環境因子の発がんリスク評価

• 研究課題/領域番号: 09253105
• 研究種目: 重点領域研究
• 配分区分: 補助金
• 研究機関: 大阪市立大学
• 研究代表者: 福島 昭治 大阪市立大学, 医学部・第一病理学教室, 教授 (00137077)
• 研究分担者: 津田 洋幸 国立がんセンター研究所, 化学療法部, 部長 (10163809) ; 立松 正衛 (立松 正衞) 愛知県がんセンター研究所, 病理, 部長 (70117836) ; 広瀬 雅雄 国立衛生試験所, 病理部, 部長 (90145748) ; 今井田 克己 名古屋市立大学, 医学部・病理学, 助教授 (90160043) ; 中江 大 奈良県立医科大学, 腫瘍病理, 助教授 (90207712) ; 高橋 道人 国立衛生試験所, 病理部, 部長 (30080005)
• 研究期間 (年度): 1996 – 1999
• 研究課題ステータス: 完了 (2000年度)
• 配分額: 105,000千円 (直接経費: 105,000千円); 1999年度: 35,000千円 (直接経費: 35,000千円); 1998年度: 35,000千円 (直接経費: 35,000千円); 1997年度: 35,000千円 (直接経費: 35,000千円)
• キーワード: 発がんリスク評価 / 環境発がん物質 / ヘテロサイクリックアミン / diethylnitrosamine / 前がん病変 / 遺伝子変異 / in vivo変異原性 / 8-ハイドロオキシグアニン / 発ガンリスク評価 / in vivo 変異原性 / PhIP / DNA付加体 / 環境因子 / 変異原性 / ニトロソ化合物 / 酸化的ストレス

研究概要

1)Diethylnitrosamine(DEN)投与ラット肝におけるglutathione S-transferase placental form(GST-P)陽性細胞巣の発生は0.0001〜0.01ppmまでは、対照群と全く差はなく0.1ppm以上で有意に増加が認められ、平坦-立ち上がり曲線を示し、DENの肝発がん性には無作用量の存在が強く示唆された。2)SCIDマウスは2-amino-3-methylimidazo[4,5-f]quinoline(IQ)の低用量の大腸発がんに高感受性で、発がんリスク評価に有用である可能性が示唆された。3)非遺伝毒性発がん物質であるphenobarbitalによりラット肝にP450を誘導し、それとともにOHラジカルを産生し、8hydroxyguanine(8-OHG)を形成することが示された。4)各種トランスジェニックあるいはノックアウト動物の変異原活性、および発がん感受性を検討した。リスク評価に有用な高い発がん受性を示すものも多いが、発がんリスク評価に対する有用性にはさらなる追究を要する。5)がん関連遺伝子変異の高感度検出法としてPLACE-SSCP法を検討した。10^<-7>の頻度で生じる突然変異の検出系を開発しつつある。6)被検物質の1回投与後3日における標的臓器の8-OHGレベルの高値を指標として発がんリスクを評価し得る可能性が示唆された。

