Genotoxicity of estrogen-and tamoxifen-derived DNA adducts in mammalian cells (第9回公開シンポジウム モデルDNA損傷と変異機構)

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概要

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• Site-specifically modified oligodeoxynucleotides were used to explore the mutagenic properties of estrogen-derived DNA adducts or anti-estrogen, tamoxifen-derived DNA adducts in mammalian cells. Using an in vitro experimental system that can quantify base substitutions and deletions, estrone 2, 3-quinone-induced DNA adducts, N^2-(2-hydroxyestron-6(α, β)-yl)-2'-deoxyguanosine(2-OHE_1-6-N^2-dG)and N^6-(2-hydroxyestron-6(α, β)-yl)-2'-deoxyadenosine(2-OHE_1-6-N^6-dA), were found to be miscoding lesions. Model estrogen-DNA adducts, N^2-[3-methoxyestra-1, 3, 5(10)-trien-6(α, β)-yl]-2'-deoxyadenosine(dG-N^2-3MeE)and N^6-[3-methoxyestra-1, 3, 5(10)-trien-6(α, β)-yl]-2'-deoxyguanosine(dA-N^6-3MeE), structurally similar to 2-OHE_1-6-N^2-dG and 2-OHE_1-6-N^6-dA, were inserted into single-stranded(ss)phagemid vectors. These modified ss vectors were transfected into simian kidney(COS-7)cells. The progeny plasmid obtained were used to transform Escherichia coli DH10B. The transformants were analyzed by oligodeoxynucleotide hybridization and sequencing to determine the mutation frequency and spectrum. Targeted mutations representing G→T and A→T transversions were mainly detected opposite 2-OHE_1-6-N^2-dG and 2-OHE_1-6-N^6-dA, respectively. These results indicate that estrogen-DNA adducts are mutagenic and act as initiators in mammalian cells. We also found that α-sulfate tamoxifens are highly reactive to DNA, forming four diastereoisomers of α-(N^2-deoxyguanosinyl)tamoxifen(dG-N^2-TAM). Sulfation of α-hydroxytamoxifen(α-OHTAM), a major metabolite of tamoxifen, catalyzed by rat or human liver hydroxysteroid sulfotransferase resulted in dG-N^2-TAM adducts in DNA. dG-N^2-TAM adducts are highly miscoding and mutagenic lesions, generating mainly G→T transversions, along with G→A transitions and/or G→C transversions in mammalian cells. These mutagenic TAM-DNA adducts were detected in endometrium obtained from patients treated with TAM. Thus, estrogen-and tamoxifen-derived DNA adducts result in mutations and pose a potential risk to women treated with estrogen or tamoxifen.

• 日本環境変異原学会の論文
• 1998-10-31

著者

• SHIBUTANI Shinya

  Department of Biochemistry, Research Institute for Wakan- Yaku (Oriental Medicines), Toyama Medical

• Shibutani Shinya

  Department Of Pharmacological Sciences State University Of New York At Stony Brook

関連論文

• Influence of Dietary Composition on the Uric Acid Level in the Arterio-venous Blood of Rats
• Genotoxicity of estrogen-and tamoxifen-derived DNA adducts in mammalian cells (第9回公開シンポジウム モデルDNA損傷と変異機構)

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