The role of active arsenic species produced by metabolic reduction of dimethylarsinic acid in genotoxicity and tumorigenesis.
The role of active arsenic species produced by metabolic reduction of dimethylarsinic acid in genotoxicity and tumorigenesis.
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DOI：
10.1016/j.taap.2003.10.025
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发表时间：
2004-08
影响因子：
3.8
通讯作者：
K. Yamanaka;Koichi Kato;Mutsumi Mizoi;Yan An;Fumiyo Takabayashi;Masayuki Nakano;M. Hoshino;S. Okada
中科院分区：
文献类型：
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作者：
K. Yamanaka;Koichi Kato;Mutsumi Mizoi;Yan An;Fumiyo Takabayashi;Masayuki Nakano;M. Hoshino;S. Okada
近年来，在砷致癌作用的研究中，无机砷的甲基化代谢产物引起了许多研究者的关注。二甲基胂酸（DMA）代谢还原产生的三价二甲基砷因其高细胞毒性和遗传毒性，从砷致癌的角度引起了人们的广泛关注。本论文研究了三价二甲基砷及其代谢产物的化学性质和生物学行为，如遗传毒性和致瘤性。我们的体外和体内实验表明，DNA中的顺式胸腺嘧啶乙二醇的形成是通过三价二甲基化砷与分子氧反应产生二甲基化过氧化砷诱导的，而不是通过产生常见的活性氧（ROS;超氧化物，过氧化氢，羟基自由基等）。因此，二甲基化过氧化砷可能是主要的物种负责的肿瘤促进皮肤肿瘤的发生诱导暴露于DMA。分子氧与二甲基胂[（CH_3）_2AsH]反应产生的自由基[（CH_3）_2As·]和[（CH_3）_2AsOO·]可能是三价二甲基砷的进一步还原代谢产物，可能是引发小鼠肺肿瘤发生的主要因素。
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. In the present paper, we examined trivalent dimethylated arsenic and its further metabolites for their chemical properties and biological behavior such as genotoxicity and tumorigenicity. Our in vitro and in vivo 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.). Thus, dimethylated arsenic peroxide may be the main species responsible for the tumor promotion in skin tumorigenesis induced by exposure to DMA. Free radical species, such as dimethylarsenic radical [(CH3)2As·] and dimethylarsenic peroxy radical [(CH3)2AsOO·], that are produced by the reaction of molecular oxygen and dimethylarsine [(CH3)2AsH], which is probably a further reductive metabolite of trivalent dimethylated arsenic, may be main agents for initiation in mouse lung tumorigenesis.