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 ABCC2gene.[5][6][7]
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.
Several different mutations in this gene have been observed in patients with Dubin–Johnson syndrome (DJS), an autosomal recessive disorder characterized by conjugated hyperbilirubinemia.[7][14]
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.[15]Tenofovir[16] and cidofovir[17] are also nucleoside phosphonates that inhibit MRP2 and have been associated with Fanconi syndrome.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
^van Kuijck MA, Kool M, Merkx GF, Geurts van Kessel A, Bindels RJ, Deen PM, van Os CH (Sep 1997). "Assignment of the canalicular multispecific organic anion transporter gene (CMOAT) to human chromosome 10q24 and mouse chromosome 19D2 by fluorescent in situ hybridization". Cytogenet Cell Genet. 77 (3–4): 285–7. doi:10.1159/000134599. PMID9284939. S2CID46739365.
^Sekine T, Miyazaki H, Endou H (February 2006). "Molecular physiology of renal organic anion transporters". Am. J. Physiol. Renal Physiol. 290 (2): F251–61. doi:10.1152/ajprenal.00439.2004. PMID16403838.
^ abBakos E, Evers R, Sinkó E, Váradi A, Borst P, Sarkadi B (April 2000). "Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions". Mol. Pharmacol.57 (4): 760–8. doi:10.1124/mol.57.4.760. PMID10727523.
^ abcdefgWeiss J, Theile D, Ketabi-Kiyanvash N, Lindenmaier H, Haefeli WE (March 2007). "Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors". Drug Metab. Dispos.35 (3): 340–4. doi:10.1124/dmd.106.012765. PMID17172311. S2CID46141353.
Gerk PM, 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 (2): 407–15. doi:10.1124/jpet.102.035014. PMID12130697. S2CID873234.
Tsujii H, König J, Rost D, et al. (1999). "Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome". Gastroenterology. 117 (3): 653–60. doi:10.1016/S0016-5085(99)70459-2. PMID10464142.
Kocher O, Comella N, Gilchrist A, et al. (1999). "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. PMID10496535.
St-Pierre MV, Serrano MA, Macias RI, et al. (2000). "Expression of members of the multidrug resistance protein family in human term placenta". Am. J. Physiol. Regul. Integr. Comp. Physiol. 279 (4): R1495–503. doi:10.1152/ajpregu.2000.279.4.R1495. PMID11004020. S2CID36043361.
Ito S, Ieiri I, Tanabe M, et al. (2001). "Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects". Pharmacogenetics. 11 (2): 175–84. doi:10.1097/00008571-200103000-00008. PMID11266082.
Mallants R, Van Oosterwyck K, Van Vaeck L, Mols R, De Clercq E, Augustijns P (2005). "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. doi:10.1080/00498250500354493. PMID16393861. S2CID6888528.