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In vivo model to predict human fetal toxicity of xenobiotics : Establishment and evaluation of humanized mice carrying multiple forms of human fetal drug metabolizing enzymes.

Research Project

Project/Area Number 13557214
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Environmental pharmacy
Research InstitutionHOKKAIDO UNIVERSITY

Principal Investigator

KAMATAKI Tetsuya (2002)  HOKKAIDO Univ., Grad. School of Pharmaceu. Sci., Prof, 大学院・薬学研究科, 教授 (00009177)

藤田 健一 (2001)  北海道大学, 大学院・薬学研究科, 助手 (60281820)

Co-Investigator(Kenkyū-buntansha) YAMAZAKI Hiroshi  HOKKAIDO Univ., Grad. School of Pharmaceu. Sci., Asso. Prof., 大学院・薬学研究科, 助教授 (30191274)
鎌滝 哲也  北海道大学, 大学院・薬学研究科, 教授 (00009177)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2001: ¥2,400,000 (Direct Cost: ¥2,400,000)
KeywordsP450 / COX / fetal toxicity / thalidomide / transgenic mice / humanized mice / animal model / teratogenicity / プロスタグランジンG / H合成酵素 / アフラトキシンB_1 / フェニトイン / チトクロームP450
Research Abstract

Most of the human fetal toxicities of xenobiotics are unpredictable, since drug metabolizing enzymes such as cytochrome P450 (CYP), which are present in human fetuses, do not exist in rodent fetuses. In order to establish and animal model to predict human fetal toxicities, we introduced multiple forms of human fetal drug metabolizing enzymes into mice by transgenic technique. Four transgenic lines of mice carrying human fetal enzymes were established. In the 36p line of mice, the expression of human CYP1A1, CYP1B1, CYP3A7, cyclooxygenase (COX)-1 and COX-2 at mRNA levels were detected in the mouse fetuses. Treatment of the 36p female mice with a single dose of thalidomide (100 mg/kg b wt.), a well-known teratogen in humans, on gestational day 9 resulted in the increased deaths or the resorptions of embryos. Thus, these humanized mice may become a suitable model to predict human fetal toxicities of chemicals.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (32 results)

All Other

All Publications (32 results)

