MRP5

MRP5 (multidrug resistance-associated protein 5)

Aliases: ABC33, EST277145, MOAT-C, MOATC (not to be confused with CMOAT, which is MRP2), SMRP, pABC11
Gene name: ATP binding cassette subfamily C member 5 (ABCC5)

Summary

MRP5 (ABCC5) is a member of the multidrug resistance-associated protein (MRP/CFTR) subfamily of ABC transporters. It is a unidirectional, ATP-dependent efflux transporter that appears to be ubiquitously expressed in humans. It may be apically or basolaterally expressed in polarized cells, but in some tissues it is reported to be expressed on both membranes. Thus, its role in drug ADME may be difficult to interpret. MRP5 has not been as extensively studied as other drug transporters; therefore, information on its potential role in drug ADME, pharmacology, or toxicity is limited. As it transports cAMP and cGMP, MRP5 may be a mediator of cell signaling processes, and it may also be upregulated in the liver during cholestasis, possibly playing a role in alleviating hepatotoxicity. A role in statin-induced muscle myopathy has also been postulated. As the clinical relevance of MRP5 has not been clearly demonstrated, there are currently no FDA or EMA recommendations for this transporter.

Localization

MRP5 has a wide tissue distribution: it is found in the epithelial cells of the urethra [1], in smooth muscle cells and endothelial cells of the heart [2], in the basal membrane of syncytiotrophoblasts, in and around fetal blood vessels in the placenta [3], and in astrocytes and pyramidal neurons of the human brain [4]. MRP5 is also present in the blood-brain-barrier (BBB), where it is localized to the luminal (i.e., apical) membrane of brain capillary endothelial cells [4]. Interestingly, MRP5 expression in the BBB and the brain-cerebrospinal fluid barrier seems to be age-related as neither MRP4 nor MRP5 was detected in the brain of fetuses, neonates, or children [5]. As compared to other transporters, information on MRP5 is rather limited, but MRP5 may be expressed on both the apical and basolateral side of some polarized cells, and thus its impact on drug transport may be challenging to predict.

Function, physiology and clinically significant polymorphisms

The putative structure of MRP5 is similar to that of MDR1, consisting of 12 transmembrane segments and 2 nucleotide binding domains (NBDs).
MRP subfamily members are generally identified as ATP-dependent efflux proteins with broad and overlapping substrate specificities. The first member of the subfamily (MRP1, ABCC1) was found to be highly expressed in different types of cancer cells. It was demonstrated that overexpression of the ABCC1 gene increased the resistance of cells to different types of natural chemotherapeutics and genotoxic agents [6, 7] by mediating the efflux of these substances. Although the anti-folate methotrexate is a substrate of MRP5, there is no strong evidence of a role for MRP5 in chemotherapy resistance. Instead, the ability of both MRP4 and MRP5 to transport cAMP and cGMP suggests that these transporters may play a role in cellular signaling by eliminating these cyclic nucleotides from the cells [8]. Of the two, MRP5 is viewed as a high affinity transporter for cGMP, while MRP4 is pictured as a moderate to high affinity transporter for cAMP, although low-affinity transport of the less-preferred cyclic nucleotide has been reported for both [9]. MRP5 has also been shown to mediate the efflux of endogenous as well as exogenous glutamate conjugates and analogues. Substrates in this class include endogenous metabolites such as N-acetylaspartylglutamate, exogenous glutamate analogues like kainic and domoic acid (excitotoxins), ZJ43 (a therapeutic analogue), and methotrexate [10]. The protective function of the placenta against xenobiotics is thought to be mediated in part by transport proteins of the ABC family, including MRP5 (reviewed in [11]). In addition, lipopolysaccharide (LPS) treatment in rats resulted in downregulation of Mrp2 and induction of Mrp5, suggesting that MRP5 may also participate in the hepatic clearance of cholephilic substances [12].
Inhibition [13] and RNA interference [14] studies have identified MRP5 as the primary efflux transporter of hyaluronan, a glycosaminoglycan that is a major component of the extracellular matrix.
Transport by MRP5 is inhibited by various nucleoside analogs [15]. Some of these, like sildenafil, vardenafil and their derivatives, behave as dual inhibitors of MRP5 and phosphodiesterase 5 (PDE5), the main enzyme responsible for cGMP hydrolysis, and the robust increase in intracellular cGMP levels elicited by such compounds may be attributed to this combined action [16].
Twenty genetic variants in the ABCC5 gene were identified by Dazert et al. in human heart samples. While the contribution of these polymorphisms to any disease or symptom has not been proven so far [2], selected SNPs show correlation with the pharmacokinetics and side effects of some chemotherapeutic agents.

Clinical significance

To date, no clinically relevant DDIs involving MRP5 have been reported, and there is limited information on its role in the clinical ADME of drugs. MRP5 may play a significant role in drug resistance in some types of cancer by transporting 5-fluorouracil and some antifolate anticancer drugs [17, 18]. On the other hand, polymorphisms in the ABCC5 gene are associated with the risk of adverse events in chemotherapy. SNPs of ABCC5 influenced the pharmacokinetics of doxorubicin in breast cancer patients [19], predisposed to doxorubicin cardiotoxicity in childhood acute lymphoblastic leukemia [20], and predicted severe irinotecan toxicity in metastatic colorectal cancer [21].
The role of MRP1, 4 and 5 in statin efflux from skeletal muscle cells was demonstrated by Knauer et al. These results suggest that drug-transporter interactions leading to statin-induced myopathy may occur not only because of increased systemic statin levels caused by hepatic transporter inhibition but also because of transporter modulation in skeletal muscle cells [22].
The quantitative analysis of MRP5 expression in ventricular heart samples by Dazert et al. showed an upregulation of MRP5 in ischemic cardiomyopathy as compared to non-failing hearts. The presence of MRP5 in cardiac and cardiovascular myocytes as well as heart endothelial cells, and the identification of cGMP as an MRP5 substrate, suggest the involvement of MRP5 in the regulation of cardiac cGMP levels. Since cGMP is a key signaling and regulatory molecule in vascular smooth muscle relaxation and cardiac contractility, MRP5 may be a possible novel pharmacological target in cardiac disorders attributed to decreased cGMP levels [2].

