Comparative toxicity of trivalent and pentavalent inorganic and methylatedarsenicals in rat and human cells

Biomethylation is considered a major detoxification pathway for inorganic a rsenicals (iAs). According to the postulated metabolic scheme, the methylat ion of iAs yields methylated metabolites in which arsenic is present in bot h pentavalent and trivalent forms. Pentavalent mono- and dimethylated arsen icals are less acutely toxic than iAs. However, little is known about the t oxicity of trivalent methylated species. In the work reported here the toxi cities of iAs and trivalent and pentavalent methylated arsenicals were exam ined in cultured human cells derived from tissues that are considered a maj or site for iAs methylation (liver) or targets for carcinogenic effects ass ociated with exposure to iAs (skin, urinary bladder, and lung). To characte rize the role of methylation in the protection against toxicity of arsenica ls, the capacities of cells to produce methylated metabolites were also exa mined. In addition to human cells, primary rat hepatocytes were used as met hylating controls. Among the arsenicals examined, trivalent monomethylated species were the most cytotoxic in all cell types. Trivalent dimethylated a rsenicals were at least as cytotoxic as trivalent iAs (arsenite) for most c ell types. Pentavalent arsenicals were significantly less cytotoxic than th eir trivalent analogs. Among the cell types examined, primary rat hepatocyt es exhibited the greatest methylation capacity for iAs followed by primary human hepatocytes, epidermal keratinocytes, and bronchial epithelial cells. Cells derived from human bladder did not methylate iAs. There was no appar ent correlation between susceptibility of cells to arsenic toxicity and the ir capacity to methylate iAs. These results suggest that (1) trivalent meth ylated arsenicals, intermediary products of arsenic methylation, may signif icantly contribute to the adverse effects associated with exposure to iAs, and (2) high methylation capacity does not protect cells from the acute tox icity of trivalent arsenicals.