Carcinogenesis, Vol. 23, No. 12, 2005-2010,
December 2002
© 2002 Oxford University Press
ACCELERATED PAPER |
High accumulation of oxidative DNA damage, 8-hydroxyguanine, in Mmh/Ogg1 deficient mice by chronic oxidative stress
1 Banyu Tsukuba Research Institute in Collaboration with Merck Research Laboratories, 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan,
2 Department of Cell Biology, The Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Toshima-Ku, Tokyo 170-8455, Japan,
3 Mouse Functional Genomics Research Group, RIKEN Genomic Sciences Center, 214 Maeda-cho, Totsuka-ku, Yokohama, Kanagawa 244-0804, Japan,
4 CREST, Japan Science and Technology Corporation, 4-1-8 Motomachi, Kawaguchi 332-0012, Japan and
5 Department of Molecular Genetics, Tohoku University School of Medicine, 2-1 Seiryo-cho, Aoba-Ku, Sendai 980-8575, Japan
8-Hydroxyguanine (8-OH-G) is a major pre-mutagenic lesion generated from reactive oxygen species. The Mmh/Ogg1 gene product plays a major role in maintaining genetic integrity by removing 8-OH-G by way of the base excision repair pathway. To investigate how oxidative stress influences the formation of 8-OH-G in Ogg1 mutant mice, a known oxidative agent, potassium bromate (KBrO3), was administered at a dose of 2 g/l in the drinking water to Ogg1+/+, Ogg1+/- and Ogg1-/- mice for 12 weeks. Apurinic (AP) site lyase activity, measured by the excision of 8-OH-G from synthetic oligonucleotides, remained unchanged in kidney cell extracts isolated from Ogg1 mutant mice when the mice were pre-treated by KBrO3. The levels of 8-OH-G in kidney DNA tremendously increased in a time-dependent manner following exposure of Ogg1-/- mice to KBrO3. Of particular note, the amount of 8-OH-G in kidney DNA from Ogg1-/- mice treated with KBrO3 was ~70 times that of KBrO3-treated Ogg1+/+ mice. The accumulated 8-OH-G did not decrease 4 weeks after discontinuing treatment with KBrO3. KBrO3 treatment for 12 weeks gave rise to increased mutation frequencies at the transgenic gpt gene in Ogg1+/+ mice kidney. Absence of the Ogg1 gene further enhanced the mutation frequency. Sequence data obtained from gpt mutants showed that the accumulated 8-OH-G caused mainly GC
TA transversion and deletion. Other mutations including GCAT transition also showed a tendency to increase. These results indicate that 8-OH-G, produced by chronic exposure to exogenous oxidative stress agents, is not repaired to any significant extent within the overall genome of Ogg1-/- mice kidney.
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