2002 年度実績報告書

がん化学予防物質の遺伝子損傷抑制と発現応答に基づく有効性の総合評価システムの開発

研究課題

研究課題/領域番号	13557030
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) 川西美知子京都大学, 大学院・医学研究科, 助手 (60025616) 平川和貴三重大学, 医学部, 助手 (60324513)
キーワード	がん化学予防 / DNA損傷 / 活性酸素 / 安全性評価 / 有効性評価 / 抗酸化物質 / クルクミン / グルタチオン
研究概要	がんは基本的に予防可能な疾患である。わが国では悪性新生物が死因の第一位を占め、がんの化学予防を含む第一次予防法の確立が重要である。野菜や果物に含まれるビタミン類やフラボノイド類などは発がん抑制への寄与が期待されている。一方、β-カロチンを用いた疫学介入調査では予期に反し喫煙者において肺がんの罹患率が増加することが報告された。そこで我々はβ-カロチンによる発がんに関連して、その代謝物が酸化的にPNAを損傷することを報告した(J. Biol. Chem.2000)。一方、フィチン酸(BBRC 2001)およびルテオリン(Free Redic.Res.2000)はDNA損傷性を示さない有効ながん予防物質であることを見いだした。本研究では上記の研究を発展させ、がん化学予防を安全かつ有効に推進する方法の確立を目指して、化学予防物質のDNA損傷性の検討に加え、遺伝子発現の解析の基盤となる研究を行った。クルクミンはウコン、ターメリックなどに含まれ抗酸化作用を有するが、一方、実験動物で肝細胞腺腫を生じるという報告がある。我々は、クルクミンをCYP2D6などの代謝酵素で前処理すると脱メチル化を受けてカテコール誘導体を生じ、ヒトがん関連遺伝子DNAを損傷することを解明した(Arch. Biochem. Biophys. 2002)。したがってクルクミンについては安全性の検討が必要である。さらに我々は、HPLCおよび金電極を装備した電気化学的検出器を用いて、生体内の抗酸化物質グルタチオンを極めて高感度に定量する方法を確立し(Biochim. Biophys.Acta 2002)、グルタチオン生合成およびグルタチオンペルオキシダーゼの発現などに関する研究の基盤を確立した。また抗酸化物質による遺伝子発現を蛋白レベルで解析するために、2次元電気泳動法を用いたプロテオーム解析法を確立しつつある。

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 sequence-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] 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] 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] 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] 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] 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] 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] S.Ohnishi: "Oxidative DNA Damage Induced by a Metabolite of 2-Naphthylamine, 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] 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 Biophys 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

がん化学予防物質の遺伝子損傷抑制と発現応答に基づく有効性の総合評価システムの開発

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 sequence-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] 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] 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] 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] 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] 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] 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] S.Ohnishi: "Oxidative DNA Damage Induced by a Metabolite of 2-Naphthylamine, 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] 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 Biophys 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)