2,142
Views
169
CrossRef citations to date
0
Altmetric
Review

Structure and function of the MRP2 (ABCC2) protein and its role in drug disposition

, &
Pages 351-366 | Published online: 30 May 2006

Bibliography

  • DEAN M, RZHETSKY A, ALLIKMETSR: The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. (2001) 11(7):1156-1166.
  • DEAN M, ANNILO T: Evolution of the ATP-Binding Cassette (ABC) transporter superfamily in vertebrates. Ann. Rev. Genomics Hum. Genet. (2005) 6:123-142.
  • MARTINOIA E, KLEIN M, GEISLER M etal.: Multifunctionality of plant ABC transporters-more than just detoxifiers. Planta (2002) 214(3):345-355.
  • HOLLAND IB, SCHMITT L, YOUNG J: Type 1 protein secretion in bacteria, the ABC-transporter dependent pathway (review). Mol. Membr. Biol. (2005) 22(1-2):29-39.
  • BORST P, EVERS R, KOOL M, WIJNHOLDS J: A family of drug transporters: the multidrug resistance-associated proteins. J. Natl. Cancer Inst. (2000) 92(16):1295-1302.
  • BORST P, ELFERINK RO: Mammalian ABC transporters in health and disease. Ann. Rev. Biochem. (2002) 71:537-592.
  • KRUH GD, BELINSKY MG: The MRP family of drug efflux pumps. Oncogene (2003) 22(47):7537-7552.
  • HOMOLYA L, VARADI A, SARKADI B: Multidrug resistance-associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate. Biofactors (2003) 17(1-4):103-114.
  • MAYER R, KARTENBECK J, BCHLERM, JEDLITSCHKY G, LEIERI, KEPPLER D: 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. (1995) 131:137-150.
  • BUECHLER M, KOENIG J, BROM M etal.: 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. (1996) 271(25):15091-15098.
  • PAULUSMA CC, BOSMA PJ, ZAMANGJ etal.: Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science (1996) 271(5252):1126-1128.
  • PAULUSMA CC, KOOL M, BOSMA PJ etal.: A mutation in the human canalicular multispecific organic anion transporter gene causes the DubinJohnson syndrome. Hepatology (1997) 25:1539-1542.
  • TANIGUCHI K, WADA M, KOHNO K etal.: A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation. Cancer Res. (1996) 56:4124-4129.
  • DUBIN IN, JOHNSON FB: Chronic idiopathic jaundice with unidentified pigment in liver cells; a new clinicopathologic entity with a report of 12 cases. Medicine (Baltimore) (1954) 33(3):155-197.
  • HUBER M, GUHLMANN A, JANSENPL, KEPPLER D: Hereditary defect of hepatobiliary cysteinyl leukotriene elimination in mutant rats with defective hepatic anion excretion. Hepatology (1987) 7:224-228.
  • JANSEN PL, PETERS WH, LAMERSWH: Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport. Hepatology (1985) 5:573-579.
  • TAKENAKA O, HORIE T, KOBAYASHIK, SUZUKI H, SUGIYAMA Y: Kinetic analysis of hepatobiliary transport for conjugated metabolites in the perfused liver of mutant rats (EHBR) with hereditary conjugated hyperbilirubinemia. Pharm. Res. (1995) 12:1746-1755.
  • KOENIG M, NIES AT, CUI Y, KEPPLERD: MRP2, the apical export pump for anionic conjugates. In: ABC Transporters from Bacteria to Man. IB Holland, SPC Cole, K Kuchler, CF Higgins (Eds), Academic press, London, UK (2003):423-443.
  • JEDLITSCHKY G, LEIER I, BUCHHOLZ U, HUMMEL-EISENBEISS J, BURCHELLB, KEPPLER D: ATP-dependent transport of bilirubin glucuronides by the multidrug resistance protein MRP1 and its hepatocyte canalicular isoform MRP2. Biochem. J. (1997) 327:305-310.
  • KAMISAKO T, LEIER I, CUI Y, KNIGJ, BUCHHOLZ U, HUMMEL-EISENBEISS J, KEPPLER D: Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2. Hepatology (1999) 30:485-490.
