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Studies on the prediction of fetal toxicity caused by drugs

Research Project

Project/Area Number 09470522
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 応用薬理学・医療系薬学
Research InstitutionChiba University

Principal Investigator

KITADA Mitsukazu  Chiba University, Hospital Pharmacy, Professor, 医学部・附属病院, 教授 (90110345)

Co-Investigator(Kenkyū-buntansha) ISHII Itsuko  Chiba University, Clinical Pharmacology, Assistant, 薬学部, 助手 (00202929)
OHMORI Shigeru  Chiba University, Hospital Pharmacy, Associate Professor, 医学部・附属病院, 助教授 (70169069)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥10,600,000 (Direct Cost: ¥10,600,000)
Fiscal Year 1998: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 1997: ¥6,200,000 (Direct Cost: ¥6,200,000)
KeywordsCYP / CYP3A7 / steroid metabolism / drug metabolism / fetal toxicity / CYP3A
Research Abstract

Human CYP3A4, CYP3A7 and their chimera CYPs expressed in TN5 or SF9 cells using baculovirus were used for the characterization of human fetal CYP3A7 in steroid metabolism, especially dehydroepiandrosterone (DHEA) and DHEA 3-sulfate (DHEA-3S).
(1) Expression levels of CYP3A enzymes and their chimera enzymes in insect cells and the stability of expressed proteins were different among these GYP enzymes. Exogenous NADPH-cytochrome P450 reductase and cytochrome b5 were essential to obtain the maximal activities for 16 - hydtoxylations of DHEA.and DHEA-3S.
(2) It was suggested that the amino acid residues from 210 to 279 in CYP3A7 were important to hydroxylate DHEA and DHEA-3S at 16 position.
(3) Computer model of CYP3A7 indicated that the protein was stabilized to bind with DHEA and DHEA-3S to form the hydrogen bond at Asp214 with hydroxyl group (DHEA) or -OSO3H (DHEA-3S) at Asp2l4 (oxygen of -CONH2 in Asp).
(4) From the kinetic studies, it was suggested that the region from 40 to 109 amino acids residues in CYP3A7 might be important to interact with NADPH-cytochrome P450 reductase and the region from 210 to 279 amino acid residues might be interact with alpha-naphthoflavone.

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (6 results)

All Other

All Publications (6 results)

  • [Publications] Chmoris, Nakasa H, Asanoue, K.Kurose Y, Ishii I, Hosokawa M, Kitada M: "Differential corolytic properties in metabolism of endogenous and exaganous substrate among CYP3A enzymes expressed in Cas celle" Biochim.Biophys.Acta. 1380. 294-304 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ohmori S, Fujiki N, Nakasa H, Nakamura H.Ishii I, Itahashi K, Kitada M: "Steroid hydroxylation by humanfetal CYP3A7 and human NAPPH-cytochrome P450 expressed in inspect cells using baculovisus" Res.Commun Molec.Pathol Pharmacol. 100. 15-28 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ohmori S,Nakasa H,Asanome K,Kurose Y,Ishii I,Hosokawa M and Kitada M: "Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells." Biochim Biophys Acta. 1380. 297-304 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ohmori S,Fujiki N,Nakasa H,Nakamura H,Ishii I, Itahashi K and Kitada M: "Steroid hydroxylation by human fetal CYP3A7 and human NADPH-cytochrome P450 reductase coexpressed in insect cells using baculovirus." Res Commun Molec Pathol Pharmacol. 100. 15-28 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ohmori S,Nakasa H,Asanoma K,Kurose Y,Ishii I,Hisakawa M,Kitada M: "Differential cadalytic properties in metabolism of endgenous and exogenous substrades among CYP3A enzymes expressed in CDS-cells" Biochim Biophys Acta. 1380. 297-304 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ohmori S,Fujiki N,Nakasa H,Nakamura H,Ishii I,Itahashi K,Kitada M: "Steroid Hydroxylation by human fetal CYP3A7 and human NADPH-cytochrome P450 expressed in insect cells using baculovirus" Res.Commun Molec Pathol Pharmacol. 100. 15-28 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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