  • [Publications] Toide, K.et al.: "Aryl hydrocarbon hydroxylase represents CYP1B1, and not CYP1A1, in human freshly isolated white cells : Trimodal distribution of Japanese population"Cancer Epidemiol.Biomarkers Prev.. 12(3). 219-222 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ozeki, T.et al.: "Hepatocyte nuclear factor(HNF)-4α/γ and HNF-1α as causal factors of interindividual difference in the expression of human dihydrodiol dehydrogenase (DD) 4 mRNA in human livers"Pharmacogenetics. 13. 49-53 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ariyoshi, N.et al.: "Genetic polymorphism of CYP2A6 gene and tobacco-induced lung cancer risk in male smokers"Cancer Epidemiol.Biomarkers Prev.. 405. 185-190 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Topcu, Z.et al.: "CYP2A6 gene deletion reduces oral cancer risk in betel quid chewers in Sri Lanka"Carcinogenesis. 23. 595-598 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujita, K.et al.: "Role of human cytochrome P450 (CYP) in the metabolic activation of N-alkyl-ntrosamines : Application of genetically engineered Salmonella typhimurium YG7108 expressing each form of CYP together with human NADPH-cytochrome P450 reductase"Mutat. Res.. 483. 35-41 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Saito, T.et al.: "Novel transcriptional regulation of the human CYP3A7 gene by specificity protein (sp) 1 and Sp3 through nuclear factor-κB-like element"J. Biol. Chem.. 276(41). 38010-38022 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 鎌滝哲也: "ヒト型代謝酵素発現モデル-ヒトP450発現トランスジェニックマウス"ヒト型モデル動物. 5 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Toide, K. et al.: "Aryl hydrocarbon hydroxylase represents CYP1B1, and not CYP1A1, in human freshly isolated white cels : Trimodal distribution of Japanese population"Cancer Epidemiol. Biomarkers Prev.. 12(3). 219-222 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ozeki, T. et al.: "Hepatocyte nuclear factor(HNF)-4α/γ and HNF-1α as casual factors of interindividual difference in the expression of human dihydrodiol dehydrogenase (DD) 4mRNA in human livers"Pharmacogenetics. 13. 49-53 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kiyotani, K. et al.: "Twenty one novel single nucleotide polymorphisms (SNPs) of the CYP2A6 gene in Japanese and Caucasians"Drug Metabol. Pharmacokin. 17(5). 482-487 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ariyoshi, N. et al.: "Genetic polymorphism of CYP2A6 gene and tobacco-induced lung cancer risk in male smokers"Cancer Epidemiol. Biomarkers Prev.. 405. 185-190 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ozeki ,T. et al.: "Hepatocyte nuclear factor (HNF)-4α/γ, HNF-1α and vHNF-1 regulate the cell-specific expression of the human dihydrodiol debydrogenase (DD) 4 / AKR1C4 gene"Archives Biochem, Biophys.. 405. 185-190 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Toide, K. et al.: "Hepatocytes nuclear factor-1α is a causal factor responsible for interindividual differences in the expession of UDP-glucuronosyltransferase 2B7 mRNA in human livers"Drug Metab. Dispos.. 30(6). 613-615 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Topcu, Z. et al.: "CYP2A6 gene deletion reduces oral cancer risk in betel quid chewers in Sri Lanka"Carcinogenesis. 23. 595-598 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Daigo, S. et al.: "A novel mutant allele of th CYP2A6 gene (CYP2A^*11) found in a cancer patient who showed poor metabolic phenotype toward tegafur"Pharmacogenetics. 12(4). 299-306 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujita, K. et al.: "Roel of human cytochrome P450 (CYP) in the metabolic activation of N-alkyl-ntrosamines : application of genetically engineered salmonella typhimurium YG7108 expressing each form of CYP together with human NADPH-cytochrome P450 reductase"Mutat. Res.. 483. 35-41 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujita, K. et al.: "Construction of salmonella typhimurium YG7108 strains each co-expressing a form of human cytochrome P450 with NADPH-cytochrome P450 reductase"Environ, and Mol. Mutagen.. 38. 329-338 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Saito, T. et al.: "Novel transcriptional regulation of the human CYP3A7 gene by specificity protein (sp) 1 and sp3 through nuclear factor-κB-like element"J. Biol. Chem.. 276(41). 38010-38022 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwano, S. et al.: "Cooperative Regulation of CYP3A5 Gene Transcription by NF-Y and Sp Family Members"Biochem. Biophys. Res. Commun.. 286. 55-60 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Toide, K. et al.: "Aryl hydrocarbon hydroxylase represents CYP1B1, and not CYP1A1, in human freshly isolated white cells Trimodal distribution of Japanese population"Cancer Epidemiol. Biomarkers Prey. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Kanamori, Y. et al.: "Large-scale Production of genetically engineered CYP3A4 in E. coil Application of a jarfermenter"Drug Metabol Pharmacokin. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Ozeki, T. et al.: "Hepatocyte nuclear factor (HNF)-4α/γ and HNF 1α as casual factors of interindividual difference in the expression of human dihydrodiol dehydrogenease (DD) 4mRNA in human livers"Pharmacogenetics. 13. 49-53 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ariyoshi, N. et al.: "Genetic polymorphism of CYP2A6gene and tobacco-induced lung cancer risk in male smokers"Cancer Epidemiol Biomarkers Prev. 11. 890-894 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ozeki, T. et al.: "Hepatocyte nuclear factor (HNF)-4α/γ, HNF 1α and vHNF-1 regulate the cellspecific expression of the human dihydrodiol dehydiogenase (DD) 4/AKR1C4 gene"Archives Biochem Biophys.. 405. 185-190 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Topcu, Z. et al.: "CYP2A6 gene deletion reduces oral cancer risk in betel quid chewers in Sri Lanka"Carcinogenesis. 23. 595-598 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 鎌滝哲也: "ヒト型モデル動物"ヒト型代謝酵素発現モデルーヒトP450発現トランスジェニックマウス. 5 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ken-ichi Fujita: "Screening of Organosulfur compounds as inhibitors of human CYP2A6"Drug Metab. Dispos.. 29. 983-989 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shigeharu Muto: "Inhibition by green tea catechins of metabolic activation of procarcinogens by human cytochrome P450"Mutat.Res.. 479. 197-206 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shunsuke Iwano: "Cooperative regulation of CYP3A5 gene transcription by NF-Y and Sp family members"Biochem.Biophys.Res.Commun.. 286. 55-60 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ken-ichi Fujita: "Construction of Salmonella typhimurium YG7108 strains each co-expressing a form of human cytochrome P450 with NADPH-cytochrome P450 reductase"Environ.Mol.Mutagen.. 38. 329-338 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ken-ichi Fujita: "Predicting the mutagenicity of tobacco-related N-nitrosamines in humans using eleven strains of Salmonella typhimurium YG7108 each co-expressing a form of human cytochrome P450 with NADPH-cytochrome P450 reduclase"Environ.Mol.Mutagen.. 38. 339-346 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ken-ichi Fujita: "Application of genetically engineered Salmonella typhimurium YG7108 expressing each form of CYP together with human NADPH-cytochrome P450 reductase"Mutat. Res.. 483. 35-41 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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