Arsenic metabolism and thioarsenicals

Arsenic has received considerable attention in the world, since it can lead to a multitude of toxic effects and has been recognized as a human carcinogen causing cancers. Here, we focus on the current state of knowledge regarding the proposed mechanisms of arsenic biotransformation, with a little about cellular uptake, toxicity and clinical utilization of arsenicals. Since pentavalent methylated metabolites were found in animal urine after exposure to iAs(III), methylation was considered to be a detoxification process, but the discovery of methylated trivalent intermediates and thioarsenicals in urine has diverted the view and gained much interest regarding arsenic biotransformation. To further investigate the partially understood phenomena relating to arsenic toxicity and the uses of arsenic as a drug, it is important to elucidate the exact pathways involved in metabolism of this metalloid, as the toxicity and the clinical uses of arsenic can be best recognized in context of its biotransformation. Thereby, in this perspective, we have focused on arsenic metabolic pathways including three proposed mechanisms: a classic pathway by Challenger in 1945, followed by a new metabolic pathway proposed by Hayakawa in 2005 involving arsenic-glutathione complexes, while the third is a new reductive methylation pathway that is proposed by our group involving As-protein complexes. According to previous and present in vivo and in vitro experiments, we conclude that the methylation reaction takes place with simultaneous reductive rather than stepwise oxidative methylation. In addition, production of pentavalent methylated arsenic metabolites are suggested to be as the end product of metabolism, rather than intermediates.