Petrick J S, Ayala-Fierro F, Cullen W R, Carter D E, Vasken Aposhian H
Department of Pharmacology and Toxicology, The University of Arizona, Tucson, Arizona 85721, USA.
Toxicol Appl Pharmacol. 2000 Mar 1;163(2):203-7. doi: 10.1006/taap.1999.8872.
Methylation has been considered to be the primary detoxication pathway of inorganic arsenic. Inorganic arsenic is methylated by many, but not all animal species, to monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MMA(III)), and dimethylarsinic acid (DMA(V)). The As(V) derivatives have been assumed to produce low toxicity, but the relative toxicity of MMA(III) remains unknown. In vitro toxicities of arsenate, arsenite, MMA(V), MMA(III), and DMA(V) were determined in Chang human hepatocytes. Leakage of lactate dehydrogenase (LDH) and intracellular potassium (K(+)) and mitochondrial metabolism of the tetrazolium salt XTT were used to assess cytotoxicity due to arsenic exposure. The mean LC50 based on LDH assays in phosphate media was 6 microM for MMA(III) and 68 microM for arsenite. Using the assay for K(+) leakage in phosphate media, the mean LC50 was 6.3 microM for MMA(III) and 19.8 microM for arsenite. The mean LC50 based on the XTT assay in phosphate media was 13.6 microM for MMA(III) and 164 microM for arsenite. The results of the three cytotoxicity assays (LDH, K(+), and XTT) reveal the following order of toxicity in Chang human hepatocytes: MMA(III) > arsenite > arsenate > MMA(V) = DMA(V). Data demonstrate that MMA(III), an intermediate in inorganic arsenic methylation, is highly toxic and again raises the question as to whether methylation of inorganic arsenic is a detoxication process.
甲基化被认为是无机砷的主要解毒途径。许多（但并非所有）动物物种会将无机砷甲基化为一甲基胂酸（MMA(V)）、一甲基亚胂酸（MMA(III)）和二甲基胂酸（DMA(V)）。As(V)衍生物被认为产生的毒性较低，但MMA(III)的相对毒性仍不清楚。在Chang人肝细胞中测定了砷酸盐、亚砷酸盐、MMA(V)、MMA(III)和DMA(V)的体外毒性。利用乳酸脱氢酶（LDH）泄漏、细胞内钾（K(+)）以及四唑盐XTT的线粒体代谢来评估砷暴露引起的细胞毒性。在磷酸盐培养基中基于LDH测定的MMA(III)平均半数致死浓度（LC50）为6微摩尔，亚砷酸盐为68微摩尔。在磷酸盐培养基中利用K(+)泄漏测定法，MMA(III)的平均LC50为6.3微摩尔，亚砷酸盐为19.8微摩尔。在磷酸盐培养基中基于XTT测定的MMA(III)平均LC50为13.6微摩尔，亚砷酸盐为164微摩尔。三种细胞毒性测定（LDH、K(+)和XTT）的结果揭示了Chang人肝细胞中以下毒性顺序：MMA(III)＞亚砷酸盐＞砷酸盐＞MMA(V) = DMA(V)。数据表明，无机砷甲基化过程中的中间体MMA(III)具有高毒性，这再次引发了无机砷甲基化是否为解毒过程的问题。
