Enhancement of lung carcinogenesis initiated with 4-(N-hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone by Ogg1 gene deficiency in female, but not male, mice.

Abstract

The present study was conducted to assess involvement of oxidative stress in lung adeno-carcinogenesis, using mice deficient in the 8-hydroxyguanine DNA glycosylase 1 (Ogg1) gene encoding an enzyme that repairs an oxidative DNA injury 8-oxoguanine (8-oxoG). Furthermore, for comparison with the human case, mutations of mouse epidermal growth factor receptor (Egfr) and K-ras genes were examined. The homo- and heterozygously Ogg1 gene-deficient and wild-type mice (C57BL6/J origin), 6 weeks old, were administered 4-(N-hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by continuous subcutaneous infusion using an osmotic pump at a total dose of 6 mg/mouse for 1 week, then treated with one of 4 antioxidants (phenyl N-tert-butyl nitrone 0.13% in drinking water, resveratrol 20 ppm in diet, lactoferrin 2% in diet and bilberry powder 2% in diet) or no supplement for 33 weeks. Development of lung adenomas and preneoplastic atypical hypreplasias was significantly enhanced by the homo- and heterozygous Ogg1 gene deficiency only in female mice with intralesion accumulation of 8-oxoG. All antioxidants tended to inhibit enhanced adeno-carcinogenesis. The Egfr and K-ras gene mutations were detected at sites also found in human lung cancers with low incidences, while the Egfr gene mutation was detected for the first time in chemical lung carcinogenesis of animals. It is indicated that the Ogg1 gene deficiency enhances lung adeno-carcinogenesis in mice by virtue of accelerated oxidative stress. The presently utilized Ogg1 gene-deficient mice model may be useful to draw mechanism-based strategies to control human lung adenocarcinomas, especially in women.

• Authors: Maki Igarashi, Manabu Watanabe, Midori Yoshida, Kouichi Sugaya, Yoshifumi Endo, Nozomi Miyajima, Masayoshi Abe, Sumio Sugano, Dai Nakae
• Journal: The Journal of toxicological sciences (J Toxicol Sci) Vol. 34 Issue 2 Pg. 163-74 (Apr 2009) ISSN: 1880-3989 [Electronic] Japan
• PMID: 19336973 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Carcinogens
• Nitrosamines
• 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
• DNA Glycosylases
• Ogg1 protein, mouse

Topics

• Adenocarcinoma (pathology)
• Adenoma (chemically induced, genetics, pathology)
• Administration, Oral
• Animals
• Antioxidants (pharmacology)
• Carcinogens (toxicity)
• DNA Glycosylases (deficiency, genetics)
• Drug Antagonism
• Female
• Genes, erbB-1 (genetics)
• Genes, ras (genetics)
• Humans
• Infusions, Subcutaneous
• Lung (drug effects, pathology)
• Lung Neoplasms (chemically induced, genetics, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mutation
• Nitrosamines (toxicity)
• Precancerous Conditions (chemically induced, genetics, pathology)
• Sex Factors