Regulatory requirements

As a clear demonstration of the clinical relevance of MRP5 is lacking, there is currently no FDA or EMA recommendation for this transporter.

References

1.    Nies, A.T., et al., Immunolocalization of multidrug resistance protein 5 in the human genitourinary system. J Urol, 2002. 167(5): p. 2271-5.
2.    Dazert, P., et al., Expression and localization of the multidrug resistance protein 5 (MRP5/ABCC5), a cellular export pump for cyclic nucleotides, in human heart. Am J Pathol, 2003. 163(4): p. 1567-77.
3.    Meyer Zu Schwabedissen, H.E., et al., Expression, localization, and function of MRP5 (ABCC5), a transporter for cyclic nucleotides, in human placenta and cultured human trophoblasts: effects of gestational age and cellular differentiation. Am J Pathol, 2005. 166(1): p. 39-48.
4.    Nies, A.T., et al., Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain. Neuroscience, 2004. 129(2): p. 349-60.
5.    Verscheijden, L.F.M., et al., Developmental patterns in human blood-brain barrier and blood-cerebrospinal fluid barrier ABC drug transporter expression. Histochem Cell Biol, 2020. 154(3): p. 265-273.
6.    Grant, C.E., et al., Overexpression of multidrug resistance-associated protein (MRP) increases resistance to natural product drugs. Cancer Res, 1994. 54(2): p. 357-61.
7.    Cole, S.P., et al., Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res, 1994. 54(22): p. 5902-10.
8.    Jedlitschky, G., B. Burchell, and D. Keppler, The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. J Biol Chem, 2000. 275(39): p. 30069-74.
9.    Sager, G. and A.W. Ravna, Cellular efflux of cAMP and cGMP - a question about selectivity. Mini Rev Med Chem, 2009. 9(8): p. 1009-13.
10.    Jansen, R.S., et al., ATP-binding Cassette Subfamily C Member 5 (ABCC5) Functions as an Efflux Transporter of Glutamate Conjugates and Analogs. J Biol Chem, 2015. 290(51): p. 30429-40.
11.    Liu, L. and X. Liu, Contributions of Drug Transporters to Blood-Placental Barrier. Adv Exp Med Biol, 2019. 1141: p. 505-548.
12.    Donner, M.G., et al., Enhanced expression of basolateral multidrug resistance protein isoforms Mrp3 and Mrp5 in rat liver by LPS. Biol Chem, 2004. 385(3-4): p. 331-9.
13.    Prehm, P. and U. Schumacher, Inhibition of hyaluronan export from human fibroblasts by inhibitors of multidrug resistance transporters. Biochem Pharmacol, 2004. 68(7): p. 1401-10.
14.    Schulz, T., U. Schumacher, and P. Prehm, Hyaluronan export by the ABC transporter MRP5 and its modulation by intracellular cGMP. J Biol Chem, 2007. 282(29): p. 20999-1004.
15.    Reid, G., et al., Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol Pharmacol, 2003. 63(5): p. 1094-103.
16.    Kashgari, F.K., et al., Identification and experimental confirmation of novel cGMP efflux inhibitors by virtual ligand screening of vardenafil-analogues. Biomed Pharmacother, 2020. 126: p. 110109.
17.    Pratt, S., et al., The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Mol Cancer Ther, 2005. 4(5): p. 855-63.
18.    Wielinga, P., et al., The human multidrug resistance protein MRP5 transports folates and can mediate cellular resistance against antifolates. Cancer Res, 2005. 65(10): p. 4425-30.
19.    Lal, S., et al., Pharmacogenetics of ABCB5, ABCC5 and RLIP76 and doxorubicin pharmacokinetics in Asian breast cancer patients. Pharmacogenomics J, 2016.
20.    Krajinovic, M., et al., Polymorphisms of ABCC5 and NOS3 genes influence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia. Pharmacogenomics J, 2016. 16(6): p. 530-535.
21.    Chen, S., et al., ABCC5 and ABCG1 polymorphisms predict irinotecan-induced severe toxicity in metastatic colorectal cancer patients. Pharmacogenet Genomics, 2015. 25(12): p. 573-83.
22.    Knauer, M.J., et al., Human skeletal muscle drug transporters determine local exposure and toxicity of statins. Circ Res, 2010. 106(2): p. 297-306.
23.    Aye, I.L., et al., Expression, localisation and activity of ATP binding cassette (ABC) family of drug transporters in human amnion membranes. Placenta, 2007. 28(8-9): p. 868-77.
24.    Pratt, S., et al., Kinetic validation of the use of carboxydichlorofluorescein as a drug surrogate for MRP5-mediated transport. Eur J Pharm Sci, 2006. 27(5): p. 524-32.
25.    Wijnholds, J., et al., Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci U S A, 2000. 97(13): p. 7476-81.