2002 年度実績報告書

酸化ストレスによる塩基配列特異的DNA損傷の解析と発がんおよび老化の予防

研究課題

研究課題/領域番号	12470084
研究機関	三重大学
研究代表者	川西正祐三重大学, 医学部, 教授 (10025637)
研究分担者	平工雄介三重大学, 医学部, 助手 (30324510) 及川伸二三重大学, 医学部, 講師 (10277006) 村田真理子三重大学, 医学部, 講師 (10171141)
キーワード	酸化ストレス / 塩基配列特異的DNA損傷 / 発がん / 老化 / 紫外線 / がん化学予防 / 活性酸素 / 酸化促進作用
研究概要	本研究は、環境因子、特に環境化学物質や食品成分、食品添加物とその代謝物および紫外線(特にUVA)が生体内物質(微量金属や還元物質、光増感物質)との共存下において生成される各種活性酸素種による塩基配列特異的DNA損傷を培養細胞や単離したがん関連遺伝子断片を用いて検討した。本年度は、調理過程で生じる発がん物質ヘテロサイクリックアミン(PhIP)が、銅イオンの存在下で活性酸素を生成しDNAを損傷することを明らかにし、今までDNA付加対の形成で説明されてきた多環芳香族化合物の発がん性に酸化的DNA損傷も重要な役割を果たしうる可能性を示した。さらに、たばこの煙に含まれている2-ナフチルアミン、ディーゼルの排気ガスに含まれる大気汚染物質ニトロフルオレンおよび産業化学物質のカテコールやトリニトロトルエン等の発がん物質またはその代謝物が金属イオンの存在下で活性酸素を生成し塩基配列特異的にDNAを損傷することを解明した。以上の結果から、これらの環境化学物質の発がん性には活性酸素が重要な役割を果たしていることを明らかにした。生薬に含まれているキサントン、内因性の光増感物質でもある葉酸が、紫外線(UVA)照射によってDNA中の特定の塩基配列を著しく酸化的に損傷する機構を解明した。発がんや老化の予防を有効に進めるため化学予防物質の安全性についてDNA損傷性を指標に検討した。最近注目されている抗酸化剤のクルクミンは、還元酵素により還元されたときは有効ながん化学予防物質になるが、薬物代謝酵素CYP2D6で脱メチル化されたときはDNA損傷性が認められる。この結果からクルクミンをがん化学予防物質として用いるには、さらなる安全性の検討が必要である。我々が開発したDNA損傷性を指標とした化学予防物質の安全性評価法は発がんや老化の予防を有効に進めるため非常に有用である。

研究成果

(19件)

すべてその他

すべて文献書誌 (19件)

[文献書誌] S, Oikawa: "Oxidative damage to cellular and isolated DNA by homocysteine : implications for carcinogenesis"Oncogene. (in press). (2003)
[文献書誌] K.Hirakawa: "Base Oxidation at 5' Site of GG Sequence in Double-stranded DNA Induced by UVA in the Presence of Xanthone Analogues : Relationship between the DNA-damaging Abilities of Photosensitizers and Their HOMO Energies"Photochem. Photobiol.. (in press). (2003)
[文献書誌] K.Hirakawa: "Carcinogenic semicarbazide induces sequnce-specific DNA damage through the generation of reactive oxygen species and the derived organic radicals"Mutat. Res.. (in press). (2003)
[文献書誌] K.Hirakawa: "Sequence-specific DNA damage induced by ultraviolet A-irradiated folic acid via its photolysis product"Arch. Biochem. Biophys.. 410. 261-268 (2003)
[文献書誌] K.Sakano: "Metabolism of carcinogenic urethane to nitric oxide is involved in oxidative DNA damage"Free Radic. Biol. Med.. 33. 703-714 (2002)
[文献書誌] Y.Hiraku: "Determination of intracellular glutathione and thiols by high performance liquid chromatography with a gold electrode at the femtomole level : comparison with a spectroscopic assay"Biochim. Biophys. Acta. 1570. 47-52 (2002)
[文献書誌] S.Kawanishi: "The role of metals in site-specific DNA damage with reference to carcinogenesis"Free Radic. Biol. Med.. 32. 822-832 (2002)
[文献書誌] M.Murata: "Oxidation of 5'-site guanine at GG and GGG sequences induced by a metabolite of carcinogenic heterocyclic amine PhIP in the presence of Cu(II) and NADH"Carcinogenesis. 23. 855-860 (2002)
[文献書誌] H.Mizutani: "Mechanism of apoptosis induced by a new topoisomerase inhibitor through the generation of hydrogen peroxide"J. Biol. Chem.. 277. 30684-30689 (2002)
[文献書誌] S.Ohnishi: "Oxidative DNA Damage Induced by a Metabolite of 2-Naphthytlamine, a Smoking-related Bladder Carcinogen"Jpn. J. Cancer Res.. 93. 736-743 (2002)
[文献書誌] S.Homma-Takeda: "2,4,6-trinitrotoluene-induced reproductive toxicity via oxidative DNA damage by its metabolite]"Free Radic. Res.. 36. 555-566 (2002)
[文献書誌] K.Midorikawa: "Hydroxylation of deoxyguanosine at 5' site of GG and GGG sequences in double-stranded DNA induced by carbamoyl radicals"Free Radic. Res.. 36. 667-675 (2002)
[文献書誌] S.Oikawa: "Site-specific hydroxylation at polyguanosine in double-stranded DNA by nickel(II) in the presence of SH compounds : comparison with singlet oxygen-induced DNA damage"Chem. Res. Toxicol.. 15. 1017-1022 (2002)
[文献書誌] K.Sakano: "Metal-mediated DNA damage induced by curcumin in the presence of human cytochrome P450 isozymes"Arch. Biochem. Biophys.. 405. 223-230 (2002)
[文献書誌] M.kawanishi: "Epstein-Barr virus BHRF1 functions downstream of Bid cleavage and upstream of mitochondrial dysfunction to inhibit TRAIL-induced apoptosis in BJAB cells"Biochem. Biophyts. Res. Commun.. 297. 682-687 (2002)
[文献書誌] M.Murata: "Oxidative DNA damage by a common metabolite of carcinogenic nitrofluorene and N-acetylaminofluorene"Int. J. Cancer. 102. 311-317 (2002)
[文献書誌] S.Kawanishi: "Distinct mechanisms of oxidative DNA damage induced by carcinogenic nickel subsulfide and nickel oxides"Environ. Health. Perspect.. 110. 789S-791S (2002)
[文献書誌] K.Hirakawa: "Photohydrolysis of methotrexate produces pteridine, which induces poly-G-specific DNA damage through photoinduced electron transfer"Photochem. Photobiol.. 76. 467-472 (2002)
[文献書誌] 及川伸二: "食と生活習慣病"昭和堂(菅原努監修). 213 (2003)

