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Identification of genes involved in drug-induced hepatotoxicity

Research Project

Project/Area Number 16590115
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

HIRANO Kazuyuki  Gifu Pharmaceutical University, Laboratory of Pharmaceutics, Professor (90057365)

Co-Investigator(Kenkyū-buntansha) USUI Shigeyuki  Gifu Pharmaceutical University, Laboratory of Pharmaceutics, Associate Professor (40176665)
IGUCHI Kazuhiro  Gifu Pharmaceutical University, Laboratory of Pharmaceutics, Assistant Professor (10295545)
Project Period (FY) 2004 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,780,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥180,000)
Fiscal Year 2007: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2006: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsDrug-induced hepatotoxicity / HepG2 cells / Lysyl hydroxylase 2 / c-myb / Acetaminophen / Isoniazid / Myb / コラーゲン関連因子 / メトホルミン / βアクチン / プロリン水酸化酵素 / Hep2細胞 / メトトレキサート / 四塩化炭素 / SSH / ビグアナイド剤 / ブホルミン / GAPDH / NADH-ubiquinone oxidoreductase / エタノール / 肝線維化
Research Abstract

In this study, we investigated the genes involved in drug-induced hepatotoxicity. The drugs we focused in this study were acetaminophen, isoniazid, metformin and buformin. To identify the genes changes their expression by the drugs in human hepatic HepG2 cells, a subtractive cDNA library was constructed. Through differential screening of the library, several clones were identified as drug induced or reduced gene. For example, acetaminophen and isoniazid increased lysyl hydroxylase, 2 (LH2) expression, and acetaminophen decreased thymidine synthetase expression. Metformin and buformin decreased glyceraldehyde 3-phosphate dehydrogenase expression and increased beta actin expression.
Lysyl hydroxylase catalyzes the posttranslational hydroxylation of lysine residues in collagen. Hydroxylation of lysine residues in collagen molecules is essential for the formation and stabilization of collagen crosslinks, and is believed to act as an important role in the process of hepatic fibrosis. We therefore focused in the increased LH2 expression by the drugs. To examine the mechanism of LH2 expression increased by the drugs, we prepared the reporter plasmid containing the LH2 upstream region, and found that the increased mRNA expression was due to the transcriptional activation of LH2 by the drugs. In addition, we found that the two drugs induce the expression of transcriptional factor c-myb and the overexpression of c-myb induces LH2 mRNA expression and the transcriptional activation of LH2. From these results, increased LH2 expression may involve in the hepatotoxicity by acetaminophen and isoniazid.

Report

(5 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (16 results)

All 2007 2006 2005 2004

All Journal Article (6 results) (of which Peer Reviewed: 2 results) Presentation (10 results)

  • [Journal Article] Buformin suppresses the expression of glyceraldehyde 3-phosphate dehydrogenase2006

    • Author(s)
      Yano A, Kubota M, Iguchi K, Usui S, Hirano K
    • Journal Title

      Biological & Pharmaceutical Bulletin 29(5)

      Pages: 1006-1009

    • NAID

      110005602230

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Buformin suppresses the expression of glyceraldehyde 3-phosphate dehydrogenase2006

    • Author(s)
      Akiko, Yano, Masafumi, Kubota, Kazuhiro, Iguchi, Shigeyuki, Usui, Kazuyuki, Hirano
    • Journal Title

      Biological & Pharmaceutical Bulletin 29(5)

      Pages: 1006-1009

    • NAID

      110005602230

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Buformin suppresses the expression of glyceraldehyde 3-phosphate dehydrogenase.2006

    • Author(s)
      Akiko Yano, et al.
    • Journal Title

      Biological & Pharmaceutical Bulletin 29・5

      Pages: 1006-1009

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Identification of differentially expressed genes in hepatic HepG2 cells treated with acetaminophen using suppression subtractive hybridization2005

    • Author(s)
      Iguchi K, Takahashi Y, Kaneto Y, Kubota M, Usui S, Hirano K
    • Journal Title

      Biological & Pharmaceutical Bulletin 28(7)

      Pages: 1148-1153

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Identification of differentially expressed genes in hepatic HepG2 cells treated with acetaminophen using suppression subtractive hybridization2005

    • Author(s)
      Kazuhiro, lguchi, Yukari, Takahashi, Yoko, Kaneto, Masafumi, Kubota, Shigeyuki, Usui, Kazuyuki, Hirano
    • Journal Title

