Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense

被引:1110
作者
Leslie, EM
Deeley, RG
Cole, SPC
机构
[1] Queens Univ, Canc Res Labs, Kingston, ON K7L 3N6, Canada
[2] Univ N Carolina, Sch Pharm, Div Drug Delivery & Disposit, Chapel Hill, NC 27599 USA
基金
加拿大健康研究院;
关键词
ATP-binding cassette transporters; MRP; P-glycoprotein; BCRP; chemical toxicity; heavy metal transport; carcinogen transport; tissue defense;
D O I
10.1016/j.taap.2004.10.012
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
in tumor cell lines, multidrug resistance is often associated with an ATP-dependent decrease in cellular drug accumulation which is attributed to the overexpression of certain ATP-binding cassette (ABC) transporter proteins. ABC proteins that confer drug resistance include (but are not limited to) P-glycoprotein (gene symbol ABCB1), the multidrug resistance protein 1 (MRP1, gene symbol ABCC1), MRP2 (gene symbol ABCC2), and the breast cancer resistance protein (BCRP, gene symbol ABCG2). In addition to their role in drug resistance, there is substantial evidence that these efflux pumps have overlapping functions in tissue defense. Collectively, these proteins are capable of transporting a vast and chemically diverse array of toxicants including bulky lipophilic cationic, anionic, and neutrally charged drugs and toxins as well as conjugated organic anions that encompass dietary and environmental carcinogens, pesticides, metals, metalloids, and lipid peroxidation products. P-glycoprotein, MRP1, MRP2, and BCRP/ABCG2 are expressed in tissues important for absorption (e.g., lung and gut) and metabolism and elimination (liver and kidney). In addition, these transporters have an important role in maintaining the barrier function of sanctuary site tissues (e.g., blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier or placenta). Thus, these ABC transporters are increasingly recognized for their ability to modulate the absorption, distribution, metabolism, excretion, and toxicity of xenobiotics. In this review, the role of these four ABC transporter proteins in protecting tissues from a variety of toxicants is discussed. Species variations in substrate specificity and tissue distribution of these transporters are also addressed since these properties have implications for in vivo models of toxicity used for drug discovery and development. (c) 2004 Elsevier Inc. All rights reserved.
引用
收藏
页码:216 / 237
页数:22
相关论文
共 224 条
[1]  
Allen JD, 2000, CANCER RES, V60, P5761
[2]  
Allen JD, 2002, MOL CANCER THER, V1, P427
[3]  
Allen JD, 2002, CANCER RES, V62, P2294
[4]  
Allen JD, 1999, CANCER RES, V59, P4237
[5]  
Allikmets R, 1998, CANCER RES, V58, P5337
[6]   Biochemical, cellular, and pharmacological aspects of the multidrug transporter [J].
Ambudkar, SV ;
Dey, S ;
Hrycyna, CA ;
Ramachandra, M ;
Pastan, I ;
Gottesman, MM .
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 1999, 39 :361-398
[7]   Role of MDR1 and MRP1 in trophoblast cells, elucidated using retroviral gene transfer [J].
Atkinson, DE ;
Greenwood, SL ;
Sibley, CP ;
Glazier, JD ;
Fairbairn, LJ .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2003, 285 (03) :C584-C591
[8]  
Bain LJ, 1996, TOXICOL APPL PHARM, V141, P288, DOI 10.1016/S0041-008X(96)80035-4
[9]   Membrane topology and glycosylation of the human multidrug resistance-associated protein [J].
Bakos, E ;
Hegedus, T ;
Hollo, Z ;
Welker, E ;
Tusnady, GE ;
Zaman, GJR ;
Flens, MJ ;
Varadi, A ;
Sarkadi, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (21) :12322-12326
[10]   MECHANISMS OF METAL TRANSPORT ACROSS LIVER-CELL PLASMA-MEMBRANES [J].
BALLATORI, N .
DRUG METABOLISM REVIEWS, 1991, 23 (1-2) :83-132