title: Selenium-dependent and -independent transport of arsenic by the human multidrug resistance protein 2 (MRP2/ABCC2): implications for the mutual detoxification of arsenic and selenium.
abstract: Simultaneous exposure of lab animals to toxic doses of the human carcinogen arsenic (As) and the essential trace element selenium (Se) results in a remarkable mutual detoxification. A likely basis for this is the in vivo formation and biliary excretion of seleno-bis(S-glutathionyl) arsinium ion [(GS)(2)AsSe](-); however, the transport protein responsible for the biliary efflux of [(GS)(2)AsSe](-) has not been identified. The multidrug resistance protein 2 (MRP2/ABCC2) is an adenosine triphosphate (ATP)-binding cassette transporter expressed at the canalicular membrane of hepatocytes. Rat Mrp2 is known to excrete the As glutathione (GSH/GS-) conjugates arsenic triglutathione [As(GS)(3)] and monomethyl arsenic diglutathione [CH(3)As(GS)(2)] into bile, and in vitro studies have established As(GS)(3) as a substrate for human MRP2. In the present study, membrane vesicles prepared from human embryonic kidney (HEK293T) cells transfected with human MRP2 were used to demonstrate that MRP2 transports [(GS)(2)AsSe](-). In addition, the characteristics of MRP2 transport of As(GS)(3) and [(GS)(2)AsSe](-) were investigated. As(GS)(3) and [(GS)(2)AsSe](-) are chemically labile and have the potential to dissociate. However, arsenite (As(III)) +/- selenite (Se(IV)) transport was not detected in the absence of GSH or in the presence of the non-reducing GSH analog, ophthalmic acid, suggesting that the conjugates are the transported forms. The apparent K(m) values for [(GS)(2)AsSe](-) and As(GS)(3) were 1.7 and 4.2 microM, respectively, signifying high relative affinities. Membrane vesicles prepared from human erythrocytes, which express the MRP2-related MRP1/ABCC1, MRP4/ABCC4 and MRP5/ABCC5, transported As(GS)(3) in an MRP1- and ATP-dependent manner but did not transport [(GS)(2)AsSe](-). These results have important implications for the Se-dependent and -independent disposition of As.
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Canada.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Carew
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Leslie
mesh_terms: D001151:Arsenic / Q000493:pharmacokinetics* / Q000633:toxicity; D001692:Biological Transport; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity; D002460:Cell Line; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D005978:Glutathione / Q000493:pharmacokinetics; D006801:Humans; D008658:Inactivation, Metabolic; D007668:Kidney / Q000196:embryology; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D012643:Selenium / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D014162:Transfection
chemical_list: D001151:Arsenic; D002273:Carcinogens; D005978:Glutathione; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012643:Selenium; C000715087:ABCC2 protein, human; C421109:multidrug resistance-associated protein 1