requirements for the apical sorting of human multidrug resistance protein 2 (ABCC2). Eur J Biochem 269:1866–1876.
  • Nies, A. T., Konig, J., Pfannschmidt, M., Klar, E., Hofmann, W. J., Keppler, D. (2001). Expression of the multidrug resistance proteins, MRP2 and MRP3, in human hepatocellular carcinoma. Int J Cancer 94:492–499.
  • Niinuma, K., Takenaka, O., Horie, T., Kobayashi, K., Kato, Y., Suzuki, H., et al. (1997). Kinetic analysis of the primary active transport of conjugated metabolites across the bile canalicular membrane: comparative study of S-(2,4-dinitrophenyl)-glutathione and 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole glucuronide. J Pharmacol Exp Ther 282:866–872.
  • Ninomiya, M., Ito, K., Hiramatsu, R., Horie, T. (2006). Functional analysis of mouse and monkey multidrug resistance–associated protein 2 (Mrp2). Drug Metab Dispos 34:2056–2063.
  • Ninomiya, M., Ito, K., Horie, T. (2005). Functional analysis of dog multidrug resistance–associated protein 2 (Mrp2) in comparison with rat Mrp2. Drug Metab Dispos 33:225–232.
  • Nishida, T., Hardenbrook, C., Gatmaitan, Z., Arias, I. M. (1992). ATP-dependent organic anion transport system in normal and TR− rat liver canalicular membranes. Am J Physiol 262:G629–G635.
  • Nishino, A., Kato, Y., Igarashi, T., Sugiyama, Y. (2000). Both cMOAT/MRP2 and another unknown transporter(s) are responsible for the biliary excretion of glucuronide conjugate of the nonpeptide angiotensin II antagonist, telmisaltan. Drug Metab Dispos 28:1146–1148.
  • Nishio, K., Nakamura, T., Koh, Y., Suzuki, T., Fukumoto, H., Saijo, N. (1999). Drug resistance in lung cancer. Curr Opin Oncol 11:109–115.
  • Nozaki, Y., Kusuhara, H., Kondo, T., Iwaki, M., Shiroyanagi, Y., Nakayama, H., et al. (2007). Species difference in the inhibitory effect of nonsteroidal anti-inflammatory drugs on the uptake of methotrexate by human kidney slices. J Pharmacol Exp Ther 322:1162–1170.
  • Ofer, M., Langguth, P., Spahn-Langguth, H. (2006). Bidirectional membrane transport: simulations of transport inhibition in uptake studies explain data obtained with flavonoids. Eur J Pharm Sci 29:251–258.
  • Oguri, T., Fujiwara, Y., Katoh, O., Daga, H., Ishikawa, N., Fujitaka, K., et al. (2000). Glutathione S-transferase-pi gene expression and platinum drug exposure in human lung cancer. Cancer Lett 156:93–99.
  • Oswald, S., Haenisch, S., Fricke, C., Sudhop, T., Remmler, C., Giessmann T., et al. (2006a). Intestinal expression of P-glycoprotein (ABCB1), multidrug resistance–associated protein 2 (ABCC2) and uridine diphosphate-glucuronosyltransferase 1A1 predicts the disposition and modulates the effects of the cholesterol absorption inhibitor, ezetimibe, in humans. Clin Pharmacol Ther 79:206–217.
  • Oswald, S., Westrup, S., Grube, M., Kroemer, H. K., Weitschies, W., Siegmund, W. (2006b). Disposition and sterol-lowering effect of ezetimibe in multidrug resistance–associated protein 2-deficient rats. J Pharmacol Exp Ther 318:1293–1299.
  • Pal, A., Mehn, D., Molnar, E., Gedey, S., Meszaros, P., Nagy, T., et al. (2007). Cholesterol potentiates ABCG2 activity in a heterologous expression system: improved in vitro model to study function of human ABCG2. J Pharmacol Exp Ther 321:1085–1094.
  • Pascolo, L., Fernetti, C., Pirulli, D., Crovella, S., Amoroso, A., Tiribelli, C. (2003). Effects of maturation on RNA transcription and protein expression of four MRP genes in human placenta and in BeWo cells. Biochem Biophys Res Commun 303:259–265.
