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 ((CH3)2AsH), an ultimate reductive metabolite of DMA, is excreted in the expired air of mice administered DMA, and furthermore, was easily converted into dimethylarsine radical ((CH3)2As•) and dimethylarsine peroxy radical ((CH3)2AsOO•) by its reaction with O2. 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 ((CH3)2As-SG) and DNA adduct assay via a photochemical approach were performed. A lung tumorigenicity assay of (CH3)2AsH suspended in argon-atmospheric olive oil for 5 days was also conducted in mice.


RESULTS
The results indicated that (CH3)2AsH was easily produced enzymatically from (CH3)2As-SG and showed tumor-initiating action in mouse lung via the production of (CH3)2As• and (CH3)2AsOO• by its reaction with O2, 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 (CH3)2AsH, which was enzymatically reduced from (CH3)2As-SG.
Kenzo
K
Yamanaka
Koichi
K
Kato
Mutsumi
M
Mizoi
Yan
Y
An
Masayuki
M
Nakanao
Mikio
M
Hoshino
Shoji
S
Okada
D000818:Animals; D001152:Arsenicals / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D005980:Glutathione Reductase / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D010545:Peroxides / Q000378:metabolism*; D051381:Rats
D001152:Arsenicals; D002273:Carcinogens; D010545:Peroxides; C062856:dimethylarsine; D005980:Glutathione Reductase