2001 Fiscal Year Annual Research Report

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

Research Project

Project/Area Number	13557030
Research Institution	Mie University
Principal Investigator	川西正祐三重大学, 医学部, 教授 (10025637)
Co-Investigator(Kenkyū-buntansha)	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)
Keywords	がん化学予防 / DNA損傷 / 活性酸素 / 第一次予防 / 有効性評価 / 安全性評価 / 抗酸化物質 / フィチン酸
Research Abstract	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が発がん抑制に重要であることが知られているが、喫煙者へのβ-カロチンの投与により肺がんの罹患率が増加することが報告されている。我々は様々な化学物質が活性酸素を生成してDNAを損傷し、発がんに関与することを明らかにしてきたが、β-カロチンなどの抗酸化物質も同様に酸化的にDNAを損傷した(J.Biol.Chem.,2000)。一方ルテオニンはDNA損傷性を示さない有効ながん予防物質であることを明らかにした(Free Radic.Res.,2000)。本研究では上記の研究を基盤として、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、化学予防物質によるヒト遺伝子損傷の抑制能について検討した。フィチン酸(イノシトール6リン酸)は穀物や豆類に多く含まれ、動物実験で大腸がんや乳がんの抑制効果が報告されている。ヒト培養細胞HL-60およびがん関連遺伝子DNA断片を用いた実験では、フィチン酸はDNA損傷を起こさなかった。細胞内で酸化的DNA損傷を起こす条件下でフィチン酸を添加すると、グアニンの酸化生成物である8-ヒドロキシデオキシグアノシンの生成量が有意に減少した。またフィチン酸はヒト遺伝子におけるGG配列の5'末端側のグアニンの酸化的損傷を抑制した。リン酸を有しないイノシトールではこのような抑制効果がなかったことから、DNA損傷抑制作用はフィチン酸のリン酸基が金属イオンをキレートし、過酸化水素と金属イオンとの相互作用による反応性の高い活性種の生成を抑制するためであると考えられた。したがってフィチン酸は遺伝子損傷作用を示さない有効で安全ながん予防物質となることが示された(BBRC,2001)。

Research Products
(26 results)

All Other

All Publications (26 results)

