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MRP2

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MRP2 Transporter (ATP Binding Cassette Protein C2/ABCC2)

MRP2 transporter plays an important role in drug disposition and distribution, particularly of organic anions and drug metabolites such as glucuronides.  MRP2 is an efflux transporter that aides in biliary excretion and renal excretion of drugs and also prevents xenobiotics from penetrating / accumulating in tissues such as lungs and from crossing the placenta.  Drugs that are substrates of MRP2 have the potential of being victims to drug drug interactions (DDI) in cases where this transporter is inhibited.  Current FDA and EMA recommendations do not include MRP2.

Localization:

MRP2 is localized to the apical membrane domain of polarized cells such as hepatocytes, renal proximal tubule and intestinal epithelia.  MRP2 is also present in the gallbladder, bronchi, and placenta. 
In contrast to efflux transporters like MDR1 and BCRP, MRP2 has not been identified in the human blood–testis barrier or in the blood–brain barrier in the human cortex. It is however, present in brain capillaries of hippocampus specimens from patients with temporal lobe epilepsy and malignant tumors from renal clear-cell, hepatocellular, ovarian, colorectal, lung, breast, and gastric carcinomas (reviewed in [1])

Function, physiology and clinically significant polymorphisms:

The predicted membrane topology of MRP2 transporter includes 12 transmembrane domains with at least two substrate binding sites, which have some overlap.  For example, although glutathione is transported by MRP2, when co-administered with high concentrations of sulfinpyrazone, the latter occupies both sites, preventing the co-transport of glutathione, yet allowing sulfinpyrazone to be transported alone [2]. 

The localization of MRP2 supports a function in the terminal excretion and detoxification of endogenous and xenobiotic organic anions, particularly conjugates of glutathione, glucuronate or sulfate as well as contribution of resistance towards anticancer drugs targeting solid malignant tumors.  MRP2 has broad substrate specificity:  organic anions with the highest affinity for glucuronate, GSH conjugates of lipophilic substances (e.g. LTC4), compounds without anionic conjugate residues (e.g. methotrexate and bromosulfophthalein) and reduced and oxidized GSH, nucleotide analogues and anticancer drugs.  MRP2 transports conjugated endogenous and xenobiotic substances, including toxins and carcinogens into bile (from hepatocytes), urine (from renal proximal tubular cells) and the intestinal lumen (from enterocytes) [3]. The hepatic MRP2 pump contributes to the driving forces of bile flow and is the major transporter responsible for the biliary excretion of bilirubin glucuronosides.  Inhibitors include probenecid, cyclosporine, PSC833 and MK571.

More than 200 naturally occurring sequence variants have been identified in the ABCC2 gene and most of these are SNPs that do not result in clinically relevant changes in function.  Impairment of MRP2 function (due to polymorphisms or chemical inhibitors) results in hyperbilirubinemia, as in the case of the hereditary disorder Dubin–Johnson syndrome.  While certain sequence variants in the ABCC2 gene correlate with loss of MRP2 function, in many cases this is compensated by upregulation of other membrane transporters (e.g. MRP3) in the basolateral membrane of hepatocytes [4].

MRP2 expression is regulated at the transcriptional and posttranscriptional level in response to many endogenous and xenobiotic substances and to different disease states. Transcriptional regulation may result from changes in the intracellular concentrations of bile acids and of a number of lipophilic compounds that are ligands for nuclear hormone receptors such as PXR, CAR, FXR and HNF4. 

Clinical significance:


MRP2 confers resistance to diverse chemotypes such as cisplatin and methotrexate and is implicated in cancer drug resistance, contributing to mitoxantrone and etoposide/teniposide resistance.  Pediatric cancer patients carrying the MRP2 -24T allele have lower levels of mitoxantrone clearance, with girls having the biggest effect, up to a 3-fold increase in AUC [5].  Renal allograft recipients carrying the -24T or the 3972T allele showed a 17% increase in the AUC of mycophenolic acid [6].  Differences in PK are reported with the SNPs -24C/T, 1249G/A, 3563T/A, 3972C/T, and 4544G/A, on irinotecan, pravastatin and doxorubicin elimination. In addition to conjugated hyperbilirubinemia, Dubin Johnson syndrome patients have elevated urinary coproporphyrin ratios, which may provide quantitative information of MRP2 in vivo activity in a patient [7].

Regulatory Requirements

At this time, there is no Guidance for MRP2 transporter to be evaluated by the FDA or EMA.  However, in vitro evaluations may be required on a case-by-case basis.

Location
Endogenous substrates
Substrates used experimentally
Substrate drugs
Inhibitors
Hepatocyte, Canalicular membrane, renal proximal tubule cells,  enterocytes, (luminal), solid tumors
Bilirubin, Leukotriene C, S-Glutathionyl, - estradiol, Cholecystokinin peptide, Ethinylestradiol-3-O-glucuronide, Estrone 3-sulfate
Bromosulfophthalein, p-Aminohippurate, E2 17βG
Glutathione and glucuronide conjugates, methotrexate, etoposide, mitoxantrone, valsartan, olmesartan, glucuronidated SN-38
Cyclosporine, delaviridine, efavirenz, emtricitabine, benzbromarone

References

  1. Nies, A.T. and D. Keppler, The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Arch, 2007. 453(5): p. 643-59.
  2. Evers, R., et al., Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export. Br J Cancer, 2000. 83(3): p. 375-83.
  3. Heredi-Szabo, K., et al., Potentiation of MRP2/Mrp2-mediated estradiol-17beta-glucuronide transport by drugs—a concise review. Chem Biodivers, 2009. 6(11): p. 1970-4.
  4. 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.
  5. Rau, T., et al., High-dose methotrexate in pediatric acute lymphoblastic leukemia: impact of ABCC2 polymorphisms on plasma concentrations. Clin Pharmacol Ther, 2006. 80(5): p. 468-76.
  6. Naesens, M., et al., Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation, 2006. 82(8): p. 1074-84.
  7. Benz-de Bretagne, I., et al., Urinary elimination of coproporphyrins is dependent on ABCC2 polymorphisms and represents a potential biomarker of MRP2 activity in humans. J Biomed Biotechnol, 2011. 2011: p. 498757.

 

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