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学科主题: 公共卫生
题名:
Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development
作者: Zhou, Shu-Feng1; Wang, Lin-Lin1,2; Di, Yuan Ming1; Xue, Charlie Changli1; Duan, Wei3; Li, Chun Guang1; Li, Yong2
关键词: MRP ; substrate ; inhibitor
刊名: CURRENT MEDICINAL CHEMISTRY
发表日期: 2008-08-01
卷: 15, 期:20, 页:1981-2039
收录类别: SCI
文章类型: Review
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology ; Chemistry, Medicinal ; Pharmacology & Pharmacy
研究领域[WOS]: Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
关键词[WOS]: ORGANIC ANION-TRANSPORTER ; CONJUGATE EXPORT PUMP ; BLOOD-BRAIN-BARRIER ; BINDING CASSETTE TRANSPORTER ; NONSTEROIDAL ANTIINFLAMMATORY DRUGS ; ATP-DEPENDENT TRANSPORT ; LUNG-CANCER CELLS ; HIV PROTEASE INHIBITORS ; REDUCED FOLATE CARRIER ; HUMAN LEUKEMIA-CELLS
英文摘要:

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 (LTC4 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.

语种: 英语
WOS记录号: WOS:000258754800003
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/62827
Appears in Collections:北京大学公共卫生学院_期刊论文

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作者单位: 1.Deakin Univ, Sch Med, Waurn Ponds, Vic 3217, Australia
2.RMIT Univ, WHO Collaborating Ctr Tradit Med, Sch Hlth Sci, Div Chinese Med, Bundoora, Vic 3083, Australia
3.Peking Univ, Sch Publ Hlth, Dept Nutr & Food Hyg, Beijing 100083, Peoples R China

Recommended Citation:
Zhou, Shu-Feng,Wang, Lin-Lin,Di, Yuan Ming,et al. Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development[J]. CURRENT MEDICINAL CHEMISTRY,2008,15(20):1981-2039.
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