Methylated Trivalent Arsenic Species Are Genotoxic

Abstract

The reactivities of methyloxoarsine (MAs^III) and iododimethylarsine (DMAs^III), two methylated trivalent arsenicals, toward supercoiled φX174 RFI DNA were assessed using a DNA nicking assay. The induction of DNA damage by these compounds in vitro in human peripheral lymphocytes was assessed using a single-cell gel (SCG, “comet”) assay. Both methylated trivalent arsenicals were able to nick and/or completely degrade φX174 DNA in vitro in 2 h incubations at 37 °C (pH 7.4) depending on concentration. MAs^III was effective at nicking φX174 DNA at 30 mM; however, at 150 μM DMAs^III, nicking could be observed. Exposure of φX174 DNA to sodium arsenite (iAs^III; from 1 nM up to 300 mM), sodium arsenate (from 1 μM to 1 M), and the pentavalent arsenicals, monomethylarsonic acid (from 1 μM to 3 M) and dimethylarsinic acid (from 0.1 to 300 mM), did not nick or degrade φX174 DNA under these conditions. In the SCG assay in human lymphocytes, methylated trivalent arsenicals were much more potent than any other arsenicals that were tested. On the basis of the slopes of the concentration−response curve for the tail moment in the SCG assay, MAs^III and DMAs^III were 77 and 386 times more potent than iAs^III, respectively. Because methylated trivalent arsenicals were the only arsenic compounds that were observed to damage naked DNA and required no exogenously added enzymatic or chemical activation systems, they are considered here to be direct-acting forms of arsenic that are genotoxic, though they are not, necessarily, the only genotoxic species of arsenic that could exist.