Role of metabolism in arsenic toxicity

Abstract

In humans, as in most mammalian species, inorganic arsenic is methylated to methylarsonic acid (MMA) and dimethylarsinic acid (DMA) by alternating reduction of pentavalent arsenic to trivalent and addition of a methyl group from S-adenosylmethionine. The methylation of inorganic arsenic may be considered a detoxification mechanism, as the end metabolites, MMA and DMA, are less reactive with tissue constituents, less toxic, and more readily excreted in the urine than is inorganic arsenic, especially the trivalent form (AsIII, arsenite). The latter is highly reactive with tissue components, due to its strong affinity for sulfhydryl groups. Thus, following exposure to AsV the first step in the biotransformation, i.e. the reduction to AsIII, may be considered a bioactivation. Also, reactive intermediate metabolites of high toxicity, mainly MMAIII, may be formed and distributed to tissues. Low levels of MMAIII and DMAIII have been detected in urine of individuals chronically exposed to inorganic arsenic via drinking water. However, the contribution of MMAIIIand DMAIII to the toxicity observed after intake of inorganic arsenic by humans remains to be elucidated. The major route of excretion of arsenic is via the kidneys. Evaluation of the methylation of arsenic is mainly based on the relative amounts of the different metabolites in urine. On average human urine contains 10-30% inorganic arsenic, 10-20% MMA and 60-80% DMA.