  • Patel, N. J., Zamek-Gliszczynski, M. J., Zhang, P., Han, Y. H., Jansen, P. L., Meier, P. J., et al. 2003). Phenobarbital alters hepatic Mrp2 function by direct and indirect interactions. Mol Pharmacol 64:154–159.
  • Pauli-Magnus, C., Meier, P. J. (2005). Hepatocellular transporters and cholestasis. J Clin Gastroenterol 39:S103–S110.
  • Paulusma, C. C., Bosma, P. J., Zaman, G. J., Bakker, C. T., Otter, M., Scheffer, G. L., et al. (1996). Congenital jaundice in rats with a mutation in a multidrug resistance–associated protein gene. Science 271:1126–1128.
  • Paulusma, C. C., de Waart, D. R., Kunne, C., Mok, K. S., Elferink, R. P. (2009). Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content. J Biol Chem 284:9947–9954.
  • Paulusma, C. C., Kool, M., Bosma, P. J., Scheffer, G. L., ter Borg, F., Scheper, R. J., et al. (1997a). A mutation in the human canalicular multispecific organic anion-transporter gene causes Dubin-Johnson syndrome. Hepatology 25:1539–1542.
  • Paulusma, C. C., Kothe, M. J., Bakker, C. T., Bosma, P. J., van Bokhoven, I. van, Marle, J. et, al. (2000). Zonal downregulation and redistribution of multidrug resistance protein 2 during bile duct ligation in rat liver. Hepatology 31:684–693.
  • Paulusma, C. C., Oude Elferink, R. P. (1997b). The canalicular multispecific organic anion transporter and conjugated hyperbilirubinemia in rat and man. J Mol Med 75:420–428.
  • Paulusma, C. C., van Geer, M. A., Evers, R., Heijn, M., Ottenhoff, R., Borst, P., et al. (1999). Canalicular multispecific organic anion transporter/multidrug resistance protein 2 mediates low-affinity transport of reduced glutathione. Biochem J 338(Pt 2):393–401.
  • Payen, L., Courtois, A., Campion, J. P., Guillouzo, A., Fardel, O. (2000). Characterization and inhibition by a wide range of xenobiotics of organic anion excretion by primary human hepatocytes. Biochem Pharmacol 60:1967–1975.
  • Pedersen, J. M., Matsson, P., Bergstrom, C. A., Norinder, U., Hoogstraate, J., Artursson, P. (2008). Prediction and identification of drug interactions with the human ATP-binding cassette transporter multidrug-resistance associated protein 2 (MRP2; ABCC2). J Med Chem 51:3275–3287.
  • Peng, K. C., Cluzeaud, F., Bens, M., Van Huyen, J. P., Wioland, M. A., Lacave, R., et al. (1999). Tissue and cell distribution of the multidrug resistance–associated protein (MRP) in mouse intestine and kidney. J Histochem Cytochem 47:757–768.
  • Perez, L. M., Milkiewicz, P., Elias, E., Coleman, R., Sanchez Pozzi, E. J., Roma, M. G. (2006). Oxidative stress induces internalization of the bile salt export pump, Bsep, and bile salt secretory failure in isolated rat hepatocyte couplets: a role for protein kinase C and prevention by protein kinase A. Toxicol Sci 91:150–158.
  • Prime-Chapman, H. M., Fearn, R. A., Cooper, A. E., Moore, V., Hirst, B. H. (2004). Differential multidrug resistance–associated protein 1 through 6 isoform expression and function in human intestinal epithelial Caco-2 cells. J Pharmacol Exp Ther 311:476–484.
  • Prueksaritanont, T., Xu, X., Deluna, P., Yamazaki, M., Lin, J. H. (2003). Stereoselective hepatic disposition of a diastereomeric pair of alphavbeta3 antagonists in rat. Xenobiotica 33:1125–1137.
  • Rau, T., Erney, B., Gores, R., Eschenhagen, T., Beck, J., Langer, T. (2006). High-dose methotrexate in pediatric acute lymphoblastic leukemia: impact of ABCC2 polymorphisms on plasma concentrations. Clin Pharmacol Ther 80:468–476.
  • Raymond, G. D., Galambos, J. T. (1971). Hepatic storage and excretion of bilirubin in man. Am J Gastroenterol 55:135–144.
