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

Abstract

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 [AsIII(GS)3] and the diglutathione conjugate of monomethylarsonous acid [MMAIII(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 AsIII(GS)3, MMAIII(GS)2, and dimethylarsenic glutathione DMAIII(GS), as well as, the seleno-bis(S-glutathionyl) arsinium ion [(GS)2AsSe]− are reviewed.