Arsenic–glutathione conjugate transport by the human multidrug resistance proteins (MRPs/ABCCs)

Millions of people world-wide are chronically exposed to inorganic forms of the environmental toxicant arsenic in drinking water. This has led to a public health crisis because arsenic is a human carcinogen, and causes a myriad of other adverse health effects. In order to prevent and treat arsenic-induced toxicity it is critical to understand the cellular handling of this metalloid. A large body of literature describes the importance of the cellular tripeptide glutathione (γ-Glu-Cys-Gly,GSH/GS) in the excretion of arsenic. The triglutathione conjugate of arsenite [As(III)(GS)(3)] and the diglutathione conjugate of monomethylarsonous acid [MMA(III)(GS)(2)] have been isolated from rat bile and mouse urine, and account for the majority of excreted arsenic, suggesting these are important transportable forms. The ATP-binding cassette (ABC) transporter proteins, multidrug resistance protein 1 (MRP1/ABCC1) and the related protein MRP2 (ABCC2), are thought to play an important role in arsenic detoxification through the cellular efflux of arsenic-GSH conjugates. Current knowledge on the cellular handling of arsenic with a special emphasis on the transport pathways of the arsenic-GSH conjugates As(III)(GS)(3), MMA(III)(GS)(2), and dimethylarsenic glutathione DMA(III)(GS), as well as, the seleno-bis(S-glutathionyl) arsinium ion [(GS)(2)AsSe](-) are reviewed.