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

点击翻译按钮获取中文摘要

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.