Arsenic essentiality: A role affecting methionine metabolism†‡

Although there is no known biological function of arsenic, considerable evidence suggests that arsenic has a physiological role related to methionine metabolism. In early studies using amino acid-based diets, it was found that arsenic deprivation had little effect on growth in rats fed adequate methionine. However, in rats fed suboptimal methionine, arsenic deprivation resulted in a significant reduction in body weight. Other studies showed that feeding methyl depletors caused severe signs of arsenic deprivation. Because it was found that alteration in methionine status or methyl metabolism affected signs of arsenic deprivation, and that many of these signs were related to methionine or methyl metabolism, it was hypothesized that arsenic has a physiological role affecting methionine metabolism. In animal studies testing this hypothesis, it was shown that arsenic deprivation reduces the hepatic concentration of S-adenosylmethionine. Additionally, arsenic status affects DNA methylation in animal and cell culture models; very low or high doses of arsenic, compared with control amounts, result in an apparent hypomethylation of DNA. Because global DNA hypomethylation is associated with an increased incidence of cancer, we tested whether dietary arsenic (deficient, adequate, or excess; 0, 0.5 or 50 μg arsenic/g diet, respectively) would affect the formation of aberrant crypts in rats treated with the carcinogen dimethylhydrazine. Aberrant crypts are preneoplastic lesions that have been associated with colon carcinomas. More aberrant crypts were observed in rats fed the high amount of dietary arsenic compared to those fed adequate arsenic. The number of aberrant crypts in the arsenic-deprived group also tended to be higher than those found in rats fed adequate arsenic. Thus, many findings indicate that arsenic plays a role in methionine/methyl metabolism; however, the site of action of arsenic remains unknown. Possibly, arsenic is instrumental in maintaining the metabolic pool of S-adenosylmethionine. These results show that compared to controlled amounts, having too little or too much arsenic in the diet is harmful. That is, there is an amount of dietary arsenic that is not only not harmful, but beneficial. J. Trace Elem. Exp. Med. 16:345–355, 2003. Published 2003 Wiley-Liss, Inc.