Monomethylarsonous acid (MMA^III) and arsenite: LD₅₀ in hamsters and in vitro inhibition of pyruvate dehydrogenase

Monomethylarsonous acid (MMA^III), a metabolite of inorganic arsenic, has received very little attention from investigators of arsenic metabolism in humans. MMA^III, like sodium arsenite, contains arsenic in the +3 oxidation state. Although we have previously demonstrated that it is more toxic than arsenite in cultured Chang human hepatocytes, there are no data showing in vivo toxicity of MMA^III. When MMA^III sodium arsenite was administered intraperitoneally to hamsters, the LD₅₀s were 29.3 and 112.0 μmol/kg of body wt, respectively. In addition, inhibition of hamster kidney or purified porcine heart pyruvate dehydrogenase (PDH) activity by MMA^III or arsenite was determined. To inhibit hamster kidney PDH activity by 50%, the concentrations (mean ± SE) of MMA^III as methylarsine oxide, MMA^III as diiodomethylarsine, and arsenite were 59.9 ± 6.5, 62.0 ± 1.8, and 115.7 ± 2.3 μM, respectively. To inhibit activity of purified porcine heart PDH activity by 50%, the concentrations (mean ± SE) of MMA^III as methylarsine oxide and arsenite were 17.6 ± 4.1 and 106.1 ± 19.8 μM, respectively. These data demonstrate that MMA^III is more toxic than inorganic arsenite, both in vivo and in vitro, and call into question the hypothesis that methylation of inorganic arsenic is a detoxication process.