How Is Inorganic Arsenic Detoxified?

A flow chart to help understand the detoxification and biotransformation of inorganic arsenic is presented. Arsenate is reduced to arsenite enzymatically by arsenate reductase and nonenzymatically by GSH. An early step in the detoxification appears to be the formation of the Galler compound, seleno-bis(S-glutathionyl) arsinium ion, which is rapidly formed and excreted in the bile. Arsenite-binding proteins initially may prevent or enhance the accumulation of toxic levels of arsenite. As these binding sites become saturated, the arsenite may be released for methylation, a biotransformation process which results in the increase of urinary arsenic. Methylation of arsenic species can occur via SAM and methyltransferases and/or nonenzymatically with methylvitamin B-12 GSH and selenite. Methylation by the methylvitamin B-12 system has been shown in vitro only. The substrate for DMA production appears to be MMA(III). The lack of methyltransferases in many primates strongly indicates that methylation may not be the primary detoxification pathway for inorganic arsenic. In fact, the EPA classifies dimethylarsinic acid, the final urinary metabolite for arsenic in humans, as a probable human carcinogen. The determination of the amino add sequences of the arsenic methyltransferases needs to be accomplished so that gene probes can be constructed to better study arsenic methyltransferase polymorphism as it relates to the various responses of people to inorganic arsenic.