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

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 firs t known human ABC transporter was P-glycoprotein (P-gp), which confers mult idrug resistance (MDR) to anticancer drugs. In recent years, we have obtain ed an increased understanding of the mechanism of action of P-gp as its ATP ase activity, substrate specificity and pharmacokinetic interactions have b een investigated. This review focuses on the functional characterization of P-gp, as well as other ABC transporters involved in MDR: the family of mul tidrug-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 relationship s, and consider the conceptual problem of defining and identifying substrat es 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 correlati ons, both for reversal of MDR in cancer and for drug delivery, are discusse d.