The enigma of arsenic carcinogenesis: Role of metabolism

Inorganic arsenic is considered a high-priority hazard, particularly becaus e of its potential to be a human carcinogen. In exposed human populations, arsenic is associated with tumors of the lung, skin, bladder, and liver. Wh ile it is known to be a human carcinogen, carcinogenesis in laboratory anim als by this metalloid has never been convincingly demonstrated. Therefore, no animal models exist for studying molecular mechanisms of arsenic carcino genesis, The apparent human sensitivity, combined with our incomplete under standing about mechanisms of carcinogenic action, create important public h ealth concerns and challenges in risk assessment, which could be met by und erstanding the role of metabolism in arsenic toxicity and carcinogenesis. T his symposium summary covers three critical major areas involving arsenic m etabolism: its biodiversity, the role of arsenic metabolism in molecular me chanisms of carcinogenesis, and the impact of arsenic metabolism on human r isk assessment. In mammals, arsenic is metabolized to mono- and dimethylate d species by methyltransferase enzymes in reactions that require S-adenosyl -methionine (SAM) as the methyl donating cofactor. A remarkable species div ersity in arsenic methyltransferase activity may account for the wide varia bility in sensitivity of humans and animals to arsenic toxicity. Arsenic in terferes with DNA methyltransferases, resulting in inactivation of tumor su ppressor genes through DNA hypermethylation, Other studies suggest that ars enic-induced malignant transformation is linked to DNA hypomethylation subs equent to depletion of SAM, which results in aberrant gene activation, incl uding oncogenes, Urinary profiles of arsenic metabolites may be a valuable tool for assessing human susceptibility to arsenic carcinogenesis. While co ntroversial, the idea that unique arsenic metabolic properties may explain the apparent non-linear threshold response for arsenic carcinogenesis in hu mans. In order to address these outstanding issues, further efforts are req uired to identify an appropriate animal model to elucidate carcinogenic mec hanisms of action, and to define dose-response relationships.