2003 Fiscal Year Annual Research Report

遺伝子変異のホットスポットの成因機構の解明と環境化学物質の発がんリスク評価

Research Project

Project/Area Number	15390187
Research Category	Grant-in-Aid for Scientific Research (B)
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)
Keywords	ホットスポット / クラスターDNA損傷 / 環境発がん物質 / DNA損傷 / 活性酸素 / がん抑制遺伝子 / がん予防 / 糖尿病
Research Abstract	がんの予防を有効に実践するためには、原因対策と同時に発がん機構の詳細な解明が必須である。がん化における遺伝子変異の主要な部位がホットスポットであり、がん原遺伝子の活性化やがん抑制遺伝子の機能喪失をもたらす。しかし、なぜその部位がホットスポットになるのかという最も重要な問題は、未だ解明されていない。いくつかの塩基が連続して損傷(クラスターDNA損傷)を受けている部位は、修復され難く複製エラーを起こしやすいのでホットスポットとなることが考えられる。本年度は、環境発がん物質や抗がん剤などによるDNA損傷性とその塩基特異性を明らかにした。その結果、大気汚染物質のベンズ[a]アントラセンの代謝物および緑茶成分のカテキン類、抗がん剤のプロカルバジンやドキソルビシン、室内汚染物質のエチルベンゼン、薬草などに存在するキサントン類、ビタミンBの一種である葉酸などが金属やNADHなどの生体内物質の存在下において塩基配列特異的にDNAを損傷することを明らかにした。また、高血糖時に生体内で上昇するアルデヒド類が塩基配列特異的にDNAを損傷し、糖尿病が発がんのリスク要因になりうることを明らかにした。以上の結果から、本研究において環境化学物質や生体内物質から生成された活性酸素が、がん関連遺伝子のエクソン部位の5'-TG-3'配列を2塩基連続して損傷することを初めて解明した。特に興味深いことに、がん抑制遺伝子p53のホットスポットのひとつであるコドン273の相補対である5'-ACG-3'配列のCG配列を2塩基連続して損傷することが認められた。従って、活性酸素によるこの様なクラスターDNA損傷がホットスポットの成因に重要な役割を果たしていることが示唆された。

Research Products

(22 results)

All Other

All Publications (22 results)

[Publications] K.Hirakawa: "Photo-irradiated Titanium Dioxide Catalyzes Site Specific DNA Damage via Generation of Hydrogen Peroxide"Free Radical Research. (in press). (2004)
[Publications] M.Murata: "Oxidative DNA damage induced by nitrotyrosine, a biomarker of inflammation"Biochem.Biophys.Res.Commun.. 316. 123-128 (2004)
[Publications] M.Murata: "Genistein and daidzein induce cell proliferation and their metabolites cause oxidative DNA damage in relation to isoflavone-induced cancer of estrogen-sensitive organs"Biochemistry. 43. 2569-2577 (2004)
[Publications] S.Nakashima: "Vacuolar H^+-ATPase inhibitor induces apoptosis via lysosomal dysfunction in the human gastric cancer cell line MKN-1"J.Biochem.. 134. 359-364 (2003)
[Publications] M.Murata: "Oxidative DNA damage by hyperglycemia-related aldehydes and its marked enhancement by hydrogen peroxide"FEBS Lett.. 554. 138-142 (2003)
[Publications] K.Seike: "Oxidative DNA damage induced by benz[a]anthracene metabolites via redox cycles of quinone and unique non-quinone"Chem.Res.Toxicol.. 16. 1470-1476 (2003)
[Publications] S.Tada-Oikawa: "Mechanism for generation of hydrogen peroxide and change of mitochondrial membrane potential during rotenone-induced apoptosis"Life Sci. 73. 3277-3288 (2003)
[Publications] A.Furukawa: "(-)-Epigallocatechin gallate causes oxidative damage to isolated and cellular DNA"Biochem.Pharmacol.. 66. 1769-1778 (2003)
[Publications] S.Pinlaor: "8-nitroguanine formation in the liver of hamsters infected with Opisthorch is viverrini"Biochem.Biophys.Res.Commun.. 309. 567-571 (2003)
[Publications] K.Ogawa: "Molecular mechanisms of DNA damage induced by procarbazine in the presence of Cu(II)"Mutat.Res.. 539. 145-155 (2003)
[Publications] H.Mizutani: "Distinct mechanisms of site-specific oxidative DNA damage by doxorubicin in the presence of copper(II) and NADPH-cytochrome P450 reductase"Cancer Sci.. 94. 686-691 (2003)
[Publications] T.Iwamoto: "Oxidative DNA damage induced by photodegradation products of 3'-azido-3'-deoxythymidine"Arch.Biochem.Biophys.. 416. 155-163 (2003)
[Publications] S.Oikawa: "Catechins induce oxidative damage to cellular and isolated DNA through the generation of reactive oxygen species"Free Radic.Res.. 37. 881-890 (2003)
[Publications] S.Oikawa: "Oxidative damage to cellular and isolated DNA by homocysteine : implications for carcinogenesis"Oncogene. 22. 3530-3538 (2003)
[Publications] C.Toda: "DNA damage by ethylbenzenehydroperoxide formed from carcinogenic ethylbenzene by sunlight irradiation"Biochem.Biophys.Res.Commun.. 304. 638-642 (2003)
[Publications] K.Hirakawa: "Carcinogenic semicarbazide induces sequence-specific DNA damage through the generation of reactive oxygen species and the derived organic radicals"Mutat.Res. 536. 91-101 (2003)
[Publications] 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.. 77. 349-355 (2003)
[Publications] K.Hirakawa: "Sequence-Specific DNA Damage Induced by Ultraviolet A-Irradiated Folic Acid via Its Photolysis Product"Arch.Biochem.Biophys.. 410. 261-268 (2003)
[Publications] N.Nakai: "Oxidative DNA Damage Induced by Toluene is Involved in its Male Reproductive Toxicity"Free Radic.Res.. 37. 69-76 (2003)
[Publications] 及川伸二: "カテキン類による酸化的DNA損傷"医学のあゆみ. 208. 688-689 (2004)
[Publications] 川西正祐: "分子予防環境医学"分子予防環境医学研究会編. 768 (2003)
[Publications] 及川伸二: "食と生活習慣病"菅原努監修. 213 (2003)

