The role of active arsenic species produced by metabolic reduction of dimethylarsinic acid in genotoxicity and tumorigenesis.
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 [(CH(3))(2)As.] and dimethylarsenic peroxy radical [(CH(3))(2)AsOO.], that are produced by the reaction of molecular oxygen and dimethylarsine [(CH(3))(2)AsH], which is probably a further reductive metabolite of trivalent dimethylated arsenic, may be main agents for initiation in mouse lung tumorigenesis.
Yamanaka
Kenzo
K
Department of Biochemical Toxicology, Nihon University College of Pharmacy, Funabashi, Chiba 274-8555, Japan. yamanaka@pha.nihon-u.ac.jp
Kato
Koichi
K
Mizoi
Mutsumi
M
An
Yan
Y
Takabayashi
Fumiyo
F
Nakano
Masayuki
M
Hoshino
Mikio
M
Okada
Shoji
S
D000818:Animals; D002101:Cacodylic Acid / Q000378:metabolism* / Q000633:toxicity; D002273:Carcinogens / Q000494:pharmacology; D006540:Herbicides / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D008813:Mice, Inbred ICR; D009153:Mutagens / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D013941:Thymine / Q000031:analogs & derivatives* / Q000378:metabolism
D002273:Carcinogens; D006540:Herbicides; D009153:Mutagens; C029389:thymine glycol; D002101:Cacodylic Acid; D013941:Thymine