Dimethylarsine likely acts as a mouse-pulmonary tumor initiator via the production of dimethylarsine radical and/or its peroxy radical.

Abstract

AIMS:

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.

MAIN 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.

KEY FINDINGS:

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.

SIGNIFICANCE:

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.

• Authors: Kenzo Yamanaka, Koichi Kato, Mutsumi Mizoi, Yan An, Masayuki Nakanao, Mikio Hoshino, Shoji Okada
• Journal: Life sciences (Life Sci) Vol. 84 Issue 17-18 Pg. 627-33 (Apr 24 2009) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 26324994 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arsenicals
• Carcinogens
• Peroxides
• dimethylarsine
• Glutathione Reductase

Topics

• Animals
• Arsenicals (adverse effects, pharmacokinetics, pharmacology)
• Carcinogens (pharmacokinetics, toxicity)
• Cell Transformation, Neoplastic (metabolism, pathology)
• Glutathione Reductase (metabolism)
• Lung (metabolism, pathology)
• Lung Neoplasms (chemically induced, metabolism, pathology)
• Male
• Mice
• Peroxides (metabolism)
• Rats