  • ROST D, KONIG J, WEISS G, KLAR E, STREMMEL W, KEPPLER D: Expression and localization of the multidrug resistance proteins MRP2 and MRP3 in human gallbladder epithelia. Gastroenterology (2001) 121(5):1203-1208.
  • SCHAUB TP, KARTENBECK J, KONIGJ etal.: Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma. J. Am. Soc. Nephrol. (1999) 10(6):1159-1169.
  • DIETRICH CG, GEIER A, OUDE ELFERINK RP: ABC of oral bioavailability: transporters as gatekeepers in the gut. Gut (2003) 52(12):1788-1795.
  • MOTTINO AD, HOFFMAN T, JENNESL, VORE M: Expression and localization of multidrug resistant protein mrp2 in rat small intestine. J. Pharmacol. Exp. Ther. (2000) 293(3):717-723.
  • CHAN LM, LOWES S, HIRST BH: The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur. J. Pharm. Sci. (2004) 21(1):25-51.
  • KUSUHARA H, SUGIYAMA Y: Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain and kidney. J. Control. Release (2002) 78(1-3):43-54.
  • NIES AT, JEDLITSCHKY G, KONIG J etal.: Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain. Neuroscience (2004) 129(2):349-360.
  • LSCHER W, POTSCHKA H: Drug resistance in brain diseases and the role of drug efflux transporters. Nat. Rev. Neurosci. (2005) 6(8):591-602.
  • DOMBROWSKI SM, DESAI SY, MARRONI M etal.: Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia (2001) 42(12):1501-1506.
  • POTSCHKA H, FEDROWITZ M, LSCHER W: Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. J. Pharmacol. Exp. Ther. (2003) 306:124-131.
  • POTSCHKA H, FEDROWITZ M, LSCHER W: Brain access and anticonvulsant efficacy of carbamazepine, lamotrigine, and felbamate in ABCC2/MRP2-deficient TR- rats. Epilepsia (2003) 44:1479-1486.
  • ST PIERRE MV, SERRANO MA, MACIAS RI etal.: Expression of members of the multidrug resistance protein family in human term placenta. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2000) 279(4):R1495-R1503.
  • MEYER ZU SCHWABEDISSEN HE, JEDLITSCHKY G, GRATZ M etal.: Variable expression of MRP2 (ABCC2) in human placenta: influence of gestational age and cellular differentiation. Drug Metab. Dispos. (2005) 33(7):896-904.
  • BART J, HOLLEMA H, GROEN HJ etal.: The distribution of drug-efflux pumps, P-gp, BCRP, MRP1 and MRP2, in the normal bloodtestis barrier and in primary testicular tumours. Eur. J. Cancer (2004) 40(14):2064-2070.
  • CHERRINGTON NJ, HARTLEY DP, LI N, JOHNSON DR, KLAASSEN CD: Organ distribution of multidrug resistance proteins 1, 2 and 3 (Mrp1, 2 and 3) mRNA and hepatic induction of Mrp3 by constitutive androstane receptor activators in rats. J. Pharmacol. Exp. Ther. (2002) 300(1):97-104.
  • NAGEL G: Differential function of the two nucleotide binding domains on cystic fibrosis transmembrane conductance regulator. Biochim. Biophys. Acta (1999) 1461:263-274.
  • RYU S, KAWABE T, NADA S, YAMAGUCHI A: Identification of basic residues involved in drug export function of human multidrug resistance-associated protein 2. J. Biol. Chem. (2000) 275(50):39617-39624.
  • ZELCER N, HUISMAN MT, REID G etal.: Evidence for two interacting ligand binding sites in human multidrug resistance protein 2 (ATP binding cassette C2). J. Biol. Chem. (2003) 278(26):23538-23544.
  • HIRONO S, NAKAGOME I, IMAI R, MAEDA K, KUSUHARA H, SUGIYAMAY: Estimation of the three-dimensional pharmacophore of ligands for rat multidrug-resistance-associated protein 2 using ligand-based drug design techniques. Pharm. Res. (2005) 22(2):260-269.
  • ITO K, SUZUKI H, SUGIYAMA Y: Charged amino acids in the transmembrane domains are involved in the determination of the substrate specificity of rat Mrp2. Mol. Pharmacol. (2001) 59(5):1077-1085.
