Aliases: Cmoat, cMRP, mrp
Gene name: ATP binding cassette subfamily C member 2 (Abcc2)
Rat Mrp2 (Abcc2) was cloned from rat liver in 1996 by Büchler et al , and it shares 88% similarity with human MRP2 at the protein level. Mrp2 is expressed at the apical membrane of polarized cells, with the highest expression in hepatocytes, proximal tubule cells, and enterocytes along the GI tract paralleling the pattern of phase II metabolic enzymes [2, 3]. Rat Mrp2 mRNA expression is reduced in the liver during cholestatic or ischemic-reperfusion events and endotoxemia, whereas only protein levels are decreasing during pregnancy [4, 5]. In most cases Mrp3 compensates for the loss of Mrp2 function in both human and rat (see MRP3/rMrp3 transporter pages), although it seems to be upregulated only when Mrp2 mRNA is altered . Downregulation and induction of Mrp2 seem to be species-specific [7, 8].
The TR- (transport-negative) and EHBR (Eisai hyperbilirubinemic) rat strains harbor mutations in the Abcc2 gene leading to premature termination codons [1, 2, 9], and thus offer natural animal models of Mrp2 deficiency. These rats display hyperbilirubinemia and defective canalicular transport of typical Mrp2 substrates. Both strains are used to model Dubin-Johnson Syndrome, as well as to explore Mrp2 function in comparison with wild-type rats [10, 11].
Like human MRP2, the rat ortholog also mediates the transport of glutathione, glucuronide and glutathione conjugates, sulfated bile salts and unconjugated organic anions [11, 12]. However, differences in the transport rate between human and rat Mrp2 were observed [13-18]. Such differences can lead to altered pharmacokinetic or toxicological profile of drugs. It is also worth noting that species differences occur not only between human and rat, but among preclinical species as well [19, 20], most likely because of the lower expression level of the protein in dog, rabbit and monkey liver compared to human, rat and mouse . Therefore, the prediction of drug safety from animal studies might not be appropriate without the consideration of differences in function and abundance of the protein across the species.
1. Buchler, M., et al., 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): p. 15091-8.
2. Paulusma, C.C., et al., Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science, 1996. 271(5252): p. 1126-8.
3. Mottino, A.D., et al., Expression and localization of multidrug resistant protein mrp2 in rat small intestine. J Pharmacol Exp Ther, 2000. 293(3): p. 717-23.
4. Jones, B.R., et al., The role of protein synthesis and degradation in the post-transcriptional regulation of rat multidrug resistance-associated protein 2 (Mrp2, Abcc2). Mol Pharmacol, 2005. 68(3): p. 701-10.
5. Tanaka, Y., et al., Ischemia-reperfusion of rat livers decreases liver and increases kidney multidrug resistance associated protein 2 (Mrp2). Toxicol Sci, 2008. 101(1): p. 171-8.
6. Cao, J., et al., Expression of rat hepatic multidrug resistance-associated proteins and organic anion transporters in pregnancy. Am J Physiol Gastrointest Liver Physiol, 2002. 283(3): p. G757-66.
7. Dietrich, C.G., et al., Consequences of bile duct obstruction on intestinal expression and function of multidrug resistance-associated protein 2. Gastroenterology, 2004. 126(4): p. 1044-53.
8. Schrenk, D., et al., Up-regulation of transporters of the MRP family by drugs and toxins. Toxicol Lett, 2001. 120(1-3): p. 51-7.
9. Ito, K., et al., Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR. Am J Physiol, 1997. 272(1 Pt 1): p. G16-22.
10. Konig, J.N., A. T.; Cui, Y.; and Keppler D., MRP2, an apical export pump for anionic conjugates, in ABC Proteins, from Bacteria to Man (Holland, B.; Cole, S.P.; Kuchler, K.; and Higgins, C. F. eds) 2003, Academic Press, London. p. 423–444.
11. Konig, J., et al., Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta, 1999. 1461(2): p. 377-94.
12. Suzuki, H. and Y. Sugiyama, Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/MRP2. Semin Liver Dis, 1998. 18(4): p. 359-76.
13. Erlinger, S., Bile flow, in The Liver: Biology and Pathobiology (Arias, I. M.; Jakoby, W. B.; Popper, H.; Schachter, D.; Shafritz D. A. eds) 1982, Raven Press Ltd., New York. p. 407–427.
14. Ishizuka, H., et al., Temocaprilat, a novel angiotensin-converting enzyme inhibitor, is excreted in bile via an ATP-dependent active transporter (cMOAT) that is deficient in Eisai hyperbilirubinemic mutant rats (EHBR). J Pharmacol Exp Ther, 1997. 280(3): p. 1304-11.
15. Jedlitschky, G., et al., ATP-dependent transport of bilirubin glucuronides by the multidrug resistance protein MRP1 and its hepatocyte canalicular isoform MRP2. Biochem J, 1997. 327 ( Pt 1): p. 305-10.
16. Niinuma, K., et al., Primary active transport of organic anions on bile canalicular membrane in humans. Am J Physiol, 1999. 276(5 Pt 1): p. G1153-64.
17. Choi, M.K., et al., Involvement of Mrp2/MRP2 in the species different excretion route of benzylpenicillin between rat and human. Xenobiotica, 2009. 39(2): p. 171-81.
18. Ellis, L.C., G.M. Hawksworth, and R.J. Weaver, ATP-dependent transport of statins by human and rat MRP2/Mrp2. Toxicol Appl Pharmacol, 2013. 269(2): p. 187-94.
19. Ishizuka, H., et al., Species differences in the transport activity for organic anions across the bile canalicular membrane. J Pharmacol Exp Ther, 1999. 290(3): p. 1324-30.
20. Ninomiya, M., K. Ito, and T. Horie, Functional analysis of dog multidrug resistance-associated protein 2 (Mrp2) in comparison with rat Mrp2. Drug Metab Dispos, 2005. 33(2): p. 225-32.