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MRP3

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MRP3 (Multidrug resistance-associated protein 3 / ABCC3)

ABCC3, more commonly referred as MRP3 (Multidrug resistance-associated protein 3) is an efflux transporter which plays a role in xenobiotic absorption, disposition and distribution, as well as in multidrug resistance. MRP3 was first identified in the liver at the sinusoidal membrane, where it was shown to transport xenobiotics from the liver into the blood [1].  MRP3 is thought to have an important physiological function in the protection of the body against xenobiotics ingested via food [2].

Localization

MRP3 transporter is highly expressed in the liver, at the basolateral membrane of both intrahepatic bile duct epithelial cells (cholangiocytes) and hepatocytes, as well as at the basolateral membrane of enterocytes [3, 4]. MRP3 mRNA is also found in adrenal glands, kidney, pancreas, placenta, and gallbladder, with lower expression in the lungs, spleen, stomach, brain, and tonsils [5]. In addition, MRP3 has been shown to be overexpressed in different tumors and in the liver under conditions that result in cholestasis [6, 7]. Caco-2 cells, a widely used cell-line derived from human colon adenocarcinoma cells, also express MRP3 transporter at the basolateral membrane [8].

Function, physiology and clinically significant polymorphisms

MRP3 transporter is a 170 kDa protein encoded by the ABCC3 gene (chromosome 17q21.3), and consists of 18 transmembrane domains [9]. MRP3 is involved in the physiological regulation of bile salt enterohepatic circulation, as well as in the disposition of phytoestrogens, a class of plant-derived compounds to which mammals are exposed via food [2].  Under cholestasitic conditions MRP3 expression is induced, suggesting that it functions in a backup detoxifying pathway in hepatocytes when the normal canalicular route is damaged and the function of the other hepatic MRPs (MRP1, MRP2) is impaired [10, 11]. The resistance capabilities of MRP3 are not as extensive as either MRP1 or MRP2, and the resistance spectrum of anticancer drugs is limited to methotrexate, vincristine, and epipodophyllotins, such as teniposide and etoposide [12].
Substrates of MRP3 include endogenous compounds (estradiol-17β-glucuronide, leukotriene C4, monovalent bile salts such as cholate and glycocholate), chemotherapeutic agents, and other drugs, such as acetaminophen glucuronide (paracetamol) and fexofenadine [13]. In contrast to MRP1 and MRP2, MRP3 has a higher affinity for glucuronate conjugates than for glutathione conjugates, and, unlike MRP1 and MRP2, MRP3 does not require glutathione to transport substrates [14].
Inhibitors of MRP3 include tenofovir, indometacin, furosemide, and probenecid, as well as non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, and nevirapine), and nucleoside reverse transcriptase inhibitors (emtricitabine and lamivudine). In in vitro studies, the highly potent and MRP specific inhibitor, MK571 is often used [15, 16].
Sasaki et al. performed a systematic screening for human ABCC3 polymorphisms and identified 61 genetic variants, including 17 novel polymorphisms, 7 of which were non-synonymous. However, the allelic frequencies of these mutations were very low (less than 4.8%) and showed high inter-ethnic variability. The authors also performed a pharmacokinetic study in 50 healthy individuals that showed no association between genetic variants in the promoter region and changes in the transport of 4-methylumbelliferone glucuronide (4-MUG, an MRP3 substrate) [17]. Furthermore, the A-189 allele of the AT regulatory polymorphism has been shown to be associated with poor treatment responses in childhood acute lymphoblastic leukemia [18]. In addition, another group conducted an in vitro study on the functional consequences of several non-synonymous polymorphisms and concluded that R1381S, S346F, and S607N may be risk factors for the acquisition of hepatotoxicity, due to the loss of functionality of these mutants in transfected cells [19].

Clinical significance

A patient’s genotype at the -189A>T regulatory polymorphism has been shown to be associated with survival outcomes in childhood acute lymphoblastic leukemia, with the A-189 genotype showing reduced survival. Carriers of this allele had higher plasma levels of methotrexate, and gene reporter assays indicated enhanced promoter activity for the A-189 allele, indicating increased efflux activity of MRP3 as the probable cause for reduced survival [18]. MRP3 tranporter has also been found to be amplified and overexpressed in HER2-positive breast cancer [7]. However, the involvement of MRP3 in multidrug resistance is very limited compared to MRP1 or MRP2. MRP3 transports bilirubin glucuronides into the blood under conditions of impaired biliary bilirubin excretion, therefore potential MRP3 inhibitors should be used carefully in the clinic. To date no clinically relevant drug-drug interactions involving MRP3 have been reported.

