Mouse Arsenic (+3 Oxidation State) Methyltransferase Genotype Affects Metabolism and Tissue Dosimetry of Arsenicals after Arsenite Administration in Drinking Water
Mouse Arsenic (+3 Oxidation State) Methyltransferase Genotype Affects Metabolism and Tissue Dosimetry of Arsenicals after Arsenite Administration in Drinking Water
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DOI：
10.1093/toxsci/kfr246
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发表时间：
2011-12-01
影响因子：
3.8
通讯作者：
Le, X. Chris
中科院分区：
文献类型：
--
作者：
Chen, Baowei;Arnold, Lora L.;Le, X. Chris
砷（+3 氧化态）甲基转移酶 (As3mt) 催化无机砷 (iAs) 的甲基化，产生许多甲基化砷代谢物。尽管甲基化通常被认为是砷解毒的一种途径，但一些高反应性的甲基化砷可能会导致与接触无机砷相关的毒性。在这里，成年雌性野生型 (WT) C57BL/6 小鼠和雌性 As3mt 敲除 (KO) 小鼠接受含有 1、10 或 25 ppm (mg/l) 亚砷酸盐的饮用水 33 天，并采集血液、肝脏、肾脏和肺进行砷形态分析。基因型显着影响组织中砷的浓度。 WT 小鼠血浆中砷的总浓度高于 KO 小鼠；在红细胞中，KO 小鼠的砷总浓度高于 WT 小鼠。在肝脏、肾脏和肺中，KO 小鼠的砷总浓度高于 WT 小鼠。尽管 KO 小鼠的砷甲基化能力大大降低，但在 KO 小鼠的组织中发现了一些单甲基化、二甲基化和三甲基化砷，这可能反映了其他组织甲基转移酶的活性或胃肠道微生物群的预吸收代谢。这些结果表明，砷甲基化的基因型决定了砷的保留和分布的表型，并影响与无机砷暴露相关的剂量和器官依赖性毒性。
Arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes methylation of inorganic arsenic (iAs) producing a number of methylated arsenic metabolites. Although methylation has been commonly considered a pathway for detoxification of arsenic, some highly reactive methylated arsenicals may contribute to toxicity associated with exposure to inorganic arsenic. Here, adult female wild-type (WT) C57BL/6 mice and female As3mt knockout (KO) mice received drinking water that contained 1, 10, or 25 ppm (mg/l) of arsenite for 33 days and blood, liver, kidney, and lung were taken for arsenic speciation. Genotype markedly affected concentrations of arsenicals in tissues. Summed concentrations of arsenicals in plasma were higher in WT than in KO mice; in red blood cells, summed concentrations of arsenicals were higher in KO than in WT mice. In liver, kidney, and lung, summed concentrations of arsenicals were greater in KO than in WT mice. Although capacity for arsenic methylation is much reduced in KO mice, some mono-, di-, and tri-methylated arsenicals were found in tissues of KO mice, likely reflecting the activity of other tissue methyltransferases or preabsorptive metabolism by the microbiota of the gastrointestinal tract. These results show that the genotype for arsenic methylation determines the phenotypes of arsenic retention and distribution and affects the dose- and organ-dependent toxicity associated with exposure to inorganic arsenic.