Can folate intake reduce arsenic toxicity?

Abstract

Arsenic-contaminated groundwater is a global environmental health concern. Inorganic arsenic is a known carcinogen, and epidemiologic studies suggest that persons with impaired arsenic metabolism are at increased risk for certain cancers, including skin and bladder carcinoma. Arsenic metabolism involves methylation to monomethylarsonic acid and dimethylarsinic acid (DMA) by a folate-dependent process. Persons possessing polymorphisms in certain genes involved in folate metabolism excrete a lower proportion of urinary arsenic as DMA, which may influence susceptibility to arsenic toxicity. A double-blind placebo-controlled trial in a population with low plasma folate observed that after 12 weeks of folic acid supplementation, the proportion of total urinary arsenic excreted as DMA increased and blood arsenic concentration decreased, suggesting an improvement in arsenic metabolism. Although no studies have directly shown that high folate intake reduces the risk of arsenic toxicity, these findings provide evidence to support an interaction between folate and arsenic metabolism.

Figure 1. Folate and arsenic metabolism

Insufficient folate and vitamin B₁₂ intake could influence arsenic toxicity through aberrant gene expression due to altered DNA methylation (1), decreased arsenic methylation (2), or impaired DNA repair (3). Genetic polymorphisms in the reduced folate carrier gene (RFC-1) can result in lower serum folate levels (A). Two genetic variants (MTHFR C667T and MTHFR A1298C) in methylenetetrahydrofolate reductase (MTHFR) (B) decrease the synthesis of 5-methyl-THF. 5-methyl-THF, along with vitamin B₁₂, is required by the methionine cycle to remethylate homocysteine to methionine (C), in a reaction catalyzed by methionine synthetase (MS, also known as 5-methyltetrahydrofolate-homocysteine methyltransferase, MTR) and to generate S-adenosylmethionine (SAM), in a reaction catalyzed by methionine adenosyltransferase (D).