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

被引:52
|
作者
Carew, Michael W. [1 ,2 ]
Leslie, Elaine M. [1 ,2 ,3 ]
机构
[1] Univ Alberta, Dept Physiol, Edmonton, AB T6G 2H7, Canada
[2] Univ Alberta, Membrane Prot Res Grp, Edmonton, AB T6G 2H7, Canada
[3] Univ Alberta, Dept Lab Med & Pathol, Div Analyt & Environm Toxicol, Edmonton, AB T6G 2H7, Canada
基金
加拿大健康研究院;
关键词
PRIMARY RAT HEPATOCYTES; BILIARY-EXCRETION; VINCRISTINE TRANSPORT; REDUCED GLUTATHIONE; MEMBRANE-VESICLES; CONJUGATE EFFLUX; AS-III; MRP1; BINDING; METABOLISM;
D O I
10.1093/carcin/bgq125
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 mu M, 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.
引用
收藏
页码:1450 / 1455
页数:6
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