[Publications] S.Ohnishi: "DNA damage induced by hypochlorite and hypobromite with reference to inflammation-associated carcinogenesis"Cancer Lett.. 178. 37-42 (2002)
[Publications] K.Hirakawa: "Catechol and Hydroquinone Have Different Redox Properties Responsible for Their Differential DNA-damaging Ability"Chem.Res.Toxicol. 15. 76-82 (2002)
[Publications] S.Ohnishi: "Double Base Lesions of DNA by a Metabolite of Carcinogenic Benzo[a]pyrene"Biochem.Biophys.Res.Commun.. 290. 778-782 (2002)
[Publications] S.Kawanishi: "Mechanism of Guanine-specific DNA Damage by Oxidative Stress and Its Role in Carcinogenesis and Aging"Mutation Res.(Reviews in Mutation Research). 488. 65-76 (2001)
[Publications] S.Kawanishi: "Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds"Free.Radic.Biol.Med.. 31. 108-116 (2001)
[Publications] T.Hishita: "Caspase-3 Activation by Lysosomal Enzymes in Cytochrome c-independent Apoptosis in a Myelodysplastic Syndrome (MDS)-derived Cell Line P39"Cancer Res.. 61. 2878-2884 (2001)
[Publications] S.Oikawa: "Site-specific DNA Damage at GGG Sequence by UVA Involves Acceleration of Telomere Shortening"Biochemistry. 40. 4763-4768 (2001)
[Publications] K.Midorikawa: "Superoxide dismutases enhance H_2O_2-induced DNA damage and alter its site specificity"FEBS Lett.. 495. 187-190 (2001)
[Publications] M.Murata: "Acrylonitril Enhances H_2O_2-Mediated DNA Damage via Nitrogen-Centered Radical Formation"Chem.Res.Toxicol.. 14. 1421-1427 (2001)
[Publications] S.Oikawa: "Site Specificity and Mechanism of Oxidative DNA Damage Induced by Carcinogenic Catechol"Carcinogenesis. 22. 1239-1245 (2001)
[Publications] M.Murata: "Mechanism of Oxidative DNA Damage Induced by Carcinogenic 4-Aminobiphenyl"Free Radic.Biol Med.. 30. 765-773 (2001)
[Publications] M.Murata: "Requirement of Glutathione and Cysteine in Guanine-specific Oxidation of DNA by Carcinogenic Potassium Bromate"Chem.Res.Toxicol.. 14. 678-685 (2001)
[Publications] K.Sakano: "Hydroxyurea Induces Site-specific DNA Damage via Formation of Hydrogen Peroxide and Nitric Oxide"Jpn.J.Cancer Res.. 92. 1166-1174 (2001)
[Publications] Y.Ohkuma: "Sequence-specific DNA damage induced by carcinogenic danthron and anthraquinone in the presence of Cu(II),cytochrome P450 reductase and NADPH"Free.Radic.Res.. 34. 595-604 (2001)
[Publications] S.Ohnishi: "Oxidative DNA damage induced by an N-hydroxy metabolite of carcinogenic 4-dimethylaminoazobenzene"Jpn.J.Cancer Res. 92. 23-29 (2001)
[Publications] K.Sakano: "Mechanism of Metal-mediated DNA Damage Induced by Metabolites of Carcinogenic 2-Nitropropane"Mutat.Res.. 479. 101-111 (2001)
[Publications] S.Ohnishi: "Oxidative DNA Damage by an N-Hydroxy Metabolite of the Mutagenic Compound Formed from Norharman and Aniline"Mutat.Res.. 494. 63-72 (2001)
[Publications] K.Midorikawa: "Protective Effect of Phytic Acid on Oxidative Damage with Reference to Cancer Chemoprevention"Biochem.Biophys.Res.Commun. 288. 552-557 (2001)
[Publications] Y.Ohkuma: "Oxidative DNA Damage Induced by a Metabolite of Carcinogenic o-Anisidine: Enhancement of DNA Damage and Alteration in its Sequence-Specificity by Superoxide Dismutase"Arch Biochem.Biophys.. 389. 49-56 (2001)
[Publications] S.Ohnishi: "Oxidative DNA Damage by a Metabolite of Carcinogenic 1-Nitropyrene"Biochem.Biophys.Res.Commun.. 280. 48-52 (2001)
[Publications] Y.Hiraku: "Amplification of Bleomycin-induced DNA Cleavage at Cytosine Residues 3' to GGG Sequences by Pyrrole Triamide"Biochem.Pharmaco. 61. 351-356 (2001)
[Publications] Y.Hiraku: "Catechol Estrogens Induce Oxidative DNA Damage and Estradiol Enhances Cell Proliferation"Int.J.Cancer. 92. 333-337 (2001)
[Publications] 及川伸二: "環境因子による酸化的DNA損傷とがん、老化"Environ.Mut.Res.Commun.. 23. 207-213 (2001)
[Publications] S.Kawanishi: "Current Problems in Dermatology Vol.29,Oxidants and Antioxidants in Cutaneous Biology"Karger(J.Thiele and P.Elsner,Eds.). 193 (2001)
[Publications] 川西正祐: "中毒学-基礎・臨床・社会医学-"朝倉書店(荒記俊一編). 408 (2002)
[Publications] 川西正祐: "別冊医学のあゆみ酸化ストレス-フリーラジカル医学生物学の最前線"医歯薬出版(吉川敏一編). 326 (2001)

2001 Fiscal Year Annual Research Report

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

Principal Investigator

川西 正祐 三重大学, 医学部, 教授 (10025637)

Research Products

[Publications] S.Ohnishi: "DNA damage induced by hypochlorite and hypobromite with reference to inflammation-associated carcinogenesis"Cancer Lett.. 178. 37-42 (2002)

[Publications] K.Hirakawa: "Catechol and Hydroquinone Have Different Redox Properties Responsible for Their Differential DNA-damaging Ability"Chem.Res.Toxicol. 15. 76-82 (2002)

[Publications] S.Ohnishi: "Double Base Lesions of DNA by a Metabolite of Carcinogenic Benzo[a]pyrene"Biochem.Biophys.Res.Commun.. 290. 778-782 (2002)

[Publications] S.Kawanishi: "Mechanism of Guanine-specific DNA Damage by Oxidative Stress and Its Role in Carcinogenesis and Aging"Mutation Res.(Reviews in Mutation Research). 488. 65-76 (2001)

[Publications] S.Kawanishi: "Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds"Free.Radic.Biol.Med.. 31. 108-116 (2001)

[Publications] T.Hishita: "Caspase-3 Activation by Lysosomal Enzymes in Cytochrome c-independent Apoptosis in a Myelodysplastic Syndrome (MDS)-derived Cell Line P39"Cancer Res.. 61. 2878-2884 (2001)

