Monomethylarsonous acid (MMAIII) and arsenite:: LD50 in hamsters and in vitro inhibition of pyruvate dehydrogenase
Monomethylarsonous acid (MMAIII) and arsenite:: LD50 in hamsters and in vitro inhibition of pyruvate dehydrogenase
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DOI：
10.1021/tx000264z
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发表时间：
2001-06-01
影响因子：
4.1
通讯作者：
Aposhian, HV
中科院分区：
文献类型：
--
作者：
Petrick, JS;Jagadish, B;Aposhian, HV
一甲基larsonous酸（MMA(III)）是无机砷的代谢物，很少受到人体砷代谢研究人员的关注。MMA（III）与亚砷酸钠一样，含有+3氧化态的砷。虽然我们之前已经证明MMA在培养的Chang人肝细胞中比亚砷酸盐毒性更大，但没有数据显示MMA的体内毒性（III）。小鼠腹腔注射MMA（III）和亚砷酸钠时，LD50S分别为29.3和112.0 mu mol/kg体重。此外，还测定了MMA（III）或亚砷酸盐对仓鼠肾脏或纯化猪心脏丙酮酸脱氢酶（PDH）活性的抑制作用。MMA（III）以氧化甲基larsin、二碘甲基larsin和亚砷酸盐的浓度（平均+/- SE）分别为59.9 +/- 6.5、62.0 +/- 1.8和115.7 +/- 2.3 muM，对仓鼠肾脏PDH活性的抑制作用为50%。MMA（III）作为氧化甲基larsine和亚砷酸盐的浓度（平均+/- SE）分别为17.6 +/- 4.1和106.1 +/- 19.8 muM，对纯化猪心脏PDH活性的抑制作用为50%。这些数据表明，MMA（III）在体内和体外都比无机亚砷酸盐毒性更大，并对无机砷的甲基化是一个解毒过程的假设提出了质疑。
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) or sodium arsenite was administered 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 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 muM, 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 muM, 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.