  • Rebbeor, J. F., Connolly, G. C., Ballatori, N. (2002). Inhibition of Mrp2- and Ycf1p-mediated transport by reducing agents: evidence for GSH transport on rat Mrp2. Biochim Biophys Acta 1559:171–178.
  • Riordan, J. R., Rommens, J. M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., et al. (1989). Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066–1073.
  • Rius, M., Nies, A. T., Hummel-Eisenbeiss, J., Jedlitschky, G., Keppler, D. (2003). Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane. Hepatology 38:374–384.
  • Roberts, L. M., Black, D. S., Raman, C., Woodford, K., Zhou, M., Haggerty, J. E., et al. (2008). Subcellular localization of transporters along the rat blood-brain barrier and blood-cerebral-spinal fluid barrier by in vivo biotinylation. Neuroscience 155:423–438.
  • Rosenthal, P., Blanckaert, N., Kabra, P. M., Thaler, M. M. (1981). Liquid-chromatographic determination of bilirubin and its conjugates in rat serum and human amniotic fluid. Clin Chem 27:1704–1707.
  • Rost, D., Kloeters-Plachky, P., Stiehl, A. (2008). Retrieval of the rat canalicular conjugate export pump, Mrp2, is associated with a rearrangement of actin filaments and radixin in bile-salt–induced cholestasis. Eur J Med Res 13:314–318.
  • Rudin, C. M., Yang, Z., Schumaker, L. M., VanderWeele, D. J., Newkirk, K., Egorin, M. J., et al. (2003). Inhibition of glutathione synthesis reverses Bcl-2-mediated cisplatin resistance. Cancer Res 63:312–318.
  • Ryan, C. M., Carter, E. A., Jenkins, R. L., Sterling, L. M., Yarmush, M. L., Malt, R. A. (1993). Isolation and long-term culture of human hepatocytes. Surgery 113:48–54.
  • Ryu, S., Kawabe, T., Nada, S., Yamaguchi, A. (2000). Identification of basic residues involved in drug export function of human multidrug resistance–associated protein 2. J Biol Chem 275:39617–39624.
  • Sakamoto, S., Kusuhara, H., Horie, K., Takahashi, K., Baba, T., Ishizaki, J., et al. (2008). Identification of the transporters involved in the hepatobiliary transport and intestinal efflux of methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-na phthoate (S-8921) glucuronide, a pharmacologically active metabolite of S-8921. Drug Metab Dispos 36:1553–1561.
  • Sandusky, G. E., Mintze, K. S., Pratt, S. E., Dantzig, A. H. (2002). Expression of multidrug resistance–associated protein 2 (MRP2) in normal human tissues and carcinomas using tissue microarrays. Histopathology 41:65–74.
  • Sarkadi, B., Price, E. M., Boucher, R. C., Germann, U. A., Scarborough, G. A. (1992). Expression of the human multidrug resistance cDNA in insect cells generates a high-activity drug-stimulated membrane ATPase. J Biol Chem 267:4854–4858.
  • Sasabe, H., Terasaki, T., Tsuji, A., Sugiyama, Y. (1997). Carrier-mediated hepatic uptake of quinolone antibiotics in the rat. J Pharmacol Exp Ther 282:162–171.
  • Sasaki, K., Kon, J., Mizuguchi, T., Chen, Q., Ooe, H., Oshima, H., et al. (2008). Proliferation of hepatocyte progenitor cells isolated from adult human livers in serum-free medium. Cell Transpl 17:1221–1230.
  • Sasaki, M., Suzuki, H., Aoki, J., Ito, K., Meier, P. J., Sugiyama, Y. (2004). Prediction of in vivo biliary clearance from the in vitro transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II monolayer expressing both rat organic anion transporting polypeptide 4 and multidrug resistance–associated protein 2. Mol Pharmacol 66:450–459.
  • Sasaki, M., Suzuki, H., Ito, K., Abe, T., Sugiyama, Y. (2002). Transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/SLC21A6) and multidrug resistance–associated protein 2 (MRP2/ABCC2). J Biol Chem 277:6497–6503.
  • Schaub, T. P., Kartenbeck, J., Konig, J., Spring, H., Dorsam, J., Staehler, G., et al. (1999). Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma. J Am Soc Nephrol 10:1159–1169.
