ATP-DEPENDENT TRANSPORT OF GLUTATHIONE S-CONJUGATES BY THE MULTIDRUG-RESISTANCE PROTEIN MRP1 AND ITS APICAL ISOFORM MRP2

The membrane proteins mediating the ATP-dependent transport of glutath ione S-conjugates and related amphiphilic anions have been identified as the multidrug resistance proteins MRP1 and MRP2. These 190-kDa memb rane glycoproteins were cloned in recent years and shown to be unidire ctional, ATP-driven, export pumps with an amino acid identity of 49% i n humans. MRP1 is detected in the plasma membrane of many cell types, including erythrocytes; whereas MRP?, also termed canalicular MRP (cMR P) or canalicular multispecific organic anion transporter (cMOAT), has been localized to the apical domain of polarized epithelia, such as t he hepatocyte canalicular membrane and kidney proximal tubule luminal membrane. Physiologically important substrates of both transporters in clude glutathione S-conjugates, such as leukotriene C-4, as well as bi lirubin glucuronides, 17 beta-glucuronosyl estradiol and glutathione d isulfide. Both transporters have been associated with multiple drug re sistance of malignant tumors because of their capacity to pump drug co njugates and drug complexes across the plasma membrane into the extrac ellular space. The substrate specificity of MRP1 and MRP2 studied in i nside-out oriented membrane vesicles is very different from MDR1 P-gly coprotein. MRP1 and MRP2 may be termed conjugate transporting ATPases, functioning in detoxification and, because of their role in glutathio ne disulfide export, in the defense against oxidative stress. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.