Dimethylarsine likely acts as a mouse-pulmonary tumor initiator via the production of dimethylarsine radical and/or its peroxy radical.
OBJECTIVE
Recent animal experiments have indicated that dimethylarsinic acid (DMA), a main metabolite of inorganic arsenic, is a complete carcinogen in the lung of mice and the urinary bladder of rats, nevertheless, no ultimate-active metabolite from DMA has been identified thus far. We have proposed that dimethylarsine ((CH(3))(2)AsH), an ultimate reductive metabolite of DMA, is excreted in the expired air of mice administered DMA, and furthermore, was easily converted into dimethylarsine radical ((CH(3))(2)As*) and dimethylarsine peroxy radical ((CH(3))(2)AsOO*) by its reaction with O(2). The aim of the present study was to elucidate the possible mode of the tumorigenic action by dimethylated arsenic.


METHODS
In vitro experiments using GSH reductase as a two-electron donor of dimethylarsenic-glutathione conjugate ((CH(3))(2)As-SG) and DNA adduct assay via a photochemical approach were performed. A lung tumorigenicity assay of (CH(3))(2)AsH suspended in argon-atmospheric olive oil for 5 days was also conducted in mice.


RESULTS
The results indicated that (CH(3))(2)AsH was easily produced enzymatically from (CH(3))(2)As-SG and showed tumor-initiating action in mouse lung via the production of (CH(3))(2)As* and (CH(3))(2)AsOO* by its reaction with O(2), and that these radicals have the ability to form DNA adducts.


CONCLUSIONS
The carcinogenicity of DMA, at least in mouse lung, could be explained based on the proposal that oral administration of DMA induces pulmonary tumors in mice, and arises from the arsine radicals produced through (CH(3))(2)AsH, which was enzymatically reduced from (CH(3))(2)As-SG.
Yamanaka
Kenzo
K
Research Unit of Environmental Toxicology & Carcinogenesis, Nihon University College of Pharmacy, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan. yamanaka.kenzo@nihon-u.ac.jp
Kato
Koichi
K
Mizoi
Mutsumi
M
An
Yan
Y
Nakanao
Masayuki
M
Hoshino
Mikio
M
Okada
Shoji
S
D000818:Animals; D001152:Arsenicals / Q000737:chemistry / Q000494:pharmacology*; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D018736:DNA Adducts; D005609:Free Radicals; D008175:Lung Neoplasms / Q000139:chemically induced*; D008297:Male; D051379:Mice; D010777:Photochemistry
D001152:Arsenicals; D002273:Carcinogens; D018736:DNA Adducts; D005609:Free Radicals; C062856:dimethylarsine