  • Schaub, T. P., Kartenbeck, J., Konig, J., Vogel, O., Witzgall, R., Kriz, W., et al. (1997). Expression of the conjugate export pump encoded by the mrp2 gene in the apical membrane of kidney proximal tubules. J Am Soc Nephrol 8:1213–1221.
  • Seitz, S., Kretz-Rommel, A., Oude Elferink, R. P., Boelsterli, U. A. (1998). Selective protein adduct formation of diclofenac glucuronide is critically dependent on the rat canalicular conjugate export pump (Mrp2). Chem Res Toxicol 11:513–519.
  • Shilling, A. D., Azam, F., Kao, J., Leung, L. (2006). Use of canalicular membrane vesicles (CMVs) from rats, dogs, monkeys, and humans to assess drug transport across the canalicular membrane. J Pharmacol Toxicol Meth 53:186–197.
  • Shoda, J., Miura, T., Utsunomiya, H., Oda, K., Yamamoto, M., Kano, M., et al. (2004). Genipin enhances Mrp2 (Abcc2)-mediated bile formation and organic anion transport in rat liver. Hepatology 39:167–178.
  • Sidler Pfandler, M. A., Hochli, M., Inderbitzin, D., Meier, P. J., Stieger, B. (2004). Small hepatocytes in culture develop polarized transporter expression and differentiation. J Cell Sci 117:4077–4087.
  • Slot, A. J., Wise, D. D., Deeley, R. G., Monks, T. J., Cole, S. P. (2008). Modulation of human multidrug resistance protein (MRP) 1 (ABCC1) and MRP2 (ABCC2) transport activities by endogenous and exogenous glutathione-conjugated catechol metabolites. Drug Metab Dispos 36:552–560.
  • Smeets, P. H., van Aubel, R. A., Wouterse, A. C., van den Heuvel, J. J., Russel, F. G. (2004). Contribution of multidrug resistance protein 2 (MRP2/ABCC2) to the renal excretion of p-aminohippurate (PAH) and identification of MRP4 (ABCC4) as a novel PAH transporter. J Am Soc Nephrol 15:2828–2835.
  • Soini, Y., Jarvinen, K., Kaarteenaho-Wiik, R., Kinnula, V. (2001). The expression of P-glycoprotein and multidrug resistance proteins 1 and 2 (MRP1 and MRP2) in human malignant mesothelioma. Ann Oncol 12:1239–1245.
  • Spears, K. J., Ross, J., Stenhouse, A., Ward, C. J., Goh, L. B., Wolf, C. R., et al. (2005). Directional transepithelial transport of organic anions in porcine LLC-PK1 cells that coexpress human OATP1B1 (OATP-C) and MRP2. Biochem Pharmacol 69:415–423.
  • St-Pierre, M. V., Serrano, M. A., Macias, R. I., Dubs, U., Hoechli, M., Lauper, U., et al. (2000). Expression of members of the multidrug resistance protein family in human term placenta. Am J Physiol Regul Integr Comp Physiol 279:R1495–R1503.
  • Steinbach, D., Lengemann, J., Voigt, A., Hermann, J., Zintl, F., Sauerbrey, A. (2003). Response to chemotherapy and expression of the genes encoding the multidrug resistance–associated proteins, MRP2, MRP3, MRP4, MRP5, and SMRP, in childhood acute myeloid leukemia. Clin Cancer Res 9:1083–1086.
  • Stieger, B., Fattinger, K., Madon, J., Kullak-Ublick, G. A., Meier, P. J. (2000). Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 118:422–430.
  • Storch, C. H., Ehehalt, R., Haefeli, W. E., Weiss, J. (2007). Localization of the human breast cancer resistance protein (BCRP/ABCG2) in lipid rafts/caveolae and modulation of its activity by cholesterol in vitro. J Pharmacol Exp Ther 323:257–264.
  • Sugie, M., Asakura, E., Zhao, Y. L., Torita, S., Nadai, M., Baba, K., et al. (2004). Possible involvement of the drug transporters P-glycoprotein and multidrug resistance–associated protein Mrp2 in disposition of azithromycin. Antimicrob Agents Chemother 48:809–814.
