The cellular metabolism and systemic toxicity of arsenic

Although it has been known for decades that humans and many other species c onvert inorganic arsenic to mono- and dimethylated metabolites, relatively little attention has been given to the biological effects of these methylat ed products. It has been widely held that inorganic arsenicals were the spe cies that accounted for the toxic and carcinogenic effects of this metalloi d and that methylation was properly regarded as a mechanism for detoxificat ion of arsenic. Elucidation of the metabolic pathway for arsenic has change d our understanding of the significance of methylation. Both methylated and dimethylated arsenicals that contain arsenic in the trivalent oxidation st ate have been identified as intermediates in the metabolic pathway. These c ompounds have been detected in human cells cultured in the presence of inor ganic arsenic and in urine of individuals who were chronically exposed to i norganic arsenic. Methylated and dimethylated arsenicals that contain arsen ic in the trivalent oxidation state are more cytotoxic, more genotoxic, and more potent inhibitors of the activities of some enzymes than are inorgani c arsenicals that contain arsenic in the trivalent oxidation state. Hence, it is reasonable to describe the methylation of arsenic as a pathway for it s activation, not as a mode of detoxification. This review summarizes the c urrent knowledge of the processes that control the formation and fate of th e methylated metabolites of arsenic and of the biological effects of these compounds. Given the considerable interest in the dose-response relationshi ps for arsenic as a toxin and a carcinogen, understanding the metabolism of arsenic may be critical to assessing the risk associated with chronic expo sure to this element. (C) 2001 Academic Press.