  • ITO K, OLESCHUK CJ, WESTLAKE C, VASA MZ, DEELEY RG, COLE SP: 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. (2001) 276(41):38108-38114.
  • ITO K, HIROSHI S, YUICHI S: Single amino acid substitution of rat MRP2 results in acquired transport activity for taurocholate. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) 281:G1034-G1043.
  • FERNANDEZ SB, HOLLO Z, KERN A etal.: 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. (2002) 277(34):31048-31055.
  • NIES AT, KONIG J, CUI Y, BROM M, SPRING H, KEPPLER D: Structural requirements for the apical sorting of human multidrug resistance protein 2 (ABCC2). Eur. J. Biochem. (2002) 269(7):1866-1876.
  • HIPFNER DR, ALMQUIST KC, LESLIEEM etal.: Membrane topology of the multidrug resistance protein (MRP). A study of glycosylation-site mutants reveals an extracytosolic NH2 terminus. J. Biol. Chem. (1997) 272(38):23623-23630.
  • ZHANG P, TIAN X, CHANDRA P, BROUWER KL: Role of glycosylation in trafficking of Mrp2 in sandwich-cultured rat hepatocytes. Mol. Pharmacol. (2005) 67(4):1334-1341.
  • ITO K, SUZUKI H, HIROHASHI T, KUME K, SHIMIZU T, SUGIYAMA Y: Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR. Am. J. Physiol. (1997) 272:G16-G22.
  • BAKOS E, EVERS R, SINKO E, VARADIA, BORST P, SARKADI B: Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions. Mol. Pharmacol. (2000) 57:760-768.
  • CUI Y, KNIG J, BUCHHOLZ U, SPRING H, LEIER I, KEPPLER D: Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol. Pharmacol. (1999) 55:929-937.
  • CUI Y, KONIG J, KEPPLER D: Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2. Mol. Pharmacol. (2001) 60:934-943.
  • SASAKI M, SUZUKI H, ITO K, ABE T, SUGIYAMA Y: Transcellular transport of organic anions across a double-transfected MadinDarby 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. (2002) 277(8):6497-6503.
  • LETSCHERT K, KOMATSU M, HUMMEL-EISENBEISS J, KEPPLER D: Vectorial transport of the peptide CCK-8 by double-transfected MDCKII cells stably expressing the organic anion transporter OATP1B3 (OATP8) and the export pump ABCC2 (MRP2). J. Pharmacol. Exp. Ther. (2005) 313:549-556.
  • SASAKI M, SUZUKI H, AOKI J, ITO K, MEIER PJ, SUGIYAMA Y: Prediction of invivo biliary clearance from the invitro transcellular transport of organic anions across a double-transfected MadinDarby canine kidney II monolayer expressing both rat organic anion transporting polypeptide 4 and multidrug resistance associated protein. Mol. Pharmacol. (2004) 66(3):450-459.
  • KOPPLOW K, LETSCHERT K, KNIGJ, WALTER B, KEPPLER D: Human hepatobiliary transport of organic anions analyzed by quadruple-transfected cells. Mol. Pharmacol. (2005) 68:1031-1038.
  • KEPPLER D: Uptake and efflux transporters for conjugates in human hepatocytes. Methods Enzymol. (2005) 400:531-542.
  • BALLATORI N, REBBEOR JF: Roles of MRP2 and oatp1 in hepatocellular export of reduced glutathione. Semin Liver Dis. (1998) 18(4):377-387.
  • LOE DW, ALMQUIST KC, DEELEY RG, COLE SP: Multidrug resistance protein (MRP)-mediated transport of leukotriene C4 and chemotherapeutic agents in membrane vesicles. Demonstration of glutathione-dependent vincristine transport. J. Biol. Chem. (1996) 271:9675-9682.
  • LESLIE EM, ITO K, UPADHYAYA P, HECHT SS, DEELEY RG, COLE S: Transport of the-O-glucuronide conjugate of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the multidrug resistance protein 1 (MRP1). Requirement for glutathione or a non-sulfur-containing analog. J Biol. Chem. (2001) 276:27846-27854.
  • ZAMAN GJ, LANKELMA J, VANTELLINGEN O etal.: Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein. Proc. Natl. Acad. Sci. USA (1995) 92:7690-7694.