  • Sugiyama, D., Kusuhara, H., Lee, Y. J., Sugiyama, Y. (2003). Involvement of multidrug resistance–associated protein 1 (Mrp1) in the efflux transport of 17beta-estradiol-D-17beta-glucuronide (E217betaG) across the blood-brain barrier. Pharm Res 20:1394–1400.
  • Sun, N., Sun, X., Chen, B., Cheng, H., Feng, J., Cheng, L., et al. (2009). MRP2 and GSTP1 polymorphisms and chemotherapy response in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol [Epub ahead of print].
  • Surowiak, P., Materna, V., Kaplenko, I., Spaczynski, M., Dolinska-Krajewska, B., Gebarowska, E., et al. (2006). ABCC2 (MRP2, cMOAT) can be localized in the nuclear membrane of ovarian carcinomas and correlates with resistance to cisplatin and clinical outcome. Clin Cancer Res 12:7149–7158.
  • Suzuki, H., Sugiyama, Y. (1998). Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/MRP2. Semin Liver Dis 18:359–376.
  • Swift, B., Tian, X., Brouwer, K. L. (2009). Integration of preclinical and clinical data with pharmacokinetic modeling and simulation to evaluate fexofenadine as a probe for hepatobiliary transport function. Pharm Res 26:1942–1951.
  • Tada, Y., Wada, M., Migita, T., Nagayama, J., Hinoshita, E., Mochida, Y., et al. (2002). Increased expression of multidrug resistance–associated proteins in bladder cancer during clinical course and drug resistance to doxorubicin. Int J Cancer 98:630–635.
  • Tahara, H., Kusuhara, H., Fuse, E., Sugiyama, Y. (2005). P-glycoprotein plays a major role in the efflux of fexofenadine in the small intestine and blood-brain barrier, but only a limited role in its biliary excretion. Drug Metab Dispos 33:963–968.
  • Takeguchi, N., Ichimura, K., Koike, M., Matsui, W., Kashiwagura, T., Kawahara, K. (1993). Inhibition of the multidrug efflux pump in isolated hepatocyte couplets by immunosuppressants FK506 and cyclosporine. Transplantation 55:646–650.
  • Takenaka, O., Horie, T., Kobayashi, K., Suzuki, H., Sugiyama, Y. (1995). Kinetic analysis of hepatobiliary transport for conjugated metabolites in the perfused liver of mutant rats (EHBR) with hereditary conjugated hyperbilirubinemia. Pharm Res 12:1746–1755.
  • Takikawa, H., Sano, N., Narita, T., Uchida, Y., Yamanaka, M., Horie, T., et al. (1991). Biliary excretion of bile acid conjugates in a hyperbilirubinemic mutant Sprague-Dawley rat. Hepatology 14:352–360.
  • Tanaka, H., Sano, N., Takikawa, H. (2003). Biliary excretion of phenolphthalein sulfate in rats. Pharmacology 68:177–182.
  • Tanaka, Y., Kobayashi, Y., Gabazza, E. C., Higuchi, K., Kamisako, T., Kuroda, M., et al. (2002). Increased renal expression of bilirubin glucuronide transporters in a rat model of obstructive jaundice. Am J Physiol Gastrointest Liver Physiol 282:G656–G662.
  • Tang, F., Horie, K., Borchardt, R. T. (2002). Are MDCK cells transfected with the human MRP2 gene a good model of the human intestinal mucosa? Pharm Res 19:773–779.
  • Taniguchi, K., Wada, M., Kohno, K., Nakamura, T., Kawabe, T., Kawakami, M., et al. (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.
  • Telbisz, A., Muller, M., Ozvegy-Laczka, C., Homolya, L., Szente, L., Varadi, A., et al. (2007). Membrane cholesterol selectively modulates the activity of the human ABCG2 multidrug transporter. Biochim Biophys Acta 1768:2698–2713.
  • Teng, S., Piquette-Miller, M. (2007). Hepatoprotective role of PXR activation and MRP3 in cholic-acid–induced cholestasis. Br J Pharmacol 151:367–376.
  • Tian, X., Zamek-Gliszczynski, M. J., Li, J., Bridges, A. S., Nezasa, K., Patel, N. J., et al. (2008). Multidrug resistance–associated protein 2 is primarily responsible for the biliary excretion of fexofenadine in mice. Drug Metab Dispos 36:61–64.