      Biological & Pharmaceutical Bulletin 28(7)

      Pages: 1148-1153

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Identification of Differentially Expressed Genes in Hepatic HepG2 Cells Treated with Acetaminophen Using Suppression Subtractive Hybridization2005

    • Author(s)
      Kazuhiro Iguchi, et al.
    • Journal Title

      Biological & Pharmaceutical Bulletin 28・7

      Pages: 1148-1153

    • Related Report
      2005 Annual Research Report
  • [Presentation] メトフォルミンによるグリセルアルデヒド3リン酸脱水素酵素の発現低下2007

    • Author(s)
      横山 雄一、井口 和弘、臼井 茂之、平野 和行
    • Organizer
      日本薬学会東海支部大会
    • Place of Presentation
      名古屋
    • Year and Date
      2007-07-07
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Decrease in glyceraldehyde 3-phosphate dehydrogenase expression by metformin2006

    • Author(s)
      Yuichi, Yokoyama, Kazuhiro, Iguchi, Shigeyuki, Usui, Kazuyuki, Hirano
    • Organizer
      Meeting of the Pharmaceutical Society of Japan Tokai Branch
    • Place of Presentation
      Nagoya
    • Year and Date
      2006-07-07
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Mybによるリジン水酸化酵素2の転写調節について2006

    • Author(s)
      篠田 綾、井口 和弘、高橋 ゆかり、窪田 傑文、臼井 茂之、平野 和行
    • Organizer
      日本薬学会東海支部大会
    • Place of Presentation
      静岡
    • Year and Date
      2006-07-01
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Transcriptional regulation of lysyl hydroxylase 2 by myb2006

    • Author(s)
      Aya, Shinoda, Kazuhiro, Iguchi, Yukari, Takahashi, Masafumi, Kubota, Shigeyuki, Usui, Kazuyuki, Hirano
    • Organizer
      Meeting of the Pharmaceutical Society of Japan Tokai Branch
    • Place of Presentation
      Shizuoka
    • Year and Date
      2006-07-01
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Regulation of lysyl hydroxylase 2 gene expression by transcription factor myb2006

    • Author(s)
      篠田 綾、井口 和弘、高橋 ゆかり、窪田 傑文、臼井 茂之、平野 和行
    • Organizer
      第21回 日本薬物動態学会年会
    • Place of Presentation
      東京
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Regulation of lysyl hydroxylase 2 gene expression by transcription factor myb2006

    • Author(s)
      Aya, Shinoda, Kazuhiro, Iguchi, Yukari, Takahashi, Masafumi, Kubota, Shigeyuki, Usui, Kazuyuki, Hirano
    • Organizer
      21st The Japanese. Society for the Study of Xenobiotics Annual Meeting
    • Place of Presentation
      Tokyo
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] アセトアミノフェンによる薬剤性肝障害誘導時におけるリジン水酸化酵素の発現誘導2004

    • Author(s)
      高橋 ゆかり、井口 和弘、窪田 傑文、臼井 茂之、平野 和行
    • Organizer
      日本薬学会東海支部例会
    • Place of Presentation
      静岡
    • Year and Date
      2004-12-02
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Induction of lysyl hydroxylase expression by acetaminophen in hepatotoxicity2004

    • Author(s)
      Yukari, Takahashi, Kazuhiro, Iguchi, Masafumi, Kubota, Shigeyuki, Usui, Kazuyuki, Hirano
    • Organizer
      Meeting of the Pharmaceutical Society of Japan Tokai. Branch
    • Place of Presentation
      Shizuoka
    • Year and Date
      2004-12-02
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] アセトアミノフェンによるリジン水酸化酵素発現誘導機序の解明2004

    • Author(s)
      高橋 ゆかり, 井口 和弘, 臼井 茂之, 平野 和行
    • Organizer
      第19回 日本薬物動態学会年会
    • Place of Presentation
      金沢
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Mechanism of lysyl hydroxylase induction by acetaminophen2004

    • Author(s)
      Yukari, Takahashi, Kazuhiro, lguchi, Shigeyuki, Usui, Kazuyuki, Hirano
    • Organizer
      19th The Japanese Society for the Study of Xenobiotics Annual Meeting
    • Place of Presentation
      Kanazawa
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary

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

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