研究成果

• [文献書誌] Salim,E.I., Fukushima,S. et al.: "Low dose-dependent carcinogenic potential of 2-amino-3-methylimidazo[4,5-f]quinoline in the immunodeficient (SCID) mouse colon."Nutrition and Cancer. 34. 220-228 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nishikawa,A., Hirose,M. et al.: "Trans-4-hydroxy-2-nonenal, an aldehydic lipid peroxidation products, lacks genotoxicity in lacl transgenic mice."Cancer Lett.. 148. 81-86 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tsukamoto,T.,Tatematsu,M. et al.: "Development and distribution of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced aberrant crypt foci in the rat large intestine. "Jpn.J.Cancer Res.. 90. 720-725 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tsuda,H. et al.: "Heterocyclic amine mixture carcinogenesis and its enhancement by caffeine in F344 rate."Cancer Lett.. 143. 229-234 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Yoshida,M., Nakae,D., et al.: "Hepatocoxicity and consequently increased cell proliferation are associated with flumequine hepatocarcinogenesis in mice."Cancer Lett.. 141. 99-107 (2000)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Imaida, K. et al.: "Delay of DNA- adduct repair and severe toxicity in xeroderma pigmentosum group A gene (XPA) deficient mice treated with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)."Cancer Lett.. 144. 1-7 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Fukushima, S. et. al.: "Differences of promoting activity and loss of heterozygosity between dimethylarsinic acid and sodium L-ascorbate in F1 rat urinary bladder carcinogenesis. In : Arsenic exposure and health effects."Elsevier, Tokyo (eds.) Chappell,W.R., Abemathy,C.O., Calderon,R.L.. 4 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Salim, E.I., Fukushima, S., et al.: "Low-dose-dependent carcinogenic potential of 2-amino-3-methylimidazo [4,5-f] quinoline in the immunodeficient (SCID) mouse colon."Nutrition and Cancer. 34. 220-228 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nishikawa, A., Hirose, M.: "Trans-4-hydroxy-2-nonenal, an aldehydic lipid peroxidation products, lacks genotoxicity in lacI transgenic mice."Cancer Lett.. 148. 81-86 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tsukamoto, T., Tatematsu, M.: "Development and distribution of 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP)-induced aberrant crypt foci in the rat large intestine."Jpn.J.Cancer Res.. 90. 720-725 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tsuda, H., et al.: "Heterocyclic amine mixture carcinogenesis and its enhancement by caffeine in F344 rats."Cancer Lett.. 143. 229-234 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Yoshida, M., Nakae, D.et al.: "Hepatocoxicity and consequently increased cell proliferation are associated with flumequine hepatocarcinogenesis in mice."Cancer Lett.. 141. 99-107 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Imaida, K., et al.: "Delay of DNA-adduct repair and severe toxicity in xeroderma pigmentosum group A gene (XPA) deficient mice treated with 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)."Cancer Lett.. 144. 1-7 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Chen, T., Fukushima, S.et al.: "Differences of promoting activity and loss of heterozygosity between dimethylarsinic acid and sodium L-ascorbate in F1 rat urinary bladder carcinogenesis. In : Arsenic exposure and health effects."(eds.) Chappell, W.R., Abernathy, C.O., Calderon, R.L., Elsevier, Tokyo. 263-266 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Salim, E. I., Fukushima, S. et al.: "Low dose-dependent carcinogenic potential of 2-amino-3-methylimidazo[4,5-f] quinoline in tge immunodeficient (SCID) mouse colon"Nutrition and Cancer. 34. 220-228 (1999)
• [文献書誌] Nishikawa, A., Hirose, M. et al.: "Trans-4-hydroxy-2-nonenal, an aldehydic lipid peroxidation products, lacks genotoxicity in lacI transgenic mice"Cancer Lett.. 148. 81-86 (1999)