  • Tian, X., Zamek-Gliszczynski, M. J., Zhang, P., Brouwer, K. L. (2004). Modulation of multidrug resistance–associated protein 2 (Mrp2) and Mrp3 expression and function with small interfering RNA in sandwich-cultured rat hepatocytes. Mol Pharmacol 66:1004–1010.
  • Tietz, P., Jefferson, J., Pagano, R., Larusso, N. F. (2005). Membrane microdomains in hepatocytes: potential target areas for proteins involved in canalicular bile secretion. J Lipid Res 46:1426–1432.
  • Toh, S., Wada, M., Uchiumi, T., Inokuchi, A., Makino, Y., Horie, Y., et al. (1999). Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome. Am J Hum Genet 64:739–746.
  • Tsuda-Tsukimoto, M., Maeda, T., Iwanaga, T., Kume, T., Tamai, I. (2006). Characterization of hepatobiliary transport systems of a novel alpha4beta1/alpha4beta7 dual antagonist, TR-14035. Pharm Res 23:2646–2656.
  • Van Aubel, R. A., Hartog, A., Bindels, R. J., Van Os, C. H., Russel, F. G. (2000). Expression and immunolocalization of multidrug resistance protein 2 in rabbit small intestine. Eur J Pharmacol 400:195–198.
  • van Aubel, R. A., Smeets, P. H., Peters, J. G., Bindels, R. J., Russel, F. G. (2002). The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J Am Soc Nephrol 13:595–603.
  • van Aubel, R. A., van Kuijck, M. A., Koenderink, J. B., Deen, P. M., van Os, C. H., Russel, F. G. (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.
  • van de Wetering, K., Zelcer, N., Kuil, A., Feddema, W., Hillebrand, M., Vlaming, M. L., et al. (2007). Multidrug resistance proteins 2 and 3 provide alternative routes for hepatic excretion of morphine-glucuronides. Mol Pharmacol 72:387–394.
  • van der Kolk, D. M., de Vries, E. G., Koning, J. A., van den Berg E., Muller, M., Vellenga, E. (1998). Activity and expression of the multidrug resistance proteins, MRP1 and MRP2, in acute myeloid leukemia cells, tumor cell lines, and normal hematopoietic CD34+ peripheral blood cells. Clin Cancer Res 4:1727–1736.
  • van Zanden, J. J., Wortelboer, H. M., Bijlsma, S., Punt, A., Usta, M., Bladeren, P. J., et al. (2005). Quantitative structure-activity relationship studies on the flavonoid-mediated inhibition of multidrug resistance proteins 1 and 2. Biochem Pharmacol 69:699–708.
  • Veggi, L. M., Crocenzi, F. A., Roma, M. G., Mottino, A. D. (2005). Dapsone impairs the bile salt-independent fraction of bile flow in rats: possible involvement of its N-hydroxylated metabolite. Toxicology 211:97–106.
  • Vlaming, M. L., Mohrmann, K., Wagenaar, E., de Waart D. R., Elferink, R. P., Lagas, J. S., et al. (2006). Carcinogen and anticancer drug transport by Mrp2 in vivo: studies using Mrp2 (Abcc2) knockout mice. J Pharmacol Exp Ther 318:319–327.
  • Vlaming, M. L., Pala, Z., van Esch A., Wagenaar, E., de Waart, D. R., van de Wetering K., et al. (2009). Functionally overlapping roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the elimination of methotrexate and its main toxic metabolite, 7-hydroxymethotrexate, in vivo. Clin Cancer Res 15:3084–3093.
  • Vlaming, M. L., Pala, Z., van Esch A., Wagenaar, E., van Tellingen, O., de Waart, D. R., et al. (2008). Impact of Abcc2 (Mrp2) and Abcc3 (Mrp3) on the in vivo elimination of methotrexate and its main toxic metabolite, 7-hydroxymethotrexate. Clin Cancer Res 14:8152–8160.
  • Wakamatsu, T., Nakahashi, Y., Hachimine, D., Seki, T., Okazaki, K. (2007). The combination of glycyrrhizin and lamivudine can reverse the cisplatin resistance in hepatocellular carcinoma cells through inhibition of multidrug resistance–associated proteins. Int J Oncol 31:1465–1472.
