From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance

TY - JOUR

T1 - From MDR to MXR

T2 - new understanding of multidrug resistance systems, their properties and clinical significance

AU - Litman, Thomas

AU - Druley, T E

AU - Stein, W D

AU - Bates, S E

N1 - A comprehensive review on ABC transporters and multidrug resistance

PY - 2001/6

Y1 - 2001/6

N2 - The ATP binding cassette (ABC) superfamily of membrane transporters is one of the largest protein classes known, and counts numerous proteins involved in the trafficking of biological molecules across cell membranes. The first known human ABC transporter was P-glycoprotein (P-gp), which confers multidrug resistance (MDR) to anticancer drugs. In recent years, we have obtained an increased understanding of the mechanism of action of P-gp as its ATPase activity, substrate specificity and pharmacokinetic interactions have been investigated. This review focuses on the functional characterization of P-gp, as well as other ABC transporters involved in MDR: the family of multidrug-resistance-associated proteins (MRP1-7), and the recently discovered ABC half-transporter MXR (also known as BCRP, ABCP and ABCG2). We describe recent progress in the analysis of protein structure-function relationships, and consider the conceptual problem of defining and identifying substrates and inhibitors of MDR. An in-depth discussion follows of how coupling of nucleotide hydrolysis to substrate transport takes place, and we propose a scheme for the mechanism of P-gp function. Finally, the clinical correlations, both for reversal of MDR in cancer and for drug delivery, are discussed.

AB - The ATP binding cassette (ABC) superfamily of membrane transporters is one of the largest protein classes known, and counts numerous proteins involved in the trafficking of biological molecules across cell membranes. The first known human ABC transporter was P-glycoprotein (P-gp), which confers multidrug resistance (MDR) to anticancer drugs. In recent years, we have obtained an increased understanding of the mechanism of action of P-gp as its ATPase activity, substrate specificity and pharmacokinetic interactions have been investigated. This review focuses on the functional characterization of P-gp, as well as other ABC transporters involved in MDR: the family of multidrug-resistance-associated proteins (MRP1-7), and the recently discovered ABC half-transporter MXR (also known as BCRP, ABCP and ABCG2). We describe recent progress in the analysis of protein structure-function relationships, and consider the conceptual problem of defining and identifying substrates and inhibitors of MDR. An in-depth discussion follows of how coupling of nucleotide hydrolysis to substrate transport takes place, and we propose a scheme for the mechanism of P-gp function. Finally, the clinical correlations, both for reversal of MDR in cancer and for drug delivery, are discussed.

KW - ATP-Binding Cassette Transporters

KW - Animals

KW - Antineoplastic Agents

KW - Drug Resistance, Multiple

KW - Forecasting

KW - Humans

KW - Mitoxantrone

KW - Neoplasm Proteins

KW - P-Glycoprotein

KW - review

KW - MDR

KW - ABCG2

KW - ABCG2/BCRP

KW - MXR

M3 - Journal article

C2 - 11497241

SN - 1023-294X

VL - 58

SP - 931

EP - 959

JO - EXS

JF - EXS

IS - 7

ER -