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

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  • Igarashi Maki
    Laboratory of Protection of Body Function, Department of Food and Nutritional Science, Graduate School of Agriculture, Tokyo University of Agriculture Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo Present address: Biochemistry Division, National Cancer Center Research Institute
  • Watanabe Manabu
    Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo
  • Yoshida Midori
    Division of Pathology, National Institute of Health Sciences
  • Sugaya Kouichi
    Laboratory of Protection of Body Function, Department of Food and Nutritional Science, Graduate School of Agriculture, Tokyo University of Agriculture
  • Endo Yoshifumi
    Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo
  • Miyajima Nozomi
    Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo
  • Abe Masayoshi
    Toxicology and Environmental Science Department, Biological Research Laboratories, Nissan Chemical Industries Ltd.
  • Sugano Sumio
    Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo
  • Nakae Dai
    Department of Environmental Health and Toxicology, Tokyo Metropolitan Institute of Public Health Tokyo University of Agriculture

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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.

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