Pharmacokinetics Branch, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Toxicol Sci. 2010 Jan;113(1):70-6. doi: 10.1093/toxsci/kfp250. Epub 2009 Oct 15.
Biotransformation of inorganic arsenic (iAs) involves methylation catalyzed by arsenic (+ 3 oxidation state) methyltransferase (As3mt) yielding mono-, di-, and trimethylated arsenicals. To investigate the evolution of molecular mechanisms that mediate arsenic biotransformation, a comparative genomic approach focusing on the invertebrate chordate Ciona intestinalis was used. Bioinformatic analyses identified an As3mt gene in the C. intestinalis genome. Constitutive As3mt RNA expression was observed in heart, branchial sac, and gastrointestinal tract. Adult animals were exposed to 0 or 1 ppm of iAs for 1 or 5 days. Steady-state As3mt RNA expression in the gastrointestinal tract was not modulated significantly by 5 days of exposure to iAs. Tissue levels of iAs and its methylated metabolites were determined by hydride generation-cryotrapping-gas chromatography-atomic absorption spectrometry. At either time point, exposure to iAs significantly increased concentrations of iAs and its methylated metabolites in tissues. After 5 days of exposure, total speciated arsenic concentrations were highest in branchial sac (3705 ng/g), followed by heart (1019 ng/g) and gastrointestinal tract (835 ng/g). At this time point, the sum of the speciated arsenical concentrations in gastrointestinal tract and heart equaled or exceeded that of iAs; in branchial sac, iAs was the predominant species present. Ciona intestinalis metabolizes iAs to its methylated metabolites, which are retained in tissues. This metabolic pattern is consistent with the presence of an As3mt ortholog in its genome and constitutive expression of the gene in prominent organs, making this basal chordate a useful model to examine the evolution of arsenic detoxification.
无机砷（iAs）的生物转化涉及砷（+3 氧化态）甲基转移酶（As3mt）催化的甲基化，生成单、二和三甲基砷。为了研究介导砷生物转化的分子机制的进化，采用了一种专注于无脊椎脊索动物文昌鱼（Ciona intestinalis）的比较基因组方法。生物信息学分析在文昌鱼基因组中鉴定出一个 As3mt 基因。在心脏、鳃囊和胃肠道中观察到组成型 As3mt RNA 表达。成年动物暴露于 0 或 1 ppm 的 iAs 中 1 或 5 天。5 天暴露于 iAs 对胃肠道中 As3mt RNA 表达的稳态没有显著调节。通过氢化物发生-冷阱-气相色谱-原子吸收光谱法测定组织中的 iAs 及其甲基化代谢物的水平。在任何时间点，暴露于 iAs 都会显著增加组织中 iAs 及其甲基化代谢物的浓度。暴露 5 天后，鳃囊中总砷形态浓度最高（3705 ng/g），其次是心脏（1019 ng/g）和胃肠道（835 ng/g）。此时，胃肠道和心脏中砷形态浓度的总和等于或超过 iAs；在鳃囊中，iAs 是主要存在的物种。文昌鱼将 iAs 代谢为其甲基化代谢物，这些代谢物保留在组织中。这种代谢模式与基因组中存在 As3mt 直系同源物以及该基因在主要器官中的组成型表达一致，使这种基础脊索动物成为研究砷解毒进化的有用模型。