Regulatory Requirements

To date, neither the FDA nor the EMA specifically recommend the study of MRP3. However the FDA guidance from 2012 states that other transporters (in addition to the 7 FDA recommended transporters) “may need to be studied based on knowledge of other drugs in the same therapeutic class as the investigational new drug.”

Location
Endogenous substrates
Substrates used experimentally
Substrate drugs
Inhibitors
Cholangiocytes, hepatocytes, enterocytes, adrenal glands, kidney, small intestine, colon, pancreas, placenta, gallbladder, lungs, spleen, stomach, brain, tonsils
bile salts, Estradiol-17β-glucuronide, leukotriene C4
Estradiol-17β-glucuronide, fexofenadine, methotrexate, vincristine, teniposide, etoposide
fexofenadine, methotrexate, vincristine, teniposide, etoposide, acetaminophen glucuronide
delavirdine, efavirenz, nevirapine, emtricitabine, lamivudine, tenofovir, indometacin, furosemide, probenecid, MK751

References

  1. Borst, P., et al., A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst., 2000. 92(16): p. 1295-302.
  2. van de Wetering, K., et al., Targeted metabolomics identifies glucuronides of dietary phytoestrogens as a major class of MRP3 substrates in vivo. Gastroenterology., 2009. 137(5): p. 1725-35. Epub 2009 Jul 3.
  3. Ortiz, D.F., et al., MRP3, a new ATP-binding cassette protein localized to the canalicular domain of the hepatocyte. Am J Physiol., 1999. 276(6 Pt 1): p. G1493-500.
  4. van de Wetering, K., et al., Intestinal breast cancer resistance protein (BCRP)/Bcrp1 and multidrug resistance protein 3 (MRP3)/Mrp3 are involved in the pharmacokinetics of resveratrol. Mol Pharmacol., 2009. 75(4): p. 876-85. Epub 2008 Dec 29.
  5. Scheffer, G.L., et al., Tissue distribution and induction of human multidrug resistant protein 3. Lab Invest., 2002. 82(2): p. 193-201.
  6. Rau, S., et al., Expression of the multidrug resistance proteins MRP2 and MRP3 in human cholangiocellular carcinomas. Eur J Clin Invest., 2008. 38(2): p. 134-42.
  7. Partanen, L., et al., Amplification and overexpression of the ABCC3 (MRP3) gene in primary breast cancer. Genes Chromosomes Cancer., 2012. 51(9): p. 832-40. doi: 10.1002/gcc.21967. Epub 2012 May 14.
  8. Hirohashi, T., et al., Function and expression of multidrug resistance-associated protein family in human colon adenocarcinoma cells (Caco-2). J Pharmacol Exp Ther., 2000. 292(1): p. 265-70.
  9. Van Aubel, R.A., R. Masereeuw, and F.G. Russel, Molecular pharmacology of renal organic anion transporters. Am J Physiol Renal Physiol., 2000. 279(2): p. F216-32.
  10. Kullak-Ublick, G.A., B. Stieger, and P.J. Meier, Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology., 2004. 126(1): p. 322-42.
  11. Zollner, G., et al., Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol., 2003. 38(6): p. 717-27.
  12. Kool, M., et al., MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci U S A., 1999. 96(12): p. 6914-9.
  13. Zhou, S.F., et al., Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr Med Chem., 2008. 15(20): p. 1981-2039.
  14. Zelcer, N., et al., Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem., 2001. 276(49): p. 46400-7.
  15. Weiss, J., et al., Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors. Drug Metab Dispos., 2007. 35(3): p. 340-4. Epub 2006 Dec 15.
  16. Bodo, A., et al., Differential modulation of the human liver conjugate transporters MRP2 and MRP3 by bile acids and organic anions. J Biol Chem., 2003. 278(26): p. 23529-37. Epub 2003 Apr 19.
  17. Sasaki, T., et al., Systematic screening of human ABCC3 polymorphisms and their effects on MRP3 expression and function. Drug Metab Pharmacokinet., 2011. 26(4): p. 374-86. Epub 2011 Apr 22.
  18. Ansari, M., et al., Polymorphism in multidrug resistance-associated protein gene 3 is associated with outcomes in childhood acute lymphoblastic leukemia. Pharmacogenomics J., 2012. 12(5): p. 386-94. doi: 10.1038/tpj.2011.17. Epub 2011 May 24.
  19. Kobayashi, K., et al., Functional analysis of nonsynonymous single nucleotide polymorphism type ATP-binding cassette transmembrane transporter subfamily C member 3. Pharmacogenet Genomics., 2008. 18(9): p. 823-33.

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