Journal Article

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

Michael W. Carew and Elaine M. Leslie

in Carcinogenesis

Volume 31, issue 8, pages 1450-1455
Published in print August 2010 | ISSN: 0143-3334
Published online June 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq125
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

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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)2AsSe]; however, the transport protein responsible for the biliary efflux of [(GS)2AsSe] 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 [CH3As(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)2AsSe]. In addition, the characteristics of MRP2 transport of As(GS)3 and [(GS)2AsSe] were investigated. As(GS)3 and [(GS)2AsSe] are chemically labile and have the potential to dissociate. However, arsenite (AsIII) ± selenite (SeIV) 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 Km values for [(GS)2AsSe] and As(GS)3 were 1.7 and 4.2 μM, 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)2AsSe]. These results have important implications for the Se-dependent and -independent disposition of As.

Journal Article.  5186 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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