Preclinical/Animal Transporters

Mrp3 - rat

Mrp3 (multidrug resistance-associated protein 3) mouse and rat

Aliases: Mlp2Gene name: ATP binding cassette subfamily C member 3
Rat and mous

e Mrp3 share 88% and 89% similarity with human MRP3 at the protein level, respectively. Mrp3 is localized at the basolateral site of renal tubule cells, enterocytes, cholangiocytes and hepatocytes [1, 2]. Although basal expression of rat Mrp3 is low in the liver, it is induced in cholestatic conditions [3], Mrp2 deficiency [4, 5], and by certain drugs and microsomal enzyme inducers [6-10]. It is interesting to note, however, that levels of Mrp2 and Mrp3 are not always inversely correlated, as physiological Mrp2 deficiency in pregnant rats or downregulation of Mrp2 in obese Zucker rats do not cause upregulation of Mrp3 [11, 12]. Unlike in rat liver, Mrp3 has a constitutively high expression in mouse hepatocytes [13] which can be further induced with chemicals [14] but not by Mrp2 deficiency [15]. Within the kidney, MRP3 can be found in different cell types in humans versus rats. While rat Mrp3 is expressed in both the proximal and distal tubules [2], human MRP3 protein was identified in the distal tubule cells only [16]. The exact localization of mouse Mrp3 in the kidney was not investigated. There is also a difference between the expression of rodent and human Mrp3 in certain regions of the intestine, as human MRP3 has an overall high expression, with decreasing levels from proximal to distal regions, while rodent Mrp3 has the highest RNA and protein levels in the colon [17]. Beside drug induction in the liver, folate deprivation for 8 weeks led to increased Mrp3 expression in the mouse small intestine [18]. Interestingly, and in contrast with the changes in the liver, Mrp3 expression in the small intestine of Mrp2-deficient rats significantly decreased compared to wild-type [5].
Mrp3 transports organic anions such as bile acids, sulfate, glutathione and glucuronide conjugates, as well as anionic drugs [19-21]. Abcc3-/- mice were generated for testing the in vivo significance of the protein [13, 22]. Pharmacokinetic properties of morphine-glucuronides [23], ezetimibe-glucuronide[24], methotrexate [25], and sulfated drugs [26] were shown to be altered in KO mice. These results confirm that Mrp3 has a role in sinusoidal elimination of its substrates for urinary excretion, and in “hepatocyte hopping” when biliary transport is blocked and toxic substances are shifted towards downstream hepatocytes [27].
Beside the partially different localization or expression levels of human and rodent Mrp3, functional differences were not reported among species.

References

1.    Rost, D., et al., Expression and localization of the multidrug resistance-associated protein 3 in rat small and large intestine. Am J Physiol Gastrointest Liver Physiol, 2002. 282(4): p. G720-6.
2.    Kuroda, M., et al., Increased hepatic and renal expressions of multidrug resistance-associated protein 3 in Eisai hyperbilirubinuria rats. J Gastroenterol Hepatol, 2004. 19(2): p. 146-53.
3.    Donner, M.G. and D. Keppler, Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver. Hepatology, 2001. 34(2): p. 351-9.
4.    Hirohashi, T., et al., Hepatic expression of multidrug resistance-associated protein-like proteins maintained in eisai hyperbilirubinemic rats. Mol Pharmacol, 1998. 53(6): p. 1068-75.
5.    Johnson, B.M., et al., Characterization of transport protein expression in multidrug resistance-associated protein (Mrp) 2-deficient rats. Drug Metab Dispos, 2006. 34(4): p. 556-62.
6.    Ogawa, K., et al., Characterization of inducible nature of MRP3 in rat liver. Am J Physiol Gastrointest Liver Physiol, 2000. 278(3): p. G438-46.
7.    Cherrington, N.J., et al., 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): p. 97-104.
8.    Kamisako, T. and H. Ogawa, Alteration of the expression of adenosine triphosphate-binding cassette transporters associated with bile acid and cholesterol transport in the rat liver and intestine during cholestasis. J Gastroenterol Hepatol, 2005. 20(9): p. 1429-34.
9.    Ruiz, M.L., et al., Ethynylestradiol increases expression and activity of rat liver MRP3. Drug Metab Dispos, 2006. 34(6): p. 1030-4.
10.    Slitt, A.L., et al., Induction of multidrug resistance protein 3 in rat liver is associated with altered vectorial excretion of acetaminophen metabolites. Drug Metab Dispos, 2003. 31(9): p. 1176-86.
11.    Accatino, L., et al., Bile secretory function after warm hepatic ischemia-reperfusion injury in the rat. Liver Transpl, 2003. 9(11): p. 1199-210.
12.    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.
13.    Zelcer, N., et al., Mice lacking Mrp3 (Abcc3) have normal bile salt transport, but altered hepatic transport of endogenous glucuronides. J Hepatol, 2006. 44(4): p. 768-75.
14.    Maher, J.M., et al., Induction of the multidrug resistance-associated protein family of transporters by chemical activators of receptor-mediated pathways in mouse liver. Drug Metab Dispos, 2005. 33(7): p. 956-62.
15.    Chu, X.Y., et al., Characterization of mice lacking the multidrug resistance protein MRP2 (ABCC2). J Pharmacol Exp Ther, 2006. 317(2): p. 579-89.
16.    Scheffer, G.L., et al., Tissue distribution and induction of human multidrug resistant protein 3. Lab Invest, 2002. 82(2): p. 193-201.
17.    Peters, S.A., et al., Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models. Clin Pharmacokinet, 2016. 55(6): p. 673-96.
18.    Liu, M., et al., Structure and regulation of the murine reduced folate carrier gene: identification of four noncoding exons and promoters and regulation by dietary folates. J Biol Chem, 2005. 280(7): p. 5588-97.
19.    Akita, H., H. Suzuki, and Y. Sugiyama, Sinusoidal efflux of taurocholate correlates with the hepatic expression level of Mrp3. Biochem Biophys Res Commun, 2002. 299(5): p. 681-7.
20.    Hirohashi, T., H. Suzuki, and Y. Sugiyama, Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (MRP3). J Biol Chem, 1999. 274(21): p. 15181-5.
21.    Hirohashi, T., et al., ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 (Mrp3). J Biol Chem, 2000. 275(4): p. 2905-10.
22.    Belinsky, M.G., et al., Analysis of the in vivo functions of Mrp3. Mol Pharmacol, 2005. 68(1): p. 160-8.
23.    Zelcer, N., et al., Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Proc Natl Acad Sci U S A, 2005. 102(20): p. 7274-9.
24.    de Waart, D.R., et al., Complex pharmacokinetic behavior of ezetimibe depends on abcc2, abcc3, and abcg2. Drug Metab Dispos, 2009. 37(8): p. 1698-702.
25.    Kitamura, Y., et al., Increasing systemic exposure of methotrexate by active efflux mediated by multidrug resistance-associated protein 3 (mrp3/abcc3). J Pharmacol Exp Ther, 2008. 327(2): p. 465-73.
26.    Zamek-Gliszczynski, M.J., et al., Evaluation of the role of multidrug resistance-associated protein (Mrp) 3 and Mrp4 in hepatic basolateral excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in Abcc3-/- and Abcc4-/- mice. J Pharmacol Exp Ther, 2006. 319(3): p. 1485-91.
27.    Iusuf, D., E. van de Steeg, and A.H. Schinkel, Hepatocyte hopping of OATP1B substrates contributes to efficient hepatic detoxification. Clin Pharmacol Ther, 2012. 92(5): p. 559-62.

 

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