  • Walle, T. (2007). Methylation of dietary flavones greatly improves their hepatic metabolic stability and intestinal absorption. Mol Pharm 4:826–832.
  • Ward, E. S., Pollack, G. M., Brouwer, K. L. (2001). Probenecid-associated alterations in valproate glucuronide hepatobiliary disposition: mechanistic assessment using mathematical modeling. J Pharmacol Exp Ther 297:141–147.
  • Westley, I. S., Brogan, L. R., Morris, R. G., Evans, A. M., Sallustio, B. C. (2006). Role of Mrp2 in the hepatic disposition of mycophenolic acid and its glucuronide metabolites: effect of cyclosporine. Drug Metab Dispos 34:261–266.
  • Wielandt, A. M., Vollrath, V., Manzano, M., Miranda, S., Accatino, L., Chianale, J. (1999). Induction of the multispecific organic anion transporter (cMoat/mrp2) gene and biliary glutathione secretion by the herbicide 2,4,5-trichlorophenoxyacetic acid in the mouse liver. Biochem J 341(Pt 1):105–111.
  • Williamson, G., Aeberli, I., Miguet, L., Zhang, Z., Sanchez, M. B., Crespy, V., et al. (2007). Interaction of positional isomers of quercetin glucuronides with the transporter, ABCC2 (cMOAT, MRP2). Drug Metab Dispos 35:1262–1268.
  • Wojnowski, L., Kulle, B., Schirmer, M., Schluter, G., Schmidt, A., Rosenberger, A., et al. (2005). NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation 112:3754–3762.
  • Wu, C. Y., Benet, L. Z. (2005). Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res 22:11–23.
  • Xie, S. M., Fang, W. Y., Liu, Z., Wang, S. X., Li, X., Liu, T. F., et al. (2008). Lentivirus-mediated RNAi silencing targeting ABCC2 increasing the sensitivity of a human nasopharyngeal carcinoma cell line against cisplatin. J Transl Med 6:55.
  • Xing, L., Hu, Y., Lai, Y. (2009). Advancement of structure-activity relationship of multidrug resistance–associated protein 2 interactions. Aaps J 11:406–413. [Epub Jun 3].
  • Xiong, H., Suzuki, H., Sugiyama, Y., Meier, P. J., Pollack, G. M., Brouwer, K. L. (2002). Mechanisms of impaired biliary excretion of acetaminophen glucuronide after acute phenobarbital treatment or phenobarbital pretreatment. Drug Metab Dispos 30:962–969.
  • Xiong, H., Turner, K. C., Ward, E. S., Jansen, P. L., Brouwer, K. L. (2000). Altered hepatobiliary disposition of acetaminophen glucuronide in isolated perfused livers from multidrug resistance–associated protein 2-deficient TR(-) rats. J Pharmacol Exp Ther 295:512–518.
  • Yamada, A., Maeda, K., Kamiyama, E., Sugiyama, D., Kondo, T., Shiroyanagi, Y., et al. (2007). Multiple human isoforms of drug transporters contribute to the hepatic and renal transport of olmesartan, a selective antagonist of the angiotensin II AT1-receptor. Drug Metab Dispos 35:2166–2176.
  • Yamada, T., Arai, T., Nagino, M., Oda, K., Shoda, J., Suzuki, H., et al. (2005). Impaired expression of hepatic multidrug resistance protein 2 is associated with posthepatectomy hyperbilirubinemia in patients with biliary cancer. Langenbecks Arch Surg 390:421–429.
  • Yamaguchi, S., Zhao, Y. L., Nadai, M., Yoshizumi, H., Cen, X., Torita, S., et al. (2006). Involvement of the drug transporters P-glycoprotein and multidrug resistance–associated protein Mrp2 in telithromycin transport. Antimicrob Agents Chemother 50:80–87.
  • Yamashiro, W., Maeda, K., Hirouchi, M., Adachi, Y., Hu, Z., Sugiyama, Y. (2006). Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans. Drug Metab Dispos 34:1247–1254.