• [文献書誌] Tsukamoto, T., Tatematsu, M. et al.: "Development and distribution of 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) -induced aberrant crypt foci in the rat large intesrtine"Jpn. J. Cancer Res,.. 90. 720-725 (1999)
• [文献書誌] Tsuda, H. et al: "Heterocyclic amine mixture carcinogenesis and its enhancemen by caffeine in F344 rats"Cance Left.. 143. 229-234 (1999)
• [文献書誌] Yoshida, M., Nakae, D., et al.: "Hepatocoxicity and consequently increased cell proliferation are associated with flumequine hepatocarcinogenesis in mice"Cancer Lett.. 141. 99-107 (2000)
• [文献書誌] Imaida, K. et al.: "Dalay of DNA-adduct repair and severe toxicity in xerodema pigmentosum group A gene (XPA) deficient mice treated with 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP)"Cancer Lett.. 144. 1-7 (1999)
• [文献書誌] 4 (1999)
• [文献書誌] Fukushima, S. et al.: "Differences of promoting activity and loss of heterozygosity between dimethylarsinic acid and sodium L-ascorbate in Fl rat uninary bladder carcinogensis, In: Arsenic exposure and health effects."Elsevier, Tokyo (eds.) Chappell, W. R., Abemathy, C. O., Calderon, R. L.. 4 (1999)
• [文献書誌] Oazaki,K.,Fukushima,S.et.al.: "High susceptibility of p53(+/-)knockout mice in N-butyl-N-(4-hydroxybutyl)nitrosamine urinary bladder carcinogenesis and lack of frequent mutation in residual allele:" Cancer Res.58. 3806-3811 (1998)
• [文献書誌] Hirose,M.,Yamaguchi,T.er al.: "Strong promoting activity of phenylethyl isothiocyanate and benzyl isothiocyanate on urinary bladder carcinogenesis in F344 male rats." Int.J.Cacer. 77. 773-777 (1998)
• [文献書誌] Tatematsu,M.,Yamamoto,M.et al.: "Induction of glandular stomach cancers in Helicobacter pylori-sensitive mongolian gerbils treated with N-methyl-N-nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine in drinking water." Jpn.J.Cancer Res.89. 97-104 (1998)
• [文献書誌] Kim,J.M.,Tsuda,H.et al.: "Chemopreventive effects of carotenoids and curcumins on mouse colon carcinogenesis after 1,2-dimethylhydrazine initiation." Carcinogenesis. 19. 81-85 (1998)
• [文献書誌] Nakae,D.,Kotake,Y.et al.: "Inhibition by phenyl N-tert-butyl nitrone of early phase carcinogenesis in the livers of rats fed a choline-defieicnt,L-amino acid-defined diet." Cancer Res.58. 4548-4551 (1998)
• [文献書誌] Imaida,K.,Taki,M.et al.: "Lack of promoting effects of the electromagnetic near-field used for cellular phones(929.2MHz)on rat liver carcinogenesis in a medium-term liverbioassay." Carcinogenesis. 19. 311-314 (1998)
• [文献書誌] Fukushima,S.et.al.: "Urinary bladder cancer.In:Carcinogenicity.(eds.)" Marcel Dekker,Inc.,(ed.Kitchin,K.T.), 26 (1998)
• [文献書誌] Wanibuchi,H.,Fukushima,S.et al.: "Promotion of rat hepatocarcinogenesis by dimethylarsinic acid:association with in elevated ornitine decarbosylase activity and formation of 8-hydroxydeoxyguanosine the liver." Jpn.j.Cancer Res.88. 1149-1154 (1997)
• [文献書誌] Nishikawa,A.,Takahashi,M.et al.: "Comparative study on organ-specificity of tumorigenicity,mutagenicity and cell proliferative activity induced by dimethylnitrosamine in Big Blue mice." Cancer Lett.117. 143-147 (1997)
• [文献書誌] Kobayashi,K.,Tatematsu,M.et al.: "Dose-dependent promoting effects of catechol on glandular stomach carcinogenesis in BALB/c mice initiated with N-methyl-N-nitorosourea." Jpn.J.Cancer Res.88. 1143-1148 (1997)
• [文献書誌] Matsumoto,K.,Tsuda,H.et al.: "Demonstration of ras and p53 gene mutations in carcinomas in the forestomach and intestine and soft tissue sarcomas induced by N-methyl-N-nitrosourea in the rat." Jpn.J.Cancer Res.88. 129-136 (1997)
• [文献書誌] Nakae,D.,Konishi,Y.et al.: "Involvement of 8-hydroxyguanine formation in the initiation of rat liver carcinogenesis by low dose levels of N-nitrosodiethylamine." Cancer Res.57. 1281-1287 (1997)
• [文献書誌] Imaida,K.,Ito,N.et al.: "Lack of promoting effects of the electromagnetic near-field used for cellular phones(929.2MHz)on rat liver carcinogenesis in a medium-term liver bioassay." Carcinogenesis. 19. 101-104 (1998)