The role of active arsenic species produced by metabolic reduction of dimethylarsinic acid in genotoxicity and tumorigenesis : The contribution of dimethylarsenic radicals and dimethylarsenic peroxide

在最近的研究中，一些研究人员已经指导了他们对非有机化学的甲基化代谢物的关注。由于其高细胞毒性和基因毒性，三甲基化的砷，可以通过二甲基化酸（DMA）的代谢减少来产生，可以从砷致癌物的标准点吸引可观察的注意力。我们研究了三重化的砷及其更多的代谢物，用于其化学性质和生物行为，如遗传学和肿瘤学。我们在体外实验中的实验认为，DNA中的顺式三甲基糖醇的形成是通过分子氧的三甲基化砷过氧化物的反应诱导产生的，但不是通过普通反应氧化物物种的产生（ROS ;超氧化物、氢过氧化物、羟基基等）。在老鼠建议的氧化性压力下，两步肿瘤起源测试表明，三重化的皮肤发挥了一个重要的作用在皮肤上的肿瘤促进。因此，二甲基化的砷过氧化物可能对皮肤肿瘤生成中的肿瘤促进的主要物种负责，可通过暴露于DMA。微核试验使用了一种可以接受的二甲基化砷的小鼠周边血液视网膜细胞，其中可能是三甲基化砷的进一步减少性代谢物，是DNA损伤比三甲基化砷的主要反应。自由基物种，如dimethylarsenic radical [（CH_3）_2As·]和/或dimethylarsenic过氧化物自由基[（CH_3）_2AsOO·]，它们由分子氧和dimethylarsine的反应产生[（CH_3）_2AsH]，可能是小鼠-肺结核中启动的主要代理。

In recent research of arsenic carcinogenesis, many researchers have directed their attention to methylated metabolites of inorganic arsenics. Because of its high cytotoxicity and genotoxicity, trivalent dimethylated arsenic, which can be produced by the metabolic reduction of dimethylarsinic acid(DMA), has attracted considerable attention from the standpoint of arsenic carcinogenesis. We examined trivalent dimethylated arsenic and its further metabolites for their chemical properties and biological behavior such as genotoxicity and tumorigenicity. Our in vitro experiments suggested that the formation of cis-thymine glycol in DNA was induced via the production of dimethylated arsenic peroxide by the reaction of trivalent dimethylated arsenic with molecular oxygen, but not via the production of common reactive oxygen species (ROS ; superoxide, hydrogen peroxide, hydroxyl radical, etc.). Two-step tumorigenesis test in mice suggested that oxidative stress by exposure to trivalent dimethylated arsenic plays an important role in tumor promotion in skin. Thus, dimethylated arsenic peroxide may be the main species responsible for the tumor promotion in skin tumorigenesis induced by exposure to DMA. Micronucleus assay using peripheral blood reticulocytes of mice suggested that dimethylarsine, which is probably a further reductive metabolite of trivalent dimethylated arsenic, is primarily responsible for DNA damage rather than trivalent dimethylated arsenic. Free radical species, such as dimethylarsenic radical [(CH_3)_2As・] and/or dimethylarsenic peroxy radical [(CH_3)_2AsOO・], that are produced by the reaction of molecular oxygen and dimethylarsine [(CH_3)_2AsH], may be main agents for initiation in mouse-lung tumorigenesis.