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 oxidatio n state. Although we have previously demonstrated that it is more toxic tha n arsenite in cultured Chang human hepatocytes, there are no data showing i n vivo toxicity of MMA(III). When MMA(III) or sodium arsenite was administe red intraperitoneally to hamsters, the LD50S were 29.3 and 112.0 mu mol/kg of body wt, respectively. In addition, inhibition of hamster kidney or puri fied porcine heart pyruvate dehydrogenase (PDH) activity by MMA(III) or ars enite was determined. To inhibit hamster kidney PDH activity by 50%, the co ncentrations (mean +/- SE) of MMA(III) as methylarsine oxide, MMA(III) as d iiodomethylarsine, and arsenite were 59.9 +/- 6.5, 62.0 +/- 1.8, and 115.7 +/- 2.3 muM, respectively. To inhibit activity of purified porcine heart PD H activity by 50%, the concentrations (mean +/- SE) of MMA(III) as methylar sine oxide and arsenite were 17.6 +/- 4.1 and 106.1 +/- 19.8 muM, respectiv ely. These data demonstrate that MMA(III) is more toxic than inorganic arse nite, both in vivo and in vitro, and call into question the hypothesis that methylation of inorganic arsenic is a detoxication process.