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Assessment of human drug metabolism by expression of cytochrome P-450 in yeasts.

Research Project

Project/Area Number 03557113
Research Category

Grant-in-Aid for Developmental Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field 応用薬理学・医療系薬学
Research InstitutionKeio University

Principal Investigator

KATO Ryuichi  Keio Univ., Sch. of Med., Professor, 医学部, 教授 (40112685)

Co-Investigator(Kenkyū-buntansha) MIYADO Shinji  Meiji Seika Kaisha, LTD,Pharmaceutical Research Center, Group Leader, 薬品総合研究所探索研究所, 室長
MURAYAMA Norie  Keio Univ., Sch. of Med., Assistant, 医学部, 助手 (90219949)
NAGATA Miki  Keio Univ., Sch. of Med., Assistant, 医学部, 助手 (10196488)
NAGATA Kiyoshi  Keio Univ., Sch. of Med., Assistant, 医学部, 助手 (80189133)
YAZUMORI Toshio  Keio Univ., Sch. of Med., Assistant, 医学部, 助手 (70182350)
甲斐 文夫  明治製菓(株)薬品総合研究所新薬研究所, 所長
Project Period (FY) 1991 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥15,200,000 (Direct Cost: ¥15,200,000)
Fiscal Year 1992: ¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 1991: ¥9,900,000 (Direct Cost: ¥9,900,000)
KeywordsCytochrome P-450 / Gene expression / Human drug metabolism / P-450 mixture / 薬物代謝 / 薬物代謝酵素 / 異所的発現 / ヒト薬物代謝能 / チトクロムP-450
Research Abstract

The purpose of this project is development of a new assessment method for human drug metabolism by using mixture of cytochrome P-450 expressed in yeast cells. We first cloned CYP3A4, a major human cytochrome P-450, and expressed it in yeast cells. On the other hand, we expressed human NADPH-cytochrome P-450 reductase and cytochrome b_5 in yeast cells. Then we improved the expression vectors to co-express different vectors in the same cells . We succeeded in co-expressing CYP3A4, NADPH-cytochrome P-450 reductase and cytochrome b_5 in the same cells and we observed high enzymic activities for several substrates. These results indicates further possible way to express sever al different cytochrome P-450 by this method.
We, then, try to increase the yield of cytochrome P-450 in yeast cells changing by conditions of the incubation. Thus, we concluded that this approach is useful method for the assessment of human drug metabolism by using a mixture of human cytochrome P-450 expressed in yeast cells.

Report

(3 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] YASUMORI,T.: "Cytochrome P-450 human-2(P-450IIC9)in mephenytoin hydroxylation polymorphism in human livers:Differences in substrate and stereoselectivities among microheterogeneous P-450IIC species expressed in yeasts." J.Biochem.109. 711-717 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 加藤 隆一: "ヒト肝ミクロソームにおけるヘキソバルビタールの立体選択的代謝の薬理遺伝学" 臨床薬理. 22. 61-62 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 安盛 俊雄: "ヒト肝P-450human-2とその変異型によるメフェニトイン.ヘキソバルビタールの立体選択的水酸化の比較" 臨床薬理. 22. 65-66 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] KATO,R.: "Polymorphism in stereoselective hydroxylations of mephenytoin and hexobaribital by Japanese liver samples in relation to cytochrome P-450 human-2(IIC9)." Xenobiotica. 22. 1083-1092 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] YAZUMORI,T.: "Species differences in stereoselective metabolism of mephenytoin by cytochrome P450(CYP2C and CYP3A)." J.Pharmacol.Exp.Ther.264. 89-94 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Chen,L.: "Hepatic microsomal hydroxylation in Japanese:in vitro evidence for rapid and slow metabolizers." Pharmacogenetics.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] KATO,R.: "Cytochrome P450(Characterization of human P450IIC isozyme by using a yeast expression system." Academic Press, 8 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yasumori, T.: "Cytochrome P-450 human-2 (P-450IIC9) in mephenytoin hydroxylation polymorphism in human livers : Differences in substrate and stereoselectivities among microheterogeneous P-450IIC species expressed in yeasts." J. Biochem.109. 711-717 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kato, R.: "Pharmacogenetics of stereoselective metabolism of hexobarbital in human liver microsomes." Jpn. J. Clin. Pharmacol. Ther.22. 61-62 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yasumori, T.: "Comparison of stereoselectivities in hydroxylation of mephenytoin and hexobarbital by microheterogeneous forms of hepatic P450 human-2." Jpn. J. Clin. Pharmacol. Ther.22. 65-66 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kato, R.: "Polymorphism in stereoselective hydroxylations of mephenytoin and hexobarbital by Japanese liver samples in relation to cytochrome P-450 human-2 (IIC9)." Xenobiotica. 22. 1083-1092 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yasumori, T.: "Species differences in stereoselective metabolism of mephenytoin by cytochrome P450 (CYP2C and CYP3A)." J. Pharmacol. Exp. Ther.264. 89-94 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Chen, L.: "Hepatic microsomal hydroxylation in Japanese : in vitro evidence for rapid and slow metabolizers." Pharmacogenetics.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kato, R.: "Cytochrome P450 : Characterization of human P450IIC isozyme by using a yeast expression system." Methods Enzymol.206. 183-190 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kato,R.: "Polymorphism in stereoselective hydroxylations of mephenytoin and hexobarbital by Japanese liver samples in relation to cytochrome P-450 human2 (IIC9)." Xenobiotica. 22. 1083-1092 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Yasumori,T.: "Species differences in stereoselective metabolism of mephenytoin by cytochrome P450 (CYP2C and CYP3A)." J.Pharmacol.Exp.Ther.264. 89-94 (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Chen,L.: "Hepatic microsomal hydroxylation in Japanese:in vitro evidence for rapid and slow metabolizers." Pharmacogenetics.

    • Related Report
      1992 Annual Research Report
  • [Publications] 山添 康: "ヒト肝におけるトルブタミド,S-メフェニトイン水酸化活性とP-450 human-2含量の相関:トルブタミドの基質濃度の差" 臨床薬理. 23. 57-58 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 加藤 隆一: "新生化学実験講座5 生体酸化・薬物代謝(薬物代謝の生化学的側面)" 東京化学同人, 10 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 加藤 隆一: "新生化学実験講座5 生体酸化・薬物代謝(ヒトにおける薬物代謝)" 東京化学同人, 13 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Yasumori,T.: "Cytochrome P-450 human-2(P-450IIC9)in mephenytoin hydroxylation polymorphism in human livers:Differences in substrate and stereoselectivities among microheterogeneous P-450IIC species expressed in yeast." J.Biochem.109. 711-717 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Miyata,M.: "A Gene structure of testosterone 6β-hydroxylase(P450IIIA)" Biochem.Biophys.Res.Commun.177. 68-73 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Chen,L.: "Evidence for correlation of microsomal tolbutamide hydoxylation with S-mephenytoin hydroxylation polymorphism in Japanese livers,mediated by P-450 human-2(a form of P450IIC9)" Pharmacogenetics.

    • Related Report
      1991 Annual Research Report
  • [Publications] Kato,R.: "Xenobiotics and Cancer" Japan Sci.Press/Taylor & Francis, 9 (1991)

    • Related Report
      1991 Annual Research Report

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Published: 1991-04-01   Modified: 2016-04-21  

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