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Multidrug resistance mediated by the ATP‐binding cassette transporter protein MRP

Resistance to multiple natural product drugs associated with reduced drug accumulation in human tumor cells may be conferred by either the 170 kDa P‐glycoprotein or the 190 kDa multidrug resistance protein, MRP. Both MRP and P‐glycoprotein belong to the large and ancient ATP‐binding cassette (ABC) superfamily of transport proteins but share only 15% amino acid identity. Unlike P‐glycoprotein, MRP actively transports conjugated organic anions such as the cysteinyl leukotriene C4 and glutathione‐conjugated aflatoxin B1. Transport of unconjugated chemotherapeutic agents appears to require cotransport of glutathione. MRP and several more recently discovered ABC proteins contain an additional NH2‐proximal membrane‐spanning domain not found in previously characterized ABC transporters. This domain, whose NH2‐terminus is extracytosolic, is essential for MRP‐mediated transport activity. This review summarizes current knowledge of the structural and transport characteristics of MRP which suggest that the physiologic functions of this protein could range from a protective role in chemical toxicity and oxidative stress to mediation of inflammatory responses involving cysteinyl leukotrienes. BioEssays 20:931–940, 1998. © 1998 John Wiley & Sons, Inc.