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ToxSci Advance Access originally published online on April 22, 2008
Toxicological Sciences 2008 104(2):274-282; doi:10.1093/toxsci/kfn081
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Combined Ascorbic Acid and Sodium Nitrite Treatment Induces Oxidative DNA Damage-Associated Mutagenicity In Vitro, but Lacks Initiation Activity in Rat Forestomach Epithelium

Yuichi Kuroiwa*, Masami Yamada{dagger}, Keiko Matsui{dagger}, Toshiya Okamura*, Yuji Ishii*, Ken-ichi Masumura{dagger}, Masako Tasaki*, Takashi Umemura*, Kunitoshi Mitsumori{ddagger}, Takehiko Nohmi{dagger}, Masao Hirose*,1 and Akiyoshi Nishikawa*,2

* Division of Pathology {dagger} Division of Genetics & Mutagenesis, National Institute of Health Sciences, Setagaya-Ku, Tokyo 158-8501, Japan {ddagger} Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo 183-8509, Japan

2 To whom correspondence should be addressed at Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-Ku, Tokyo 158-8501, Japan. Fax: +81-3-3700-1425. E-mail: nishikaw{at}nihs.go.jp

Received December 6, 2007; accepted April 11, 2008


  Abstract

Combination treatment with sodium nitrite (NaNO2) and ascorbic acid (AsA) is well known to promote forestomach carcinogenesis in rats and weakly enhance esophageal carcinogenesis under acid reflux conditions. Nitric oxide generation and oxidative DNA damage are considered to be related to the enhancement of carcinogenesis. The purpose of the present study was to investigate whether oxidative DNA damage-associated genotoxicity and tumor initiating potential are involved in the carcinogenesis. In the bacterial reverse mutation assay using Escherichia coli deficient in the mutM gene encoding 8-hydroxydeoxyguanosine (8-OHdG) DNA glycosylase, the combination with NaNO2 and AsA increased the mutation frequency dramatically, slight increase being evident in the parental strain. In vivo, a significant increase in 8-OHdG levels in the rat forestomach epithelium occurred at 24 h after combined treatment. Six-week-old F344 male rats were given drinking water containing 0.2% NaNO2 and a diet supplemented with 1% AsA in combination, or the chemicals individually or basal diet alone for 12 weeks. After an interval of 2 weeks, they received 1% butylated hydroxyanisole in the diet for promotion until the end of weeks 52 and 78. Although one squamous cell carcinoma was observed in the combined group, there was no significant variation in tumor development among the groups. The study indicated that the combination of NaNO2 with AsA induces genotoxicity due to oxidative DNA damage in vitro, and elevates 8-OHdG levels in the forestomach epithelium, but lacks initiating activity in the rat two-stage carcinogenesis model.

Key Words: ascorbic acid; nitrite; 8-hydroxydeoxyguanosine (8-OHdG); mutM-deficient E. coli strain; genotoxicity.

1 Present address: Food Safety Commission, Cabinet Office Government of Japan, 6th Floor, Prudential Tower, 2-13-10 Nagata-cho, Chiyoda-ku, Tokyo 100-8989, Japan.


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