Advance Access publication July 25, 2010 TOXICOLOGICAL HIGHLIGHT Arsenolysis and Thiol-Dependent Arsenate Reduction

Conversion of arsenate to arsenite is a critical event in the pathway that leads from inorganic arsenic to a variety of methylated metabolites. The formation of methylated metabolites influences distribution and retention of arsenic and affects the reactivity and toxicity of these intermediates. Indeed, some of the toxic and carcinogenic effects associated with exposure to arsenate or arsenite are probably mediated by methylated arsenicals. Recent work has demonstrated a biologically plausible role for phosphorolytic-arsenolytic enzymes in a reaction scheme in which an ‘‘activated’ ’ arsenate ester is readily reduced by thiols to arsenite. Thiol-dependent reduction of arsenate esters formed by arsenolysis may be one of several functionally reductant processes that control the flux of arsenic into the cellular pathway for arsenic methylation. Integrating these reductive processes into a conceptual model for arsenic metabolism may provide new insights into the cellular machinery for handling this toxic metalloid. Key Words: arsenate; arsenolysis; thiols; glutathione; arsenate esters