Dimethylarsine and trimethylarsine are potent genotoxins in vitro.

Abstract

The mechanism of arsenic carcinogenesis is unclear. A complicating factor receiving increasing attention is that arsenic is biomethylated to form various metabolites. Eleven different arsenicals were studied for in vitro genotoxicity to supercoiled DNA (pBR 322 and phiX174). Five arsenicals showed various degrees of positivity-monomethylarsonous acid, dimethylarsinous acid, monomethylarsine, dimethylarsine, and trimethylarsine. Supercoiled DNA, blotted on nitrocellulose filter paper, was exposed to gaseous arsines by suspending the filter paper above aqueous reaction mixtures of sodium borohydride and an appropriate arsenical. All three methylated arsines damaged DNA; inorganic arsine did not. Arsines were generated in situ in reaction mixtures containing DNA by reaction of sodium borohydride with arsenite, monomethylarsonous acid, dimethylarsinous acid, and trimethylarsine oxide, at pH 8.0. Both dimethylarsine and trimethylarsine (generated from 200 micro M dimethylarsinous acid and trimethylarsine oxide, respectively) damaged DNA in less than 30 min. Under certain conditions, the two most potent genotoxic arsines, trimethylarsine and dimethylarsine, are about 100 times more potent than dimethylarsinous acid (the most potent genotoxic arsenical previously known). There was no evidence to suggest that anything other than the arsines caused the DNA damage. Possible models for the biological production of arsines were examined. The coenzymes, NADH and NADPH, are biological hydride donors. When NADH or NADPH (5 mM) were incubated with dimethylarsinous acid (0-2 mM) for 2 h, DNA damage was increased by at least 10-fold. A possible explanation for this result is that these compounds react with dimethylarsinous acid to generate dimethylarsine. DNA was incubated with a dithiol compound, dithioerythritol (5 mM), and trimethylarsine oxide (0.5 mM) for 2 h, and the reduction of trimethylarsine oxide to trimethylarsine resulted in DNA damage.