  • VAN AUBEL RA, KOENDERINK JB, PETERS JG, VAN OS CH, RUSSEL FG: Mechanisms and interaction of vinblastine and reduced glutathione transport in membrane vesicles by the rabbit multidrug resistance protein Mrp2 expressed in insect cells. Mol. Pharmacol. (1999) 56(4):714-719.
  • EVERS R, DE HAAS M, SPARIDANS R etal.: Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export. Br. J. Cancer (2000) 83:375-383.
  • COLE SP, DEELEY RG: Multidrug resistance mediated by the ATP-binding cassette transporter protein MRP. BioEssays (1998) 20(11):931-940.
  • QIAN YM, SONG WC, CUI H, COLESP, DEELEY RG: Glutathione stimulates sulfated estrogen transport by multidrug resistance protein 1. J. Biol. Chem. (2001) 276(9):6404-6411.
  • LOE DW, DEELEY RG, COLE SP: Verapamil stimulates glutathione transport by the 190-kDa multidrug resistance protein 1 (MRP1). J. Pharmacol. Exp. Ther. (2000) 293(2):530-538.
  • LESLIE EM, MAO Q, OLESCHUK CJ, DEELEY RG, COLE SP: Modulation of multidrug resistance protein 1 (MRP1/ABCC1) transport and atpase activities by interaction with dietary flavonoids. Mol. Pharmacol. (2001) 59(5):1171-1180.
  • ITO K, KORESAWA T, NAKANO K, HORIE T: Mrp2 is involved in benzylpenicillin-induced choleresis. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) 287(1):G42-G49.
  • BODE KA, DONNER MG, LEIER I, KEPPLER D: Inhibition of transport across the hepatocyte canalicular membrane by the antibiotic fusidate. Biochem. Pharmacol. (2002) 64(1):151-158.
  • CHEN C, MIRELES RJ, CAMPBELL SD etal.: Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab. Dispos. (2005) 33(4):537-546.
  • KIVISTO KT, GRISK O, HOFMANN U etal.: Disposition of oral and intravenous pravastatin in mrp2-deficient tr- rats. Drug Metab. Dispos. (2005) 33(11):1593-1596.
  • MATSUSHIMA S, MAEDA K, KONDOC etal.: Identification of the hepatic efflux transporters of organic anions using double transfected MDCKII cells expressing human OATP1B1/MRP2, OATP1B1/MDR1 and OATP1B1/BCRP. J. Pharmacol. Exp. Ther. (2005) 314(3):1059-1067.
  • LEIER I, HUMMEL-EISENBEISS J, CUIY, KEPPLER D: ATP-dependent para-aminohippurate transport by apical multidrug resistance protein MRP2. Kidney Int. (2000) 57(4):1636-1642.
  • SMEETS PH, VAN AUBEL RA, WOUTERSE AC, VAN DEN HEUVEL JJ, RUSSEL FG: 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. (2004) 15(11):2828-2835.
  • CANTZ T, NIES AT, BROM M, HOFMANN AF, KEPPLER D: MRP2, a human conjugate export pump, is present and transports fluo 3 into apical vacuoles of Hep G2 cells. Am. J. Physiol. Gastrointest. Liver Physiol. (2000) 278(4):G522-G531.
  • SU Y, ZHANG X, SINKO PJ: Human organic anion-transporting polypeptide OATP-A (SLC21A3) acts in concert with P-glycoprotein and multidrug resistance protein 2 in the vectorial transport of saquinavir in Hep G2 cells. Mol. Pharm. (2004) 1(1):49-56.
  • HUISMAN MT, SMIT JW, CROMMENTUYN KM etal.: Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs. AIDS (2002) 16(17):2295-2301.
  • LOSCHER W, POTSCHKA H: Drug resistance in brain diseases and the role of drug efflux transporters. Nat. Rev. Neurosci. (2005) 6(8):591-602.
  • CHEN C, HENNIG GE, MANAUTOUJE: Hepatobiliary excretion of acetaminophen glutathione conjugate and its derivatives in transport-deficient (TR-) hyperbilirubinemic rats. Drug Metab. Dispos. (2003) 31(6):798-804.
