Structural and Functional Properties of Human Multidrug Resistance Protein 1 (MRP1/ABCC1)

Author(s): S.-M. He, R. Li, J. R. Kanwar, S.-F. Zhou.

Journal Name: Current Medicinal Chemistry

Volume 18 , Issue 3 , 2011

Abstract:

Multidrug ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1) play an important role in the extrusion of drugs from the cell and their overexpression can be a cause of failure of anticancer and antimicrobial chemotherapy. Recently, the mouse P-gp/Abcb1a structure has been determined and this has significantly enhanced our understanding of the structure-activity relationship (SAR) of mammalian ABC transporters. This paper highlights our current knowledge on the structural and functional properties and the SAR of human MRP1/ABCC1. Although the crystal structure of MRP1/ABCC1 has yet to be resolved, the current topological model of MRP1/ABCC1 contains two transmembrane domains (TMD1 and TMD2) each followed by a nucleotide binding domain (NBD) plus a third NH2-terminal TMD0. MRP1/ABCC1 is expressed in the liver, kidney, intestine, brain and other tissues. MRP1/ABCC1 transports a structurally diverse array of important endogenous substances (e.g. leukotrienes and estrogen conjugates) and xenobiotics and their metabolites, including various conjugates, anticancer drugs, heavy metals, organic anions and lipids. Cells that highly express MRP1/ABCC1 confer resistance to a variety of natural product anticancer drugs such as vinca alkaloids (e.g. vincristine), anthracyclines (e.g. etoposide) and epipodophyllotoxins (e.g. doxorubicin and mitoxantrone). MRP1/ABCC1 is associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. However, most compounds that efficiently reverse P-gp/ABCB1-mediated multidrug resistance have only low affinity for MRP1/ABCC1 and there are only a few effective and relatively specific MRP1/ABCC1 inhibitors available. A number of site-directed mutagenesis studies, biophysical and photolabeling studies, SAR and QSAR, molecular docking and homology modeling studies have documented the role of multiple residues in determining the substrate specificity and inhibitor selectivity of MRP1/ABCC1. Most of these residues are located in the TMs of TMD1 and TMD2, in particular TMs 4, 6, 7, 8, 10, 11, 14, 16, and 17, or in close proximity to the membrane/cytosol interface of MRP1/ABCC1. The exact transporting mechanism of MRP1/ABCC1 is unclear. MRP1/ABCC1 and other multidrug transporters are front-line mediators of drug resistance in cancers and represent important therapeutic targets in future chemotherapy. The crystal structure of human MRP1/ABCC1 is expected to be resolved in the near future and this will provide an insight into the SAR of MRP1/ABCC1 and allow for rational design of anticancer drugs and potent and selective MRP1/ABCC1 inhibitors.

Keywords: MRP1, substrate, inhibitor, structure-activity relationship, homology model, mutation, ATP-binding cassette (ABC), hydrolysis, ions, sugars, amino, vitamins, metals, drugs, oligosaccharides, oligopeptides, inorganic ions, xenobiotics including, nucleotide-binding domains (NBDs), glucuronate conjugates, bile salt transport, prostaglandin, methotrexate, potassium antimonyl tartrate, sulfonylurea receptors, potassium channel, cell membranes, neonatal diabetes, vincristine, vinblastine, multidrug resistant, vinca alkaloids, cadmium chloride, oxidized glutathione, cerebrospinal fluid barrier, kidney, liver, syncytiotrophoblasts, fluorescein, fluorescent substrates, anthracycline doxorubicin, doxorubicin, physiological role, anticancer drugs, anthracyclines, epipodophyllotoxins, drug efflux, ovarian carcinoma, antifolate, vesicles, alkylating agents, dihydrotestosterone, immunodeficiency virus, myocardial infarction, hyperlipidemia, stroke, carboxyfluorescein, eosinophils, high-affinity substrate, pharmacotherapy, neuroblastoma, oxadiazole, H-bond acceptor, vancomycin, losartan, sulfasalazine, zafirlukast, phenyl ring, leaflet, nucleotide-binding, electron microscopy, intrahelical interactions, radiolabeled, sulfatolithocholyl

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Article Details

VOLUME: 18
ISSUE: 3
Year: 2011
Page: [439 - 481]
Pages: 43
DOI: 10.2174/092986711794839197
Price: $58

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