Fig. 1.

Arsenic biotransformation in humans. Worldwide, the most prevalent source of arsenic exposure in humans is drinking water contaminated with inorganic arsenic (iAs), which exists in two oxidation states, namely pentavalent arsenate (iAs^V) and trivalent arsenite (iAs^III). IAs^V is reduced to iAs^III mainly in the blood or liver by one of several mammalian enzymes that utilize glutathione (GSSH) or dithiothreitol (DTT) as reductants. The remaining steps of iAs biotransformation, which involve alternating oxidative methylation and reduction steps, occur mainly in the liver. In this process, iAs^III undergoes an oxidative methylation step catalyzed by arsenic (+3 oxidation state) methyltransferase (AS3MT) to produce monomethylarsonic acid (MMA^V). MMA^V is subsequently reduced to monomethylarsonous acid (MMA^III), which is the substrate for another round of oxidative methylation and reduction in which dimethylarsinic acid (DMA^V) and dimethylarsinous acid (DMA^III), respectively, are produced. AS3MT has been shown to catalyze both the oxidative methylation and successive reduction reactions using s-adenosyl methionine (SAM) as a methyl donor and various molecules such as nicotinamide adenine dinucleotide phosphate (NADPH), thioredoxin, DTT, or GSH as reductants (2e^-) [43, 45]. In general, total urinary arsenic in iAs-exposed individuals is composed of 10–20 % total (i.e. trivalent + pentavalent) iAs, 10–20 % total MMAs, and 60–80 % total DMAs [44]. (Modified from: Bailey KA and Fry RC, Arsenic-induced Changes to the Epigenome, in Toxicology and Epigenetics, S.C. Sahu, Editor. 2012, John Wiley & Sons, Ltd.: Chichester, UK) [22]