The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia

Drug Metabolism and Disposition

Volumn 42, Issue 4, 2014, Pages 561-565

  Keppler, Dietrich ^a  

^a GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ABC TRANSPORTER; BILIRUBIN; BILIRUBIN GLUCURONIDE; GLUCURONIC ACID; GLUCURONOSYLTRANSFERASE 1A1; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 2; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 3; ORGANIC ANION TRANSPORTER F; SOLUTE CARRIER ORGANIC ANION TRANSPORTER 1B1; SOLUTE CARRIER ORGANIC ANION TRANSPORTER 1B3;

ANION TRANSPORT; BASOLATERAL MEMBRANE; BILE; BILIRUBIN BINDING; BILIRUBIN BLOOD LEVEL; CONJUGATED HYPERBILIRUBINEMIA; DETOXIFICATION; DUBIN JOHNSON SYNDROME; GLUCURONIDATION; HUMAN; HYPERBILIRUBINEMIA; INTESTINE EPITHELIUM CELL; INTRAHEPATIC BILE DUCT; LIVER CELL; LIVER SINUSOID; MOLECULAR PATHOLOGY; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; ROTOR SYNDROME; SHORT SURVEY; UPREGULATION; URINARY EXCRETION;

ANIMALS; BILE; BILIRUBIN; BIOLOGICAL TRANSPORT; HEPATOCYTES; HUMANS; HYPERBILIRUBINEMIA, HEREDITARY; JAUNDICE, CHRONIC IDIOPATHIC; MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS; ORGANIC ANION TRANSPORTERS; ORGANIC ANION TRANSPORTERS, SODIUM-INDEPENDENT;

EID: 84896104969     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.113.055772     Document Type: Short Survey

References (59)