  • HOFFMASTER KA, ZAMEK-GLISZCZYNSKI MJ, POLLACK GM, BROUWER KL: Multiple transport systems mediate the hepatic uptake and biliary excretion of the metabolically stable opioid peptide [d-penicillamine2,5]enkephalin. Drug Metab. Dispos. (2005) 33(2):287-293.
  • JAGER W, GEHRING E, HAGENAUERB, AUST S, SENDEROWICZ A, THALHAMMER T: Biliary excretion of flavopiridol and its glucuronides in the perfused rat liver: role of multidrug resistance protein 2 (Mrp2). Life Sci. (2003) 73(22):2841-2854.
  • KOBAYASHI M, SAITOH H, KOBAYASHI M, TADANO K, TAKAHASHI Y, HIRANO T: 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. (2004) 309(3):1029-1035.
  • SMITHERMAN PK, TOWNSEND AJ, KUTE TE, MORROW CS: Role of multidrug resistance protein 2 (MRP2, ABCC2) in alkylating agent detoxification: MRP2 potentiates glutathione S-transferase A1-1-mediated resistance to chlorambucil cytotoxicity. J. Pharmacol. Exp. Ther. (2004) 308(1):260-267.
  • BARNOUIN K, LEIER I, JEDLITSCHKYG etal.: Multidrug resistance protein-mediated transport of chlorambucil and melphalan conjugated to glutathione. Br. J. Cancer (1998) 77:201-209.
  • QIU R, KALHORN TF, SLATTERY JT: ABCC2-mediated biliary transport of 4-gluta-thionyl-cyclophosphamide and its contribution to elimination of 4-hydroxycyclophosphamide in rat. J. Pharmacol. Exp. Ther. (2004) 308(3):1204-1212.
  • LALLOO AK, LUO FR, GUO A etal.: Membrane transport of camptothecin: facilitation by human P-glycoprotein (ABCB1) and multidrug resistance protein 2 (ABCC2). BMC Med. (2004) 2(1):16.
  • TAKEMOTO I, ITAGAKI S, CHIBA M, ITOH T, HIRANO T, ISEKI K: Characterization of secretory intestinal transport of the lactone form of CPT-11. Cancer Chemother. Pharmacol. (2005) 57(1):129-133.
  • HOOIJBERG JH, PETERS GJ, ASSARAFYG etal.: The role of multidrug resistance proteins MRP1, MRP2 and MRP3 in cellular folate homeostasis. Biochem. Pharmacol. (2003) 65(5):765-771.
  • CHEN C, SCOTT D, HANSON E etal.: Impact of Mrp2 on the biliary excretion and intestinal absorption of furosemide, probenecid, and methotrexate using Eisai hyperbilirubinemic rats. Pharm. Res. (2003) 20(1):31-37.
  • BREEDVELD P, ZELCER N, PLUIM D etal.: Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drugdrug interactions. Cancer Res. (2004) 64(16):5804-5811.
  • HULOT JS, VILLARD E, MAGUY A etal.: A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination. Pharmacogenet. Genomics (2005) 15(5):277-285.
  • KOOL M, DE HAAS M, SCHEFFER GL etal.: 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. (1997) 57:3537-3547.
  • LIEDERT B, MATERNA V, SCHADENDORF D, THOMALE J, LAGE H: Overexpression of cMOAT (MRP2/ABCC2) is associated with decreased formation of platinum-DNA adducts and decreased G2-arrest in melanoma cells resistant to cisplatin. J. Invest. Dermatol. (2003) 121(1):172-176.
  • MATERNA V, LIEDERT B, THOMALEJ, LAGE H: Protection of platinum-DNA adduct formation and reversal of cisplatin resistance by anti-MRP2 hammerhead ribozymes in human cancer cells. Int. J. Cancer (2005) 115(3):393-402.
  • OBRIEN E, DIETRICH DR: Ochratoxin A: the continuing enigma. Crit. Rev. Toxicol. (2005) 35(1):33-60.
  • CLARK HA, SNEDEKER SM: Ochratoxin A: its cancer risk and potential risk for exposure. J. Toxicol. Environ. Health B. Crit. Rev. (2006) 9(3):265-296.
