Does tamoxifen-induced DNA damage cause endometrial cancer? (第11回公開シンポジウム 環境変異原の活性発現と抑制の化学的機構)
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I have previously described genotoxicity of tamoxifen-derived DNA adducts in this journal (Environ. Mutagen Res., 20 : 201-211, 1998) . However, a large number of reports regarding this issue have published in last two years. Here I review the recent findings from my laboratory and others. Tamoxifen-DNA adducts are primarily formed via sulfation of α-hydroxy moieties of tamoxifen. N- desmethyltamoxifen, and tamoxifen N- oxide. α- (N^2- Deoxyguanosinyl) tamoxifen (dG-N^2-TAM) and a- (N^2- deoxyguanosinyl) -N- desmethyltamoxifen (dG-N^2-N- desmethylTAM) were major adducts in the liver of rats and mice treated with tamoxifen.α- (N^2-Deoxyguanosinyl) tamoxifen N-oxide (dG-N^2-TAM N-oxide) was also detected as a minor adduct in mouse liver. Site-specific mutagenesis studies showed that dG-N^2-TAM is a potential mutagenic lesion, generating mainly G → T transversions, accompanied by fewer G → A transitions in mammalian cells. This tamoxifen adduct can be removed from DNA by nucleotide excision repair. Significant amounts of dG-N^2-TAM adducts were detected in the endometrium of women treated with tamoxifen; a marked inter-individual variation was observed in the level of tamoxifen-DNA adducts. Such mutagenic tamoxifen-DNA adducts, if not repaired, may act as initiators, leading to development of endometrial cancer. Genotoxicity of toremifene, a chlorinated tamoxifen analog, was much lower than tamoxifen, due to the limited formation of DNA adducts induced by toremifene metabolites. Use of toremifene, instead of tamoxifen, may reduce incidence of endometrial cancer in women receiving breast cancer prevention treatment.
- 日本環境変異原学会の論文
- 2000-12-22
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関連論文
- DNA damage and altered gene expression of enzymes for metabolism and DNA repair by tamoxifen and toremifene in the female rat liver
- Does tamoxifen-induced DNA damage cause endometrial cancer? (第11回公開シンポジウム 環境変異原の活性発現と抑制の化学的機構)
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