权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

二甲基砷酸代谢还原产生的活性砷在遗传毒性和肿瘤发生中的作用：二甲基砷自由基和二甲基砷过氧化物的贡献

基本信息

批准号：
14572114
负责人：
YAMANAKA Kenzo
金额：
$ 1.66万
依托单位：
Nihon University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

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.

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。我们研究了三价二甲基砷及其进一步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过氧化二甲基化砷诱导的，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）。两步致瘤实验表明，氧化应激暴露于三价二甲基砷在皮肤中的肿瘤促进中起重要作用。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。小鼠外周血网织红细胞微核试验表明，二甲基胂，这可能是一个进一步的还原代谢产物的三价二甲基砷，是主要负责的DNA损伤，而不是三价二甲基砷。分子氧与二甲基胂[（CH_3）_2AsH]反应产生的自由基[（CH_3）_2As·]和/或二甲基胂过氧自由基[（CH_3）_2AsOO·]可能是引发小鼠肺肿瘤发生的主要因素。

项目成果

期刊论文数量（34）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Specific induction of oxidative stress in terminal bronchiolar Clara cells during dimethylarsenic-induced lung tumor promoting process in mice

DOI：
10.1016/j.canlet.2004.12.029
发表时间：
2005-12-08
期刊：
CANCER LETTERS
影响因子：
9.7
作者：
An, Y;Kato, K;Yamanaka, K
通讯作者：
Yamanaka, K

Koichi Kato et al.: "Active arsenic species produced by GSH-dependent reduction of dimethylarsinic acid cause micronuclei formation in peripheral reticulocytes of mice."Mutation Research. 539. 55-63 (2003)

Koichi Kato 等人：“二甲基胂酸的 GSH 依赖性还原产生的活性砷物质导致小鼠外周网织红细胞微核形成。”突变研究。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

The role of active arsenic species produced by metabolic reduction of dimethylarsinic acid in genotoxicity and tumorigenesis.

DOI：
10.1016/j.taap.2003.10.025
发表时间：
2004-08
期刊：
Toxicology and applied pharmacology
影响因子：
3.8
作者：
K. Yamanaka;Koichi Kato;Mutsumi Mizoi;Yan An;Fumiyo Takabayashi;Masayuki Nakano;M. Hoshino;S. Okada
通讯作者：
K. Yamanaka;Koichi Kato;Mutsumi Mizoi;Yan An;Fumiyo Takabayashi;Masayuki Nakano;M. Hoshino;S. Okada

Immunohistochemical analysis of oxidative DNA damage in arsenic-related human skin samples from arsenic-contaminated area of China