Importance of being thiomethylated: formation, fate, and effects of methylated thioarsenicals.

Although inorganic arsenic has long been recognized as a potent toxicant and carcinogen in humans, recent evidence shows that at least some of its effects are mediated by methylated metabolites. Elucidating the conversion of inorganic arsenic to mono-, di-, and trimethylated species has provided insights into the enzymology of this pathway and identified genetic and environmental factors that influence the susceptibility of individuals to this metalloid's adverse health effects. Notably, almost all work on the formation, fate, and effects of methylated arsenicals has focused on oxoarsenicals in which arsenic is bound to one or more oxygen atoms. However, thioarsenicals are a class of arsenicals in which a sulfur atom has replaced one or more oxygens that are bound to arsenic. Thioarsenicals have been identified as urinary metabolites in humans and other animals following exposure to inorganic arsenic. Studies find that methylated thioarsenicals exhibit kinetic behavior and toxicological properties that distinguish them from methylated oxoarsenicals. This perspective considers that formation, fate, and effects of methylated thioarsenicals with an emphasis on examining the linkages between the molecular processes that underlie both methylation and thiolation reactions. Integrating this information will provide a more comprehensive view of the relationship between the metabolism of arsenic and the risk posed by chronic exposure to this environmental contaminant.