Arsenic Methylation, Oxidative Stress and Cancer--Is There a Link?

Abstract

Arsenic is a multiorgan human carcinogen. The best-known example of this effect occurred in subgroups of the Taiwanese population who were chronically exposed to high levels of naturally occurring arsenic in drinking water and developed cancers of the skin, lung, urinary bladder, and potentially the kidney ( 1 ). Nonneoplastic effects that are attributed to arsenic exposure under similar conditions include vascular disease, hypertension, diabetes, and dermal lesions ( 2 , 3 ). Many countries today still have arseniccontaminated drinking water and are facing a potential public health crisis ( 4 ). Although the carcinogenicity of arsenic in humans has been known for more than 100 years, there is no defi nitive understanding of the mechanism of action for this effect. This gap in knowledge has been partly because of the lack of positive animal carcinogenicity studies for a number of years, because arsenic is not a point mutagen, and because the mechanism for the biotransformation of arsenic was not completely known. In the 1990s, attention became focused on the potential tumor-promoting and carcinogenic effects of the methylated metabolites of arsenic. Investigations found that dimethylarsinic acid [DMAs(V)], a pentavalent metabolite of inorganic arsenic, was a multiorgan tumor promoter in rodents ( 5 ) and was carcinogenic in rat urinary bladder following chronic dietary or drinking water exposure ( 6 , 7 ). Arsenic was also found to be carcinogenic in more recent studies using transgenic animals ( 5 ) or transplacental exposure in mice ( 8 ). In the 1940s, Challenger ( 9 ) proposed a pathway for arsenic metabolism that included reduction of a pentavalent (V) arsenical to a trivalent (III) arsenical by transfer of two electrons, followed by oxidative methylation using the methyl donor, S -adenosyl methionine. The pathway is shown below: Arsenate [iAs(V)] + 2 e → Arsenite [iAs(III)] + CH 3 → Monomethylarsonic acid [MAs(V)] + 2 e → Monomethylarsonous acid [MAs(III)] + CH 3 → Dimethylarsinic acid [DMAs(V)] + 2 e → Dimethylarsinous acid [DMAs(III)] + CH 3 → Trimethylarsine oxide [TMAsO(V)] For years, the methylation of arsenic was considered to be a detoxifi cation mechanism. The reasons for this hypothesis were that the pentavalent methylated arsenicals [MAs(V), DMAs(V), and TMAsO(V)] were less acutely toxic than either arsenate [iAs(V)] or arsenite [iAs(III)] and that these methylated metabolites were rapidly excreted by mammals ( 10 ). The exception is in the rat, which retains administered arsenic ( 10 ) and has hemoglobin that avidly binds DMAs(III) ( 11 ). Also, the trivalent methylated arsenicals, MAs(III) and DMAs(III), had never been detected in vitro or in vivo.