2003 Fiscal Year Annual Research Report

遺伝子変異のホットスポットの成因機構の解明と環境化学物質の発がんリスク評価

Principal Investigator

川西 正祐 三重大学, 医学部, 教授 (10025637)

Research Products

[Publications] K.Hirakawa: "Photo-irradiated Titanium Dioxide Catalyzes Site Specific DNA Damage via Generation of Hydrogen Peroxide"Free Radical Research. (in press). (2004)

[Publications] M.Murata: "Oxidative DNA damage induced by nitrotyrosine, a biomarker of inflammation"Biochem.Biophys.Res.Commun.. 316. 123-128 (2004)

[Publications] M.Murata: "Genistein and daidzein induce cell proliferation and their metabolites cause oxidative DNA damage in relation to isoflavone-induced cancer of estrogen-sensitive organs"Biochemistry. 43. 2569-2577 (2004)

[Publications] S.Nakashima: "Vacuolar H^+-ATPase inhibitor induces apoptosis via lysosomal dysfunction in the human gastric cancer cell line MKN-1"J.Biochem.. 134. 359-364 (2003)

[Publications] M.Murata: "Oxidative DNA damage by hyperglycemia-related aldehydes and its marked enhancement by hydrogen peroxide"FEBS Lett.. 554. 138-142 (2003)

[Publications] K.Seike: "Oxidative DNA damage induced by benz[a]anthracene metabolites via redox cycles of quinone and unique non-quinone"Chem.Res.Toxicol.. 16. 1470-1476 (2003)

[Publications] S.Tada-Oikawa: "Mechanism for generation of hydrogen peroxide and change of mitochondrial membrane potential during rotenone-induced apoptosis"Life Sci. 73. 3277-3288 (2003)

[Publications] A.Furukawa: "(-)-Epigallocatechin gallate causes oxidative damage to isolated and cellular DNA"Biochem.Pharmacol.. 66. 1769-1778 (2003)

[Publications] S.Pinlaor: "8-nitroguanine formation in the liver of hamsters infected with Opisthorch is viverrini"Biochem.Biophys.Res.Commun.. 309. 567-571 (2003)

[Publications] K.Ogawa: "Molecular mechanisms of DNA damage induced by procarbazine in the presence of Cu(II)"Mutat.Res.. 539. 145-155 (2003)

[Publications] H.Mizutani: "Distinct mechanisms of site-specific oxidative DNA damage by doxorubicin in the presence of copper(II) and NADPH-cytochrome P450 reductase"Cancer Sci.. 94. 686-691 (2003)

[Publications] T.Iwamoto: "Oxidative DNA damage induced by photodegradation products of 3'-azido-3'-deoxythymidine"Arch.Biochem.Biophys.. 416. 155-163 (2003)

[Publications] S.Oikawa: "Catechins induce oxidative damage to cellular and isolated DNA through the generation of reactive oxygen species"Free Radic.Res.. 37. 881-890 (2003)

[Publications] S.Oikawa: "Oxidative damage to cellular and isolated DNA by homocysteine : implications for carcinogenesis"Oncogene. 22. 3530-3538 (2003)

[Publications] C.Toda: "DNA damage by ethylbenzenehydroperoxide formed from carcinogenic ethylbenzene by sunlight irradiation"Biochem.Biophys.Res.Commun.. 304. 638-642 (2003)

[Publications] K.Hirakawa: "Carcinogenic semicarbazide induces sequence-specific DNA damage through the generation of reactive oxygen species and the derived organic radicals"Mutat.Res. 536. 91-101 (2003)

[Publications] 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.. 77. 349-355 (2003)

[Publications] K.Hirakawa: "Sequence-Specific DNA Damage Induced by Ultraviolet A-Irradiated Folic Acid via Its Photolysis Product"Arch.Biochem.Biophys.. 410. 261-268 (2003)

[Publications] N.Nakai: "Oxidative DNA Damage Induced by Toluene is Involved in its Male Reproductive Toxicity"Free Radic.Res.. 37. 69-76 (2003)

[Publications] 及川伸二: "カテキン類による酸化的DNA損傷"医学のあゆみ. 208. 688-689 (2004)

[Publications] 川西正祐: "分子予防環境医学"分子予防環境医学研究会 編. 768 (2003)

[Publications] 及川伸二: "食と生活習慣病"菅原努 監修. 213 (2003)

川西正祐三重大学, 医学部, 教授 (10025637)

[Publications] 川西正祐: "分子予防環境医学"分子予防環境医学研究会編. 768 (2003)

[Publications] 及川伸二: "食と生活習慣病"菅原努監修. 213 (2003)