Arsenic methylation - Lessons from three decades of research.

Between 1990 and 2020, our understanding of the significance of arsenic biomethylation changed in remarkable ways. At the beginning of this period, the conversion of inorganic arsenic into mono- and di-methylated metabolites was viewed primarily as a process that altered the kinetic behavior of arsenic. By increasing the rate of clearance of arsenic, the formation of methylated metabolites reduced exposure to this toxin; that is, methylation was detoxification. By 2020, it was clear that at least some of the toxic effects associated with As exposure depended on formation of methylated metabolites containing trivalent arsenic. Because the trivalent oxidation state of arsenic is associated with increased potency as a cytotoxin and clastogen, these findings were consistent with methylation-related changes in the dynamic behavior of arsenic. That is, methylation was activation. Our current understanding of the role of methylation as a modifier of kinetic and dynamic behaviors of arsenic is the product of research at molecular, cellular, organismic, and population levels. This information provides a basis for refining our estimates of risk associated with long term exposure to inorganic arsenic in environmental media, food, and water. This report summarizes the growth of our knowledge of enzymatically catalyzed methylation of arsenic over this period and considers the prospects for new discoveries.