  • Yamazaki, K., Mikami, T., Hosokawa, S., Tagaya, O., Nozaki, Y., Kawaguchi, A., et al. (1995). A new mutant rat with hyperbilirubinuria (hyb). J Hered 86:314–317.
  • Yasunaga, M., Takemura, M., Fujita, K. Yabuuchi, H., Wada, M. (2008). Molecular cloning and functional characterization of cynomolgus monkey multidrug resistance–associated protein 2 (MRP2). Eur J Pharm Sci 35:326–334.
  • Yoshida, N., Takada, T., Yamamura, Y., Adachi, I., Suzuki, H., Kawakami, J. (2008). Inhibitory effects of terpenoids on multidrug resistance–associated protein 2- and breast cancer resistance protein-mediated transport. Drug Metab Dispos 36:1206–1211.
  • Young, L. C., Campling, B. G., Cole, S. P., Deeley, R. G., Gerlach, J. H. (2001). Multidrug resistance proteins MRP3, MRP1, and MRP2 in lung cancer: correlation of protein levels with drug response and messenger RNA levels. Clin Cancer Res 7:1798–1804.
  • Young, L. C., Campling, B. G., Voskoglou-Nomikos, T., Cole, S. P., Deeley, R. G., Gerlach J, H. (1999). Expression of multidrug resistance protein-related genes in lung cancer: correlation with drug response. Clin Cancer Res 5:673–680.
  • Zalups, R. K., Bridges, C. C. (2009). MRP2 involvement in renal proximal tubular elimination of methylmercury mediated by DMPS or DMSA. Toxicol Appl Pharmacol 235:10–17.
  • Zamek-Gliszczynski, M. J., Hoffmaster, K. A., Humphreys, J. E., Tian, X., Nezasa, K., Brouwer, K. L. (2006). Differential involvement of Mrp2 (Abcc2) and Bcrp (Abcg2) in biliary excretion of 4-methylumbelliferyl glucuronide and sulfate in the rat. J Pharmacol Exp Ther 319:459–467.
  • Zamek-Gliszczynski, M. J., Hoffmaster, K. A., Tian, X., Zhao, R., Polli, J. W., Humphreys, J. E., et al. (2005). Multiple mechanisms are involved in the biliary excretion of acetaminophen sulfate in the rat: role of Mrp2 and Bcrp1. Drug Metab Dispos 33:1158–1165.
  • Zamek-Gliszczynski, M. J., Xiong, H., Patel, N. J., Turncliff, R. Z., Pollack, G. M., Brouwer, K. L. (2003). Pharmacokinetics of 5 (and 6)-carboxy-2’,7’-dichlorofluorescein and its diacetate promoiety in the liver. J Pharmacol Exp Ther 304:801–809.
  • Zelcer, N., Huisman, M. T., Reid, G., Wielinga, P., Breedveld, P., Kuil, A., et al. (2003). Evidence for two interacting ligand binding sites in human multidrug resistance protein 2 (ATP binding cassette C2). J Biol Chem 278:23538–23544.
  • Zhang, H., Xiang, M. L., Zhao, Y. L., Wei, Y. Q., Yang, S. Y. (2009). Support vector machine and pharmacophore-based prediction models of multidrug-resistance protein 2 (MRP2) inhibitors. Eur J Pharm Sci 36:451–457.
  • Zhang, L., Lin, G., Kovacs, B., Jani, M., Krajcsi, P., Zuo, Z. (2007). Mechanistic study on the intestinal absorption and disposition of baicalein. Eur J Pharm Sci 31:221–231.
  • Zimmermann, C., van de Wetering K., van de Steeg, E., Wagenaar, E., Vens, C., Schinkel, A. H. (2008). Species-dependent transport and modulation properties of human and mouse multidrug resistance protein 2 (MRP2/Mrp2, ABCC2/Abcc2). Drug Metab Dispos 36:631–640.
  • Zollner, G., Fickert, P., Zenz, R., Fuchsbichler, A., Stumptner, C., Kenner, L., et al. (2001). Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 33:633–646.
  • Zollner, G., Wagner, M., Fickert, P., Silbert, D., Fuchsbichler, A., Zatloukal, K., et al. (2005). Hepatobiliary transporter expression in human hepatocellular carcinoma. Liver Int 25:367–379.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.