  • BERGER V, GABRIEL AF, SERGENT T, TROUET A, LARONDELLE Y, SCHNEIDER YJ: Interaction of ochratoxin A with human intestinal Caco-2 cells: possible implication of a multidrug resistance-associated protein (MRP2). Toxicol. Lett. (2003) 140-141:465-476.
  • SHODA J, MIURA T, UTSUNOMIYA H etal.: Genipin enhances Mrp2 (Abcc2)-mediated bile formation and organic anion transport in rat liver. Hepatology (2004) 39(1):167-178.
  • JAGER W, GEHRING E, HAGENAUERB, AUST S, SENDEROWICZ A, THAL-HAMMERT: The role of hepatic Mrp2 in the interaction of flavopiridol and bilirubin: impact on therapy. Int. J. Clin. Pharmacol. Ther. (2003) 41(12):610-611.
  • AKAO T, SAKASHITA Y, HANADA M, GOTO H, SHIMADA Y, TERASAWA K: Enteric excretion of baicalein, a flavone of Scutellariae Radix, via glucuronidation in rat: involvement of multidrug resistance-associated protein 2. Pharm. Res. (2004) 21(11):2120-2126.
  • LOU H, OOKHTENS M, STOLZ A, KAPLOWITZ N: Chelerythrine stimulates GSH transport by rat Mrp2 (Abcc2) expressed in canine kidney cells. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) 285(6):G1335-G1344.
  • DIETRICH CG, DE WAART DR, OTTENHOFF R, SCHOOTS IG, ELFERINK RP: Increased bioavailability of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in MRP2-deficient rats. Mol. Pharmacol. (2001) 59(5):974-980.
  • BALLATORI N: Transport of toxic metals by molecular mimicry. Environ. Health Perspect. (2002) 110 (Suppl. 5):689-694.
  • KALA SV, KALA G, PRATER CI, SARTORELLI AC, LIEBERMAN MW: Formation and urinary excretion of arsenic triglutathione and methylarsenic diglutathione. Chem. Res. Toxicol. (2004) 17(2):243-249.
  • CUI X, KOBAYASHI Y, HAYAKAWA T, HIRANO S: Arsenic speciation in bile and urine following oral and intravenous exposure to inorganic and organic arsenics in rats. Toxicol. Sci. (2004) 82(2):478-487.
  • TERLOUW SA, GRAEFF C, SMEETSPH etal.: Short- and long-term influences of heavy metals on anionic drug efflux from renal proximal tubule. J. Pharmacol. Exp. Ther. (2002) 301(2):578-585.
  • ALEO MF, MORANDINI F, BETTONI F etal.: Endogenous thiols and MRP transporters contribute to Hg2+ efflux in HgCl2- treated tubular MDCK cells. Toxicology (2005) 206(1):137-151.
  • KAUFFMANN HM, SCHRENK D: Sequence analysis and functional characterization of the 5-flanking region of the rat multidrug resistance protein 2 (mrp2) gene. Biochem. Biophys. Res. Commun. (1998) 245:325-331.
  • STOCKEL B, KONIG J, NIES AT, CUI Y, BROM M, KEPPLER D: Characterization of the 5-flanking region of the human multidrug resistance protein 2 (MRP2) gene and its regulation in comparison withthe multidrug resistance protein 3 (MRP3) gene. Eur. J. Biochem. (2000) 267(5):1347-1358.
  • TANAKA T, UCHIUMI T, HINOSHITAE etal.: The human multidrug resistance protein 2 gene: functional characterization of the 5-flanking region and expression in hepatic cells. Hepatology (1999) 30:1507-1512.
  • KAUFFMANN HM, KEPPLER D, KARTENBECK J, SCHRENK D: Induction of cMrp/cMOAT gene expression by cisplatin, 2-acetylaminofluorene, or cycloheximide in rat hepatocytes. Hepatology (1997) 26:980-985.
  • COURTOIS A, PAYEN L, GUILLOUZOA, FARDEL O: Up-regulation of multidrug resistance-associated protein 2 (MRP2) expression in rat hepatocytes by dexamethasone. FEBS Lett. (1999) 459:381-385.
  • KUBITZ R, WETTSTEIN M, WARSKULAT U, HAUSSINGER D: Regulation of the multidrug resistance protein 2 in the rat liver by lipopolysaccharide and dexamethasone. Gastroenterology (1999) 116:401-410.
