TRANSPORT OF GLUTATHIONE CONJUGATES AND GLUCURONIDES BY THE MULTIDRUG-RESISTANCE PROTEINS MRP1 AND MRP2

The search for the membrane proteins mediating the ATP-dependent trans port of conjugates with glutathione, glucuronate, or sulfate has led t o the identification of the multidrug resistance proteins MRP1 and MRP 2 Both 190-kDa membrane glycoproteins were cloned in the recent years and shown to be unidirectional ATP-driven export pumps with an amino a cid identity of 49% in human, MRP1 is detected in the plasma membrane of many cell types, including erythrocytes, whereas MRP2, also termed canalicular MRP (cMRP) or canalicular multispecific organic anion tran sporter (cMOAT), has been localized to the apical domain of polarized epithelia, particularly to the hepatocyte canalicular membrane. Physio logically important substrates of both transporters include glutathion e S-conjugates such as leukotriene C-4, bilirubin glucuronides, 17 bet a-glucuronosyl estradiol, dianionic bile salts such as 6 alpha-glucuro nosyl hyodeoxycholate, and glutathione disulfide, Both transporters ha ve been associated with multiple drug resistance of malignant tumors b ecause of their capacity to pump drug conjugates and drug complexes ac ross the plasma membrane into the extracellular space, The substrate s pecificity of MRP1 and MRP2 is very different from MDR1 P-glycoprotein . MRP1 and MRP2 may be termed conjugate transporting ATPases functioni ng in detoxification and, because of their role in glutathione disulfi de export, in the defense against oxidative stress.