Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development

Zhou, Shu-Feng, Wang, Lin-Lin, Di, Yuan, Xue, Charlie C., Duan, Wei, Li, Chun and Li, Yong 2008, Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development, Current medicinal chemistry, vol. 15, no. 20, pp. 1981-2039.

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Title Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development
Author(s) Zhou, Shu-Feng
Wang, Lin-Lin
Di, Yuan
Xue, Charlie C.
Duan, Wei
Li, Chun
Li, Yong
Journal name Current medicinal chemistry
Volume number 15
Issue number 20
Start page 1981
End page 2039
Publisher Bentham Science Publishers Ltd.
Place of publication Schiphol, Netherlands
Publication date 2008-08
ISSN 0929-8673
1875-533X
Keyword(s) MRP
substrate
inhibitor
Summary Human contains 49 ATP-binding cassette (ABC) transporter genes and the multidrug resistance associated proteins (MRP1/ABCC1, MRP2/ABCC2, MRP3/ABCC3, MRP4/ABCC4, MRP5/ABCC5, MRP6/ABCC6, MRP7/ABCC10, MRP8/ABCC11 and MRP9/ABCC12) belong to the ABCC family which contains 13 members. ABCC7 is cystic fibrosis transmembrane conductance regulator; ABCC8 and ABCC9 are the sulfonylurea receptors which constitute the ATP-sensing subunits of a complex potassium channel. MRP10/ABCC13 is clearly a pseudo-gene which encodes a truncated protein that is highly expressed in fetal human liver with the highest similarity to MRP2/ABCC2 but without transporting activity. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. MRP/ABCC members transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. The human MRP/ABCC transporters except MRP9/ABCC12 are all able to transport organic anions, such as drugs conjugated to glutathione, sulphate or glucuronate. In addition, selected MRP/ABCC members may transport a variety of endogenous compounds, such as leukotriene C(4) (LTC(4) by MRP1/ABCC1), bilirubin glucuronides (MRP2/ABCC2, and MRP3/ABCC3), prostaglandins E1 and E2 (MRP4/ABCC4), cGMP (MRP4/ABCC4, MRP5/ABCC5, and MRP8/ABCC11), and several glucuronosyl-, or sulfatidyl steroids. In vitro, the MRP/ABCC transporters can collectively confer resistance to natural product anticancer drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and in concert with alterations in phase II conjugating or biosynthetic enzymes, classical alkylating agents, alkylating agents. Several MRP/ABCC members (MRPs 1-3) are 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. Drug targeting of these transporters to overcome MRP/ABCC-mediated multidrug resistance may play a role in cancer chemotherapy. Most MRP/ABCC transporters are subject to inhibition by a variety of compounds. Based on currently available preclinical and limited clinical data, it can be expected that modulation of MRP members may represent a useful approach in the management of anticancer and antimicrobial drug resistance and possibly of inflammatory diseases and other diseases. A better understanding of their substrates and inhibitors has important implications in development of drugs for treatment of cancer and inflammation.
Language eng
Field of Research 111502 Clinical Pharmacology and Therapeutics
Socio Economic Objective 929999 Health not elsewhere classified
HERDC Research category C1 Refereed article in a scholarly journal
HERDC collection year 2008
Copyright notice ©2008, Bentham Science Publishers Ltd.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30017724

Document type: Journal Article
Collection: School of Medicine
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