2002 年度 実績報告書

酸化ストレスによる塩基配列特異的DNA損傷の解析と発がんおよび老化の予防

研究代表者

川西 正祐 三重大学, 医学部, 教授 (10025637)

研究成果

[文献書誌] S, Oikawa: "Oxidative damage to cellular and isolated DNA by homocysteine : implications for carcinogenesis"Oncogene. (in press). (2003)

[文献書誌] K.Hirakawa: "Base Oxidation at 5' Site of GG Sequence in Double-stranded DNA Induced by UVA in the Presence of Xanthone Analogues : Relationship between the DNA-damaging Abilities of Photosensitizers and Their HOMO Energies"Photochem. Photobiol.. (in press). (2003)

[文献書誌] K.Hirakawa: "Carcinogenic semicarbazide induces sequnce-specific DNA damage through the generation of reactive oxygen species and the derived organic radicals"Mutat. Res.. (in press). (2003)

[文献書誌] K.Hirakawa: "Sequence-specific DNA damage induced by ultraviolet A-irradiated folic acid via its photolysis product"Arch. Biochem. Biophys.. 410. 261-268 (2003)

[文献書誌] K.Sakano: "Metabolism of carcinogenic urethane to nitric oxide is involved in oxidative DNA damage"Free Radic. Biol. Med.. 33. 703-714 (2002)

[文献書誌] Y.Hiraku: "Determination of intracellular glutathione and thiols by high performance liquid chromatography with a gold electrode at the femtomole level : comparison with a spectroscopic assay"Biochim. Biophys. Acta. 1570. 47-52 (2002)

[文献書誌] S.Kawanishi: "The role of metals in site-specific DNA damage with reference to carcinogenesis"Free Radic. Biol. Med.. 32. 822-832 (2002)

[文献書誌] M.Murata: "Oxidation of 5'-site guanine at GG and GGG sequences induced by a metabolite of carcinogenic heterocyclic amine PhIP in the presence of Cu(II) and NADH"Carcinogenesis. 23. 855-860 (2002)

[文献書誌] H.Mizutani: "Mechanism of apoptosis induced by a new topoisomerase inhibitor through the generation of hydrogen peroxide"J. Biol. Chem.. 277. 30684-30689 (2002)

[文献書誌] S.Ohnishi: "Oxidative DNA Damage Induced by a Metabolite of 2-Naphthytlamine, a Smoking-related Bladder Carcinogen"Jpn. J. Cancer Res.. 93. 736-743 (2002)

[文献書誌] S.Homma-Takeda: "2,4,6-trinitrotoluene-induced reproductive toxicity via oxidative DNA damage by its metabolite]"Free Radic. Res.. 36. 555-566 (2002)

[文献書誌] K.Midorikawa: "Hydroxylation of deoxyguanosine at 5' site of GG and GGG sequences in double-stranded DNA induced by carbamoyl radicals"Free Radic. Res.. 36. 667-675 (2002)

[文献書誌] S.Oikawa: "Site-specific hydroxylation at polyguanosine in double-stranded DNA by nickel(II) in the presence of SH compounds : comparison with singlet oxygen-induced DNA damage"Chem. Res. Toxicol.. 15. 1017-1022 (2002)

[文献書誌] K.Sakano: "Metal-mediated DNA damage induced by curcumin in the presence of human cytochrome P450 isozymes"Arch. Biochem. Biophys.. 405. 223-230 (2002)

[文献書誌] M.kawanishi: "Epstein-Barr virus BHRF1 functions downstream of Bid cleavage and upstream of mitochondrial dysfunction to inhibit TRAIL-induced apoptosis in BJAB cells"Biochem. Biophyts. Res. Commun.. 297. 682-687 (2002)

[文献書誌] M.Murata: "Oxidative DNA damage by a common metabolite of carcinogenic nitrofluorene and N-acetylaminofluorene"Int. J. Cancer. 102. 311-317 (2002)

[文献書誌] S.Kawanishi: "Distinct mechanisms of oxidative DNA damage induced by carcinogenic nickel subsulfide and nickel oxides"Environ. Health. Perspect.. 110. 789S-791S (2002)

[文献書誌] K.Hirakawa: "Photohydrolysis of methotrexate produces pteridine, which induces poly-G-specific DNA damage through photoinduced electron transfer"Photochem. Photobiol.. 76. 467-472 (2002)

[文献書誌] 及川 伸二: "食と生活習慣病"昭和堂(菅原努 監修). 213 (2003)

2002 年度実績報告書

川西正祐三重大学, 医学部, 教授 (10025637)

[文献書誌] 及川伸二: "食と生活習慣病"昭和堂(菅原努監修). 213 (2003)