Multidrug resistance-associated protein 2 explained
Multidrug resistance-associated protein 2 (MRP2) also called canalicular multispecific organic anion transporter 1 (cMOAT) or ATP-binding cassette sub-family C member 2 (ABCC2) is a protein that in humans is encoded by the ABCC2 gene.
Function
MRP2 is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). More specifically, this protein is a member of the MRP subfamily, which is involved in multi-drug resistance. This protein is expressed in the canalicular (apical) part of the hepatocyte and functions in biliary transport. Substrates include anticancer drugs such as vinblastine; therefore, this protein appears to contribute to drug resistance in mammalian cells.
MRP2 is also expressed in the apical membrane of proximal renal tubule endothelial cells where they are involved in the excretion of small organic anions.[1]
MRP2 inhibitors
Clinical significance
Dubin–Johnson syndrome
Several different mutations in this gene have been observed in patients with Dubin–Johnson syndrome (DJS), an autosomal recessive disorder characterized by conjugated hyperbilirubinemia.[2]
Iatrogenic Fanconi syndrome
Many negatively charged metabolic waste products are eliminated from the body by the kidneys. These organic anions are transported from the blood into the endothelial cells of the renal proximal tubules by the OAT1 transporter. From there, these waste molecules are transported into the lumen of the tubule by the MRP2 transporter. Many drugs are eliminated from the body by this mechanism. Some of these drugs pass through the MRP2 transporter slowly. This may cause a buildup of organic anions in the cytoplasm of the cells.
Drugs that inhibit the MRP2 transporter can cause a buildup of organic anions inside renal proximal tubule cells. If some of these organic anions inhibit mitochondrial DNA synthesis, it may cause iatrogenic Fanconi syndrome. The nucleoside phosphonate adefovir is a MRP2 inhibitor that has been linked to kidney disease. Tenofovir and cidofovir are also nucleoside phosphonates that inhibit MRP2 and have been associated with Fanconi syndrome.
See also
Further reading
- Keppler D, König J . Hepatic secretion of conjugated drugs and endogenous substances. . Semin. Liver Dis. . 20 . 3 . 265–72 . 2001 . 11076395 . 10.1055/s-2000-9391 . 25626705 .
- 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. . 302 . 2 . 407–15 . 2002 . 12130697 . 10.1124/jpet.102.035014 . 873234 .
- Mayer R, Kartenbeck J, Büchler M, etal . 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 . 1 . 137–50 . 1995 . 7559771 . 10.1083/jcb.131.1.137 . 2120605 .
- Büchler M, König 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. . 271 . 25 . 15091–8 . 1996 . 8662992 . 10.1074/jbc.271.25.15091 . free .
- Paulusma CC, Kool M, Bosma PJ, etal . A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. . Hepatology . 25 . 6 . 1539–42 . 1997 . 9185779 . 10.1002/hep.510250635 . 22635775 . free .
- Wada M, Toh S, Taniguchi K, etal . Mutations in the canilicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome. . Hum. Mol. Genet. . 7 . 2 . 203–7 . 1998 . 9425227 . 10.1093/hmg/7.2.203 . free .
- Evers R, Kool M, van Deemter L, etal . Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA. . J. Clin. Invest. . 101 . 7 . 1310–9 . 1998 . 9525973 . 10.1172/JCI119886 . 508708 .
- Kajihara S, Hisatomi A, Mizuta T, etal . A splice mutation in the human canalicular multispecific organic anion transporter gene causes Dubin-Johnson syndrome. . Biochem. Biophys. Res. Commun. . 253 . 2 . 454–7 . 1999 . 9878557 . 10.1006/bbrc.1998.9780 .
- Toh S, Wada M, Uchiumi T, etal . 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 . 3 . 739–46 . 1999 . 10053008 . 10.1086/302292 . 1377791 .
- Schaub TP, Kartenbeck J, König J, etal . Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma. . J. Am. Soc. Nephrol. . 10 . 6 . 1159–69 . 1999 . 10.1681/ASN.V1061159 . 10361853 . free .
- Tsujii H, König J, Rost D, etal . Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome. . Gastroenterology . 117 . 3 . 653–60 . 1999 . 10464142 . 10.1016/S0016-5085(99)70459-2 .
- Kocher O, Comella N, Gilchrist A, etal . PDZK1, a novel PDZ domain-containing protein up-regulated in carcinomas and mapped to chromosome 1q21, interacts with cMOAT (MRP2), the multidrug resistance-associated protein. . Lab. Invest. . 79 . 9 . 1161–70 . 1999 . 10496535 .
- Tanaka T, Uchiumi T, Hinoshita E, etal . The human multidrug resistance protein 2 gene: functional characterization of the 5'-flanking region and expression in hepatic cells. . Hepatology . 30 . 6 . 1507–12 . 1999 . 10573531 . 10.1002/hep.510300617 . 22514353 . free .
- 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. . 279 . 4 . R1495–503 . 2000 . 11004020 . 10.1152/ajpregu.2000.279.4.R1495. 36043361 .
- Keitel V, Kartenbeck J, Nies AT, etal . 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 . 6 . 1317–28 . 2001 . 11093739 . 10.1053/jhep.2000.19791 . 20920288 . free .
- Ito S, Ieiri I, Tanabe M, etal . Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. . Pharmacogenetics . 11 . 2 . 175–84 . 2001 . 11266082 . 10.1097/00008571-200103000-00008 .
- Mor-Cohen R, Zivelin A, Rosenberg N, etal . 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 . 40 . 36923–30 . 2001 . 11477083 . 10.1074/jbc.M105047200 . free .
- Mallants R, Van Oosterwyck K, Van Vaeck L, Mols R, De Clercq E, Augustijns P . Multidrug resistance-associated protein 2 (MRP2) affects hepatobiliary elimination but not the intestinal disposition of tenofovir disoproxil fumarate and its metabolites. Xenobiotica. 35. 10–11. 1055–66. 2005. 16393861. 10.1080/00498250500354493 . 6888528.
Notes and References
- Sekine T, Miyazaki H, Endou H . Molecular physiology of renal organic anion transporters . Am. J. Physiol. Renal Physiol. . 290 . 2 . F251–61 . February 2006 . 16403838 . 10.1152/ajprenal.00439.2004 .
- Morii. Kazuhiko. Yamamoto. Takeharu. 2016-07-06. Dubin–Johnson Syndrome. New England Journal of Medicine. EN. 375. 1. 10.1056/nejmicm1509529. e1. 27406372.