[Publications] S.Oikawa: "Site-specific DNA Damage at GGG Sequence by UVA Involves Acceleration of Telomere Shortening"Biochemistry. 40. 4763-4768 (2001)

[Publications] K.Midorikawa: "Superoxide dismutases enhance H_2O_2-induced DNA damage and alter its site specificity"FEBS Lett.. 495. 187-190 (2001)

[Publications] M.Murata: "Acrylonitril Enhances H_2O_2-Mediated DNA Damage via Nitrogen-Centered Radical Formation"Chem.Res.Toxicol.. 14. 1421-1427 (2001)

[Publications] S.Oikawa: "Site Specificity and Mechanism of Oxidative DNA Damage Induced by Carcinogenic Catechol"Carcinogenesis. 22. 1239-1245 (2001)

[Publications] M.Murata: "Mechanism of Oxidative DNA Damage Induced by Carcinogenic 4-Aminobiphenyl"Free Radic.Biol Med.. 30. 765-773 (2001)

[Publications] M.Murata: "Requirement of Glutathione and Cysteine in Guanine-specific Oxidation of DNA by Carcinogenic Potassium Bromate"Chem.Res.Toxicol.. 14. 678-685 (2001)

[Publications] K.Sakano: "Hydroxyurea Induces Site-specific DNA Damage via Formation of Hydrogen Peroxide and Nitric Oxide"Jpn.J.Cancer Res.. 92. 1166-1174 (2001)

[Publications] Y.Ohkuma: "Sequence-specific DNA damage induced by carcinogenic danthron and anthraquinone in the presence of Cu(II),cytochrome P450 reductase and NADPH"Free.Radic.Res.. 34. 595-604 (2001)

[Publications] S.Ohnishi: "Oxidative DNA damage induced by an N-hydroxy metabolite of carcinogenic 4-dimethylaminoazobenzene"Jpn.J.Cancer Res. 92. 23-29 (2001)

[Publications] K.Sakano: "Mechanism of Metal-mediated DNA Damage Induced by Metabolites of Carcinogenic 2-Nitropropane"Mutat.Res.. 479. 101-111 (2001)

[Publications] S.Ohnishi: "Oxidative DNA Damage by an N-Hydroxy Metabolite of the Mutagenic Compound Formed from Norharman and Aniline"Mutat.Res.. 494. 63-72 (2001)

[Publications] K.Midorikawa: "Protective Effect of Phytic Acid on Oxidative Damage with Reference to Cancer Chemoprevention"Biochem.Biophys.Res.Commun. 288. 552-557 (2001)

[Publications] Y.Ohkuma: "Oxidative DNA Damage Induced by a Metabolite of Carcinogenic o-Anisidine: Enhancement of DNA Damage and Alteration in its Sequence-Specificity by Superoxide Dismutase"Arch Biochem.Biophys.. 389. 49-56 (2001)

[Publications] S.Ohnishi: "Oxidative DNA Damage by a Metabolite of Carcinogenic 1-Nitropyrene"Biochem.Biophys.Res.Commun.. 280. 48-52 (2001)

[Publications] Y.Hiraku: "Amplification of Bleomycin-induced DNA Cleavage at Cytosine Residues 3' to GGG Sequences by Pyrrole Triamide"Biochem.Pharmaco. 61. 351-356 (2001)

[Publications] Y.Hiraku: "Catechol Estrogens Induce Oxidative DNA Damage and Estradiol Enhances Cell Proliferation"Int.J.Cancer. 92. 333-337 (2001)

[Publications] 及川伸二: "環境因子による酸化的DNA損傷とがん、老化"Environ.Mut.Res.Commun.. 23. 207-213 (2001)

[Publications] S.Kawanishi: "Current Problems in Dermatology Vol.29,Oxidants and Antioxidants in Cutaneous Biology"Karger(J.Thiele and P.Elsner,Eds.). 193 (2001)

[Publications] 川西正祐: "中毒学-基礎・臨床・社会医学-"朝倉書店(荒記俊一 編). 408 (2002)

[Publications] 川西正祐: "別冊 医学のあゆみ 酸化ストレス-フリーラジカル医学生物学の最前線"医歯薬出版(吉川敏一 編). 326 (2001)

川西正祐三重大学, 医学部, 教授 (10025637)

[Publications] 川西正祐: "中毒学-基礎・臨床・社会医学-"朝倉書店(荒記俊一編). 408 (2002)

[Publications] 川西正祐: "別冊医学のあゆみ酸化ストレス-フリーラジカル医学生物学の最前線"医歯薬出版(吉川敏一編). 326 (2001)