Monomethylarsonous Acid (MMAIII) and Arsenite: LD50 in Hamsters and In Vitro Inhibition of Pyruvate Dehydrogenase

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Abstract
Monomethylarsonous acid (MMAIII), a metabolite of inorganic arsenic, has received very little attention from investigators of arsenic metabolism in humans. MMAIII, 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 MMAIII. When MMAIII or 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 MMAIII or arsenite was determined. To inhibit hamster kidney PDH activity by 50%, the concentrations (mean ± SE) of MMAIII as methylarsine oxide, MMAIII 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 MMAIII as methylarsine oxide and arsenite were 17.6 ± 4.1 and 106.1 ± 19.8 μM, respectively. These data demonstrate that MMAIII 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.