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Basic Study for Regenerative Medicine : Differentiate of Human Fetal Liver Cells and Application for Drug Pharmacokinetic Experiments

Research Project

Project/Area Number 16590109
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical pharmacy
Research InstitutionShinshu University

Principal Investigator

MATSUNAGA Tamihide  Shinshu University, Shinshu University Hospital, Division of Pharmacy, Associate Professor, 医学部附属病院, 助教授 (40209581)

Co-Investigator(Kenkyū-buntansha) OHMORI Shigeru  Shinshu University, Shinshu University Hospital, Division of Pharmacy, Professor, 医学部附属病院, 教授 (70169069)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2005: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2004: ¥3,000,000 (Direct Cost: ¥3,000,000)
Keywordshuman fetal liver cell / cytochrome P450 / dexamethasone / glucocorticoid receptor / CYP3A4 / CYP3A7 / rifampicin / RU486 / 正常ヒト胎児肝細胞 / オンコスタチンM / グルココルチコイド受容 / メチル化 / サイトケラチン7 / 移植 / 分化 / RU-486
Research Abstract

Human fetal liver (HFL) cell culture was initiated from a pool of six normal human liver tissues. The proliferation and viability of HFL cells were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay, and the cells increased by more than 100-fold by culture for 15 days. The levels of expression of albumin (ALB), hepatocyte growth factor 4 α, hepatocyte growth factor, CYP3A4, CYP3A5, and CYP3A7 mRNAs in HFL cells increased with culture period, while that of α-fetoprotein (AFP) mRNA decreased gradually. In HepG2 cells, however, the expression levels of ALB and AFP mRNAs were not changed, and the levels of expression of CYP3A4, CYP3A5, and CYP3A7 mRNAs decreased gradually. The mRNA expression of major CYP isoforms including CYP3As, i.e., CYP1A2, CYP2A6, CYP2B6, CYP2C (2C9 and 2C19), CYP2D6, and CYP2E1, could be detected in HepG2 cells. With the exception of CYP1A2, all of the CYP mRNAs expressed in HepG2 cells were detected in HFL cells. In HFL cells, CYP3A … More 4 and CYP3A7 mRNA expression levels were markedly up-regulated by dexamethasone (DEX), but not by rifampicin (RIF). CYP3A5 mRNA level was not increased significantly by DEX, RIF, or phenobarbital (PB). On the other hand, CYP3A4, CYP3A5, and CYP3A7 mRNA expression levels in HepG2 cells were increased from 2- to 3-fold by treatment with DEX, PB, and RIF. Pregnane X receptor mRNA was expressed in HepG2 cells, but not HFL cells. Testosterone 6β -hydroxylase activity was induced to about 2-fold of control by DEX. However, concomitant treatment with RIF did not alter DEX-mediated induction of CYP3A mRNA expression and testosterone 6β-hydroxylase activity. DEX-mediated induction of CYP3A mRNA was suppressed in a dose-dependent manner by RU486, a glucocorticoid receptor (GR) antagonist. At 5 μM RU486, DEX-mediated induction of CYP3A4, CYP3A5, and CYP3A7 mRNA expression was inhibited almost completely. These results suggest that, in human fetal hepatocytes, PXR is not involved in DEX-mediated induction of CYP3A4 and CYP3A7, and that the induction is mediated directly by GR. Less

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (11 results)

All 2006 2005 2004

All Journal Article (11 results)

  • [Journal Article] Determination of P-glycoprotein ATPase activity using luciferase.2006

    • Author(s)
      Matsunaga T et al.
    • Journal Title

      Biol Pharm Bull 29

      Pages: 560-564

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Effective NADH-Dependent Oxidation of 7β-Hydroxy-Δ^8-tetrahydrocannabinol to the Corresponding Ketone by Japanese Monkey Hepatic Microsomes2005

    • Author(s)
      Matsunaga T et al.
    • Journal Title

      Biol Pharm Bull 28

      Pages: 646-651

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] Characterization of Human Fetal Hepatocytes : Expression and Induction of CYP3As2005

    • Author(s)
      Matsunaga T et al.
    • Journal Title

      Proceedings of the 15^<th> Intl. Symposium on MDO

      Pages: 99-102

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Induction mechanisms of CYP3As in human fetal hepatocytes by glucocorticoids.2005

    • Author(s)
      Maruyama M et al.
    • Journal Title

      Drug Metab Rev 37

      Pages: 147-147

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Simple and highly sensitive method for determination of P-glycoprotein ATPase activity using Luciferase.2005

    • Author(s)
      Ohmori S et al.
    • Journal Title

      Drug Metab Rev 37

      Pages: 176-176

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Expressions of cytochrome P450 in differentiating mouse embryonic stem cells.2005

    • Author(s)
      Matsunaga T et al.
    • Journal Title

      Drug Metab Rev 37

      Pages: 200-200

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Effective NADH-Dependent Oxidation of 7β-Hydroxy-Δ^8-tetrahydrocannabinol to the Corresponding Ketone by Japanese Monkey Hepatic Microsomes.2005

    • Author(s)
      Matsunaga T et al.
    • Journal Title

      Biol Pharm Bull 28

      Pages: 646-651

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Induction mechanisms of CYP3As in human fetal hepatocytes by glucocorticoids.2005

    • Author(s)
      Matsunaga T et al.
    • Journal Title

      Drug Metab Rev 37

      Pages: 147-147

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Characterization of Human Fetal Hepatocytes : Expression and Induction of CYP3As2005

    • Author(s)
      Matsunaga T et al.
    • Journal Title

      Proceedings of the 15^<th> Intl. Symposium on MDO (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression and induction of CYP3As in human fetal hepatocytes.2004

    • Author(s)
      Matsunaga T et al.
    • Journal Title

      Biochem Biophys Res Commun 318

      Pages: 428-434

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] Characterization of Human Fetal Hepatocytes : Expression and Induction of CYP3As.2004

    • Author(s)
      Matsunaga T et al.
    • Journal Title

      Proceedings of the 15^<th> Intl.Symposium on MDO (Medimond S.r.l., Bologna, Italy)

      Pages: 99-102

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary

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Published: 2004-04-01   Modified: 2016-04-21  

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