Transport of glutathione conjugates and glucuronides by the multidrug resistance proteins MRP1 and MRP2.
The search for the membrane proteins mediating the ATP-dependent transport of conjugates with glutathione, glucuronate, or sulfate has led to the identification of the multidrug resistance proteins MRP1 and MRP2. Both 190-kDa membrane glycoproteins were cloned in the recent years and shown to be unidirectional ATP-driven export pumps with an amino acid 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 transporter (cMOAT), has been localized to the apical domain of polarized epithelia, particularly to the hepatocyte canalicular membrane. Physiologically important substrates of both transporters include glutathione S-conjugates such as leukotriene C4, bilirubin glucuronides, 17 beta-glucuronosyl estradiol, dianionic bile salts such as 6 alpha-glucuronosyl hyodeoxycholate, and glutathione disulfide. Both transporters have been associated with multiple drug resistance of malignant tumors because of their capacity to pump drug conjugates and drug complexes across the plasma membrane into the extracellular space. The substrate specificity of MRP1 and MRP2 is very different from MDR1 P-glycoprotein. MRP1 and MRP2 may be termed conjugate transporting ATPases functioning in detoxification and, because of their role in glutathione disulfide export, in the defense against oxidative stress.
Keppler
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Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Leier
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I
Jedlitschky
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G
D000818:Animals; D019742:Chemokines, CC; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D018432:Drug Resistance, Multiple / Q000235:genetics; D005965:Glucuronates / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D019402:Macrophage Inflammatory Proteins; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology
D019742:Chemokines, CC; D016207:Cytokines; D005965:Glucuronates; D005978:Glutathione; D019803:Glutathione Disulfide; D019402:Macrophage Inflammatory Proteins; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human; C095218:Ccl9 protein, mouse; C421109:multidrug resistance-associated protein 1