  • KAST HR, GOODWIN B, TARR PT etal.: Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor and constitutive androstane receptor. J. Biol. Chem. (2002) 277:2908-2915.
  • FERNANDEZ-CHECA JC, OOKHTENSM, KAPLOWITZ N: Selective induction by phenobarbital of the electrogenic transport of glutathione and organic anions in rat liver canalicular membrane vesicles. J. Biol. Chem. (1993) 268:10836-10841.
  • KIUCHI Y, SUZUKI H, HIROHASHI T, TYSON CA, SUGIYAMA Y: cDNA cloning and inducible expression of human multidrug resistance associated protein 3 (MRP3). FEBS Lett. (1998) 433:149-152.
  • OGAWA K, SUZUKI H, HIROHASHI T etal.: Characterization of inducible nature of MRP3 in rat liver. Am. J. Physiol. Gastrointest. Liver Physiol. (2000) 278:G438-G446.
  • HAGENBUCH N, REICHEL C, STIEGER B etal.: Effect of phenobarbital on the expression of bile salt and organic anion transporters of rat liver. J. Hepatol. (2001) 34:881-887.
  • JOHNSON DR, HABEEBU SS, KLAASSEN CD: Increase in bile flow and biliary excretion of glutathione-derived sulfhydryls in rats by drug-metabolizing enzyme inducers is mediated by multidrug resistance protein 2. Toxicol. Sci. (2002) 66:16-26.
  • KAUFFMANN HM, KEPPLER D, GANT TW, SCHRENK D: Induction of hepatic mrp2 (cMrp/cMOAT) gene expression in nonhuman primates treated with rifampicin or tamoxifen. Arch. Toxicol. (1998) 72:763-768.
  • GIESSMANN T, MODESS C, HECKERU etal.: CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects. Clin. Pharmacol. Ther. (2004) 75(3):213-222.
  • FROMM MF, KAUFFMANN HM, FRITZ P etal.: The effect of rifampin treatment on intestinal expression of human MRP transporters. Am. J. Pathol. (2000) 157(5):1575-1580.
  • TRAUNER M, ARRESE M, SOROKA CJ etal.: The rat canalicular conjugate export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis. Gastroenterology (1997) 113:255-264.
  • CAO J, HUANG L, LIU Y etal.: Differential regulation of hepatic bile salt and organic anion transporters in pregnant and postpartum rats and the role of prolactin. Hepatology (2001) 33:140-147.
  • KIPP H, ARIAS IM: Intracellular trafficking and regulation of canalicular ATP-binding cassette transporters. Semin. Liver Dis. (2000) 20:339-351.
  • BOYER JL, SOROKA CJ: Vesicle targeting to the apical domain regulates bile excretory function in isolated rat hepatocyte couplets. Gastroenterology (1995) 109:1600-1611.
  • GATMAITAN ZC, NIES AT, ARIAS IM: Regulation and translocation of ATP-dependent apical membrane proteins in rat liver. Am. J. Physiol. (1997) 272:G1041-G1049.
  • ROELOFSEN H, SOROKA CJ, KEPPLER D, BOYER JL: CAMP stimulates sorting of the canalicular organic anion transporter (Mrp2/cMoat) to the apical domain in hepatocyte couplets. J. Cell Sci. (1998) 111:1137-1145.
  • ROST D, KARTENBECK J, KEPPLER D: Changes in the localization of the rat canalicular conjugate export pump Mrp2 in phalloidin-induced cholestasis. Hepatology (1999) 29:814-821.
  • MOTTINO AD, CAO J, VEGGI LM, CROCENZI F, ROMA MG, VORE M: Altered localization and activity of canalicular multidrug resistance-associated protein 2 in estradiol-17-d-glucuronide-induced cholestasis. Hepatology (2002) 35:1409-1419.
  • KIKUCHI S, HATA M, FUKUMOTO K etal.: Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes. Nat. Genet. (2002) 31(3):320-325.
  • KOJIMA H, NIES AT, KNIG J etal.: Changes in the expression and localization of hepatocellular transporters and radixin in primary biliary cirrhosis. J. Hepatol. (2003) 39:693-702.
