O-6 Enhancement of NNK-induced Lung Carcinogenesis and EGFR Gene Mutation in Ogg1 Gene Deficient Mice
The present study was conducted to assess involvement of oxidative stress in lung adeno-carcinogenesis, using mice deficient in the 8-hydroxyguanine DNA glycosylase (Ogg1) gene that encodes an enzyme repairing oxidative DNA damage 8-oxoguanine (8-oxoG). Homo- and heterozygously Ogg1-deficient and wi...
Saved in:
Published in | Journal of Toxicologic Pathology Vol. 21; no. 2; p. 134 |
---|---|
Main Authors | , , , , , |
Format | Journal Article |
Language | Japanese |
Published |
The Japanese Society of Toxicologic Pathology
2008
|
Online Access | Get full text |
Cover
Loading…
Summary: | The present study was conducted to assess involvement of oxidative stress in lung adeno-carcinogenesis, using mice deficient in the 8-hydroxyguanine DNA glycosylase (Ogg1) gene that encodes an enzyme repairing oxidative DNA damage 8-oxoguanine (8-oxoG). Homo- and heterozygously Ogg1-deficient and wild type mice (C57BL6/J origin), 6 weeks old, were administered 4-(N-hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by a continuous subcutaneous infusion using an osmotic pump at a total dose of 6 mg/mouse for 1 week, then treated with nothing or one of the 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) for 33 weeks, and sacrificed to obtain the lung. The development of lung adenoma and preneoplastic, atypical hypreplasia was significantly enhanced by the homo- and heterozygous Ogg1 gene deficiency only in female mice with the accumulation of 8-oxoG. All antioxidants tended to inhibit this enhanced adeno-carcinogenesis. Furthermore, mutations were detected in the epidermal growth factor receptor (EGFR) and K-ras genes within the NNK-induced lung proliferative lesions in mice, at the same sites as those found in human lung cancers. While demonstrating the human-relevant EGFR gene mutation in exogenously induced animal tumors for the first time, the present results indicate that the deficiency in the Ogg1 gene enhances lung adeno-carcinogenesis in mice initiated with NNK by virtue of accelerated oxidative stress. |
---|---|
ISSN: | 0914-9198 1881-915X |