Multidrug resistance proteins (MRPs) and implication in drug development

Abstract

The multidrug resistance protein (MRP)-related ABCC family (MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, MRP8, and MRP9) belongs to the ATP-binding cassette (ABC) superfamily of transport proteins. They are capable of transporting a structurally diverse array of endo-and xenobiotics and their metabolites across cell membranes. These transporters play an important role in the absorption, disposition, and elimination of these compounds in the body. In particular, increased expression of these drug transporters in tumor cells is associated with resistance to a number of important chemotherapeutic agents. This review highlights the biochemical and pharmacological properties of MRP1-9 and their implications in drug development. A detailed study on the biochemical function and regulation of MRPs is important in drug development, as this may help to avoid drug toxicity, drug resistance, and drug-drug interactions and to optimize cancer chemotherapy. Drug Dev. Res. 64:1-18, 2005.

ABC transporters, neural stem cells and neurogenesis – a different perspective

“…Insofar, MRP1-MRP6 are the best-characterized members of the ABCC subfamily. Conjugates of lipophilic compounds with glutathione, glucuronate or sulfate are the preferred physiological substrates of MRP1 and MRP3 [78][79][80][81][82][83]. MRP6 is described to transport glutathione conjugates as well as the endothelin receptor antagonist BQ123 [78][79][80][81][82].…”

“…Conjugates of lipophilic compounds with glutathione, glucuronate or sulfate are the preferred physiological substrates of MRP1 and MRP3 [78][79][80][81][82][83]. MRP6 is described to transport glutathione conjugates as well as the endothelin receptor antagonist BQ123 [78][79][80][81][82]. Substrates for MRP4 and MRP5 include cyclic AMP, cyclic GMP and nucleotide analogues [78][79][80][81][82].…”

“…Reduced glutathione (GSH) has been recognized as a co-substrate for MRP1, for MRP2 and most recently for MRP4 [78][79][80][81][82]. In addition to being important export pumps for physiological substances, MRP subfamily members are involved in the active efflux of toxic organic anions [78][79][80][81][82]. MRP transporters have been shown to confer resistance to harmful drugs, possibly by the above-mentioned ATP-dependent export of such molecules [54][55][56][57].…”

Role of Multidrug Resistance Associated Proteins in Drug Development

“…One of the important and clinically relevant defense mechanisms include the active extrusion of xenobiotics by commonly shared transport proteins, mainly located in kidney, liver and intestine. The ATP-binding cassette (ABC) superfamily of transporters consist of a large number of functionally diverse transmembrane proteins which have been subdivided into seven families designated A through G (1)(2)(3)(4). Members of this transport superfamily display high amino acid similarity of the 200 amino acids surrounding the ATP-binding folds.…”

“…In humans, members of this family serve a variety of physiological roles in transmembrane transport and cell signalling, many of which are associated with disease phenotypes such as multidrug resistance, cystic fibrosis, Tangier disease, adrenoleukodystrophy and Zellwegers' syndrome (1,2,4). The available outline of the human genome contains 48 ABC genes (5); 16 of these have a known function and 14 are associated with a defined human disease (6).…”