  • KARTENBECK J, LEUSCHNER U, MAYER R, KEPPLER D: Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in DubinJohnson syndrome. Hepatology (1996) 23:1061-1066.
  • MOR-COHEN R, ZIVELIN A, ROSENBERG N, SHANI M, MUALLEM, S SELIGSOHN U: Identification and functional analysis of two novel mutations in the multidrugresistance protein 2 gene in Israeli patients with DubinJohnson syndrome. J. Biol. Chem. (2001) 276:36923-36930.
  • TSUJII H, KNIG J, ROST D, STCKEL B,LEUSCHNER U, KEPPLERD: Exonintron organization of the human multidrug resistance protein 2 (MRP2) gene mutated in DubinJohnson syndrome. Gastroenterology (1999) 117:653-660.
  • WADA M, TOH S, TANIGUCHI K etal.: Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/DubinJohnson syndrome. Hum. Mol. Genet. (1998) 7:203-207.
  • ITO S, IEIRI I, TANABE M, SUZUKI A, HIGUCHI, S OTSUBO K: Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics (2001) 11:175-184.
  • GERK PM, VORE M: Regulation of expression of the multidrug resistance-associated protein 2 (MRP2) and its role in drug disposition. J. Pharmacol. Exp. Ther. (2002) 302:407-415.
  • AKITA H, SUZUKI H, ITO K etal.: Characterization of bile acid transport mediated by multidrug resistance associated protein 2 and bile salt export pump. Biochim. Biophys. Acta (2001) 1511:7-16.
  • BREEDVELD P, ZELCER N, PLUIM D etal.: Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res. (2004) 64(16):5804-5811.
  • GIESSMANN T, MAY K, MODESS C etal.: Carbamazepine regulates intestinal P-glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans. Clin. Pharmacol. Ther. (2004) 76(3):192-200.
  • POLGAR O, BATES SE: ABC transporters in the balance: is there a role in multidrug resistance? Biochem. Soc. Trans. (2005) 33(Pt 1):241-245.
  • NIES AT, KONIG J, PFANNSCHMIDTM, KLAR E, HOFMANN WJ, KEPPLER D: Expression of the multidrug resistance proteins MRP2 and MRP3 in human hepatocellular carcinoma. Int. J. Cancer (2001) 94(4):492-499.
  • SOINI Y, JARVINEN K, KAARTEENAHO-WIIK R, KINNULA V: The expression of P-glycoprotein and multidrug resistance proteins 1 and 2 (MRP1 and MRP2) in human malignant mesothelioma. Ann. Oncol. (2001) 12(9):1239-1245.
  • YOUNG LC, CAMPLING BG, COLE SP, DEELEY RG, GERLACH JH: Multidrug resistance proteins MRP3, MRP1, and MRP2 in lung cancer: correlation of protein levels with drug response and messenger RNA levels. Clin. Cancer Res. (2001) 7(6):1798-1804.
  • FANEYTE IF, KRISTEL PM, VAN DE VIJVER MJ: Multidrug resistance associated genes MRP1, MRP2 and MRP3 in primary and anthracycline exposed breast cancer. Anti-Cancer Res. (2004) 24(5A):2931-293.
  • TADA Y, WADA M, MIGITA T etal.: Increased expression of multidrug resistance-associated proteins in bladder cancer during clinical course and drug resistance to doxorubicin. Int. J. Cancer (2002) 98(4):630-635.
  • GEKELER V, ISE W, SANDERS KH, ULRICH WR, BECK J: The leukotriene LTD4 receptor antagonist MK-571 specifically modulates MRP associated multidrug resistance. Biochem. Biophys. Res. Commun. (1995) 208:345-352.
  • WANG EJ, JOHNSON WW: The farnesyl protein transferase inhibitor lonafarnib (SCH66336) is an inhibitor of multidrug resistance proteins 1 and 2. Chemotherapy (2003) 49(6):303-308.
  • LISCOVITCH M, LAVIE Y: Cancer multidrug resistance: a review of recent drug discovery research. Drugs (2002) 5(4):349-355.
  • TIAN Q, ZHANG J, CHAN E, DUAN W, ZHOU S: Multidrug resistance proteins (MRPs) and implication in drug development. Drug Dev. Res. (2005) 64(1):1-18.

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:

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:

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.