1. Arias IM, Johnson L, and Wolfson S (1961) Biliary excretion of injected conjugated and unconjugated bilirubin by normal and Gunn rats. Am J Physiol 200:1091-1094.
2. Bar-Meir S, Baron J, Seligson U, Gottesfeld F, Levy R, and Gilat T (1982) 99mTc-HIDA cholescintigraphy in Dubin-Johnson and Rotor syndromes. Radiology 142:743-746. (Pubitemid 12180963)
3. Borst P, de Wolf C, and van de Wetering K (2007) Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch 453:661-673. (Pubitemid 46192537)
4. Briz O, Serrano MA, MacIas RI, Gonzalez-Gallego J, and Marin JJ (2003) Role of organic anion-transporting polypeptides, OATP-A, OATP-C and OATP-8, in the human placenta-maternal liver tandem excretory pathway for foetal bilirubin. Biochem J 371:897-905. (Pubitemid 36578888)
5. Bronger H, König J, Kopplow K, Steiner HH, Ahmadi R, Herold-Mende C, Keppler D, and Nies AT (2005) ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier. Cancer Res 65:11419-11428. (Pubitemid 41821699)
6. Campbell SD, de Morais SM, and Xu JJ (2004) Inhibition of human organic anion transporting polypeptide OATP 1B1 as a mechanism of drug-induced hyperbilirubinemia. Chem Biol Interact 150:179-187. (Pubitemid 39463281)
7. Chowdhury JR, Wolkoff AW, Chowdhury NR, and Arias IM (2001) Hereditary jaundice and disorders of bilirubin metabolism, in The Metabolic & Molecular Bases of Inherited Disease, Ed. 8th (Scriver CR, Sly WS, Childs B, Beaudet AL, Valle D, Kinzler KW, and Vogelstein B, eds) pp 3063-3101, McGraw-Hill, New York.
8. Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AMV, and Deeley RG (1992) Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258:1650-1654. (Pubitemid 23012438)
9. Cui Y, König J, Buchholz JK, Spring H, Leier I, and 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. (Pubitemid 29214613)
10. Cui Y, König J, and Keppler D (2001a) Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2. Mol Pharmacol 60:934-943. (Pubitemid 33027428)
11. Cui Y, König J, Leier I, Buchholz U, and Keppler D (2001b) Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J Biol Chem 276:9626-9630.
12. de Waart DR, Häusler S, Vlaming ML, Kunne C, Hänggi E, Gruss HJ, Oude Elferink RP, and Stieger B (2010) Hepatic transport mechanisms of cholyl-L-lysyl-fluorescein. J Pharmacol Exp Ther 334:78-86.
13. Donner MG and Keppler D (2001) Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver. Hepatology 34:351-359. (Pubitemid 32702348)
14. Evers R, de Haas M, Sparidans R, Beijnen J, Wielinga PR, Lankelma J, and Borst P (2000) Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export. Br J Cancer 83:375-383. (Pubitemid 30453579)
15. Evers R, Kool M, van Deemter L, Janssen H, Calafat J, Oomen LC, Paulusma CC, Oude Elferink RP, Baas F, and Schinkel AH, 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. (Pubitemid 28166828)
16. Fujiwara R, Chen S, Karin M, and Tukey RH (2012) Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-κB leads to hyperbilirubinemia. Gastroenterology 142:109-118.e2.
17. Jansen PL, Peters WH, and Lamers WH (1985) Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport. Hepatology 5:573-579. (Pubitemid 15029725)
18. Jirsa M, Knisely AS, Schinkel A, and Kmoch S (2012) Rotor syndrome, in GeneReviews (Pagon RA, Adam MP, and Bird TD, et al., eds) pp 1993-2013, University of Washington, Seattle.
19. Jedlitschky G, Leier I, Buchholz U, Center M, and Keppler D (1994) ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Res 54: 4833-4836. (Pubitemid 24289409)
20. Johnson AD, Kavousi M, Smith AV, Chen MH, Dehghan A, Aspelund T, Lin JP, van Duijn CM, Harris TB, and Cupples LA, et al. (2009) Genome-wide association meta-analysis for total serum bilirubin levels. Hum Mol Genet 18:2700-2710.
21. Kamisako T, Leier I, Cui Y, König J, Buchholz U, Hummel-Eisenbeiss J, and Keppler D (1999) Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2. Hepatology 30:485-490. (Pubitemid 29357515)
22. Kartenbeck J, Leuschner U, Mayer R, and Keppler D (1996) Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome. Hepatology 23:1061-1066.
23. Keitel V, Kartenbeck J, Nies AT, Spring H, Brom M, and 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.
24. Keppler D (2011a) Multidrug resistance proteins (MRPs, ABCCs): importance for pathophysiology and drug therapy. Handbook Exp Pharmacol 201:299-323.
25. Keppler D (2011b) Cholestasis and the role of basolateral efflux pumps. Z Gastroenterol 49: 1553-1557.
26. Keppler D (2012) MRP2 (ABCC2) and disorders of bilirubin handling in liver, in Hepatobiliary Transport in Health and Disease (Häussinger D, Keitel V, and Kubitz R eds) pp 171-182, De Gruyter, Berlin.
27. Keppler D and Kartenbeck J (1996) The canalicular conjugate export pump encoded by the cmrp/ cmoat gene. Prog Liver Dis 14:55-67. (Pubitemid 26381335)
28. König J, Cui Y, Nies AT, and Keppler D (2000a) A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol 278:G156-G164. (Pubitemid 30108080)
29. König J, Cui Y, Nies AT, and Keppler D (2000b) Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem 275:23161-23168. (Pubitemid 30646210)
30. König J, Rost D, Cui Y, and Keppler D (1999) Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatology 29:1156-1163. (Pubitemid 29168750)
31. Kool M, van der Linden M, de Haas M, Scheffer GL, de Vree JM, Smith AJ, Jansen G, Peters GJ, Ponne N, and Scheper RJ, et al. (1999) MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci USA 96:6914-6919. (Pubitemid 29274984)
32. Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, Fattinger K, Meier PJ, and Hagenbuch B (2001) Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 120: 525 - 533.
33. Lee YM, Cui Y, König J, Risch A, Jäger B, Drings P, Bartsch H, Keppler D, and Nies AT (2004) Identification and functional characterization of the natural variant MRP3-Arg1297His of human multidrug resistance protein 3 (MRP3/ABCC3). Pharmacogenetics 14:213-223. (Pubitemid 38530513)
34. Leier I, Jedlitschky G, Buchholz U, Cole SPC, Deeley RG, and Keppler D (1994) The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. J Biol Chem 269:27807-27810. (Pubitemid 24354499)
35. McDonagh AF (2010) Controversies in bilirubin biochemistry and their clinical relevance. Semin Fetal Neonatal Med 15:141-147.
36. Mor-Cohen R, Zivelin A, Rosenberg N, Shani M, Muallem S, and 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.
37. Muraca M and Blanckaert N (1983) Liquid-chromatographic assay and identification of monoand diester conjugates of bilirubin in normal serum. Clin Chem 29:1767-1771. (Pubitemid 13017237)
38. Nies AT, Cantz T, Brom M, Leier I, and Keppler D (1998) Expression of the apical conjugate export pump, Mrp2, in the polarized hepatoma cell line, WIF-B. Hepatology 28:1332-1340. (Pubitemid 28493845)
39. Nies AT and Keppler D (2007) The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Arch 453:643-659. (Pubitemid 46192536)
40. Ogawa K, Suzuki H, Hirohashi T, Ishikawa T, Meier PJ, Hirose K, Akizawa T, Yoshioka M, and Sugiyama Y (2000) Characterization of inducible nature of MRP3 in rat liver. Am J Physiol Gastrointest Liver Physiol 278:G438-G446. (Pubitemid 30152490)
41. Paulusma CC, Kool M, Bosma PJ, Scheffer GL, ter Borg F, Scheper RJ, Tytgat GN, Borst P, Baas F, and Oude Elferink RP (1997) A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. Hepatology 25:1539-1542. (Pubitemid 27250780)
42. Pedersen JM, Matsson P, Bergström CA, Norinder U, Hoogstraate J, and 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. (Pubitemid 351821886)
43. Rius M, Hummel-Eisenbeiss J, Hofmann AF, and Keppler D (2006) Substrate specificity of human ABCC4 (MRP4)-mediated cotransport of bile acids and reduced glutathione. Am J Physiol Gastrointest Liver Physiol 290:G640-G649.
44. Rost D, Mahner S, Sugiyama Y, and Stremmel W (2002) Expression and localization of the multidrug resistance-associated protein 3 in rat small and large intestine. Am J Physiol Gastrointest Liver Physiol 282:G720-G726. (Pubitemid 34651651)
45. Rotor AB, Manahan L, and Florentin A (1948) Familial non-hemolytic jaundice with direct van den Bergh reaction. Acta Med Philipp 5:37-49.
46. Sanna S, Busonero F, Maschio A, McArdle PF, Usala G, Dei M, Lai S, Mulas A, Piras MG, and Perseu L, et al. (2009) Common variants in the SLCO1B3 locus are associated with bilirubin levels and unconjugated hyperbilirubinemia. Hum Mol Genet 18:2711-2718.
47. Scheffer GL, Kool M, de Haas M, de Vree JM, Pijnenborg AC, Bosman DK, Elferink RP, van der Valk P, Borst P, and Scheper RJ (2002) Tissue distribution and induction of human multidrug resistant protein 3. Lab Invest 82:193-201. (Pubitemid 34160456)
48. Schmid R and Hammaker L (1963) Metabolism and disposition of C14-bilirubin in congenital nonhemolytic jaundice. J Clin Invest 42:1720-1734.
49. Soroka CJ, Lee JM, Azzaroli F, and Boyer JL (2001) Cellular localization and up-regulation of multidrug resistance-associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver. Hepatology 33:783-791. (Pubitemid 32246625)
50. Toh S, Wada M, Uchiumi T, Inokuchi A, Makino Y, Horie Y, Adachi Y, Sakisaka S, and Kuwano M (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. (Pubitemid 30460416)
51. Tsujii H, König J, Rost D, Stöckel B, Leuschner U, and Keppler D (1999) Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome. Gastroenterology 117:653-660. (Pubitemid 29409252)
52. Tukey RH and Strassburg CP (2000) Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 40:581-616. (Pubitemid 30340694)
53. van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Hřebíček M, Wagenaar E, van Esch A, de Waart DR, Oude Elferink RP, and Kenworthy KE, et al. (2012) Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 122:519-528.
54. van de Steeg E, van Esch A, Wagenaar E, Kenworthy KE, and Schinkel AH (2013) Influence of human OATP1B1, OATP1B3, and OATP1A2 on the pharmacokinetics of methotrexate and paclitaxel in humanized transgenic mice. Clin Cancer Res 19:821-832.
55. van de Steeg E, Wagenaar E, van der Kruijssen CM, Burggraaff JE, de Waart DR, Elferink RP, Kenworthy KE, and Schinkel AH (2010) Organic anion transporting polypeptide 1a/1b-knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs. J Clin Invest 120:2942-2952.
56. Wang P, Kim RB, Chowdhury JR, and Wolkoff AW (2003) The human organic anion transport protein SLC21A6 is not sufficient for bilirubin transport. J Biol Chem 278:20695-20699. (Pubitemid 36806371)
57. Wolpert E, Pascasio FM, Wolkoff AW, and Arias IM (1977) Abnormal sulfobromophthalein metabolism in Rotor's syndrome and obligate heterozygotes. N Engl J Med 296:1099-1101. (Pubitemid 8091589)
58. Zeng H, Liu G, Rea PA, and Kruh GD (2000) Transport of amphipathic anions by human multidrug resistance protein 3. Cancer Res 60:4779-4784.
59. Zhang W, He YJ, Gan Z, Fan L, Li Q, Wang A, Liu ZQ, Deng S, Huang YF, and Xu LY, et al. (2007) OATP1B1 polymorphism is a major determinant of serum bilirubin level but not associated with rifampicin-mediated bilirubin elevation. Clin Exp Pharmacol Physiol 34:1240-1244. (Pubitemid 350013247)