Petrick J S, Jagadish B, Mash E A, Aposhian H V
Department of Pharmacology and Toxicology, and Center for Toxicology, The University of Arizona, Tucson, Arizona 85721, USA.
Chem Res Toxicol. 2001 Jun;14(6):651-6. doi: 10.1021/tx000264z.
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 LD(50)s were 29.3 and 112.0 micromol/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 microM, 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 microM, 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.
一甲基亚胂酸（MMA(III)）是无机砷的一种代谢产物，在人体砷代谢研究中很少受到研究者的关注。MMA(III)与亚砷酸钠一样，砷的氧化态为 +3。尽管我们之前已证明，在培养的张氏人肝细胞中，它比亚砷酸盐毒性更大，但尚无数据表明MMA(III)的体内毒性。当向仓鼠腹腔注射MMA(III)或亚砷酸钠时，半数致死量（LD(50)）分别为29.3和112.0微摩尔/千克体重。此外，还测定了MMA(III)或亚砷酸盐对仓鼠肾脏或纯化的猪心丙酮酸脱氢酶（PDH）活性的抑制作用。为使仓鼠肾脏PDH活性抑制50%，以氧化甲基胂形式存在的MMA(III)、以二碘甲基胂形式存在的MMA(III)和亚砷酸盐的浓度（平均值±标准误）分别为59.9±6.5、62.0±1.8和115.7±2.3微摩尔/升。为使纯化的猪心PDH活性抑制50%，以氧化甲基胂形式存在的MMA(III)和亚砷酸盐的浓度（平均值±标准误）分别为17.6±4.1和106.1±19.8微摩尔/升。这些数据表明，MMA(III)在体内和体外都比亚砷酸盐毒性更大，这对无机砷甲基化是解毒过程这一假说提出了质疑。
