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Novel hypothesis for phenobarbital induction of drug metabolizing enzyme: Investigation of a model and a mechanism

Research Project

Project/Area Number 16K15148
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Environmental and hygienic pharmacy
Research InstitutionKyushu University

Principal Investigator

ISHII YUJI  九州大学, 薬学研究院, 准教授 (90253468)

Research Collaborator Miyauchi Yuu  
Hidaka Kyoko  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsシトクロムP450 / UDP-グルクロン酸転移酵素 / フェノバルビタール / マウス / UGT / Ugt / 薬学
Outline of Final Research Achievements

We investigated a model and a mechanism that the novel hypothesis for phenobarbital (PB) induction of drug metabolizing enzymes. In this study, we made attempt to establish cytochrome P450 3A (CYP3A)-null HepG2 cells. So that we obtained CYP3A-hetero-knockout cells. In addition, we established the expression system for all the UDP-glucuronosyltransferase (Ugt) isoforms in mouse liver. We carried out comprehensive analysis for the Ugt isoforms and found Ugt isoforms predominantly participated in morphine and acetaminophen glucuronidation, respectively. Further, we carried out metabolomic analysis of PB-treated mice. There are marked difference in metabolome on the basis of OPLS-plot and S-plot. Some metabolites including steroids are found to be altered by PB. Further studies are necessary to elucidate the novel hypothesis of PB-induction.

Academic Significance and Societal Importance of the Research Achievements

古くから知られている薬物代謝酵素の誘導現象について新たな仮説を検証しようと試みた挑戦的研究である。得られた成果には更なる発展が期待される。また、その途上に、医薬品開発に汎用されるマウスの主要薬物代謝酵素UDP-グルクロン酸転移酵素の包括的特性評価系を確立した。これは、医薬品開発における前臨床試験の精度の向上に資する研究であると期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (9 results)

All 2018 2017 2016 Other

All Int'l Joint Research (3 results) Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results) Presentation (4 results) (of which Int'l Joint Research: 1 results) Remarks (1 results)

  • [Int'l Joint Research] Flinders University(オーストラリア)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Flinders University School of Medicine(Australia)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] Flinders University of South Australia(Australia)

    • Related Report
      2016 Research-status Report
  • [Journal Article] Comprehensive Characterization of Mouse UDP-Glucuronosyltransferase (Ugt) Belonging to the Ugt2b Subfamily: Identification of Ugt2b36 as the Predominant Isoform Involved in Morphine Glucuronidation.2017

    • Author(s)
      Kurita A, Miyauchi Y, Ikushiro S, Mackenzie PI, Yamada H, Ishii Y.
    • Journal Title

      J Pharmacol Exp Ther.

      Volume: 361 Issue: 2 Pages: 199-208

    • DOI

      10.1124/jpet.117.240382

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Comprehensive characterization of mouse hepatic UDPglucuronosyltransferases: Major participation of Ugt2b34 in acetaminophen glucuronidation2018

    • Author(s)
      Ryohei Yamashita, Ayumi Kurita, Yuu Miyauchi, Shinichi Ikushiro, Peter I Mackenzie, Yoshitaka Tanaka, Yuji Ishii
    • Organizer
      2018 International Meeting on 22nd MDO (The International symposium on microsomes and Drug Oxidations) and 33rd JSSX (The Japanese Society of Study for Xenobiotics)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Comprehensive characterization of mouse hepatic UDP-glucuronosyltransferases: major participation of Ugt1a1 in SN-38 glucuronidation2017

    • Author(s)
      Kohei Yamashita, Ayumi Kurita, Yuu Miyauchi, Shin’ichi Ikushiro, Peter I. Mackenzie, Yuji Ishii
    • Organizer
      日本薬物動態学会第32年会
    • Related Report
      2017 Research-status Report
  • [Presentation] マウス肝の全UDP-グルクロン酸転移酵素分子種の包括的特性評価2016

    • Author(s)
      栗田歩実, 宮内優, Mackenzie, P.I., 山田英之, 石井祐次
    • Organizer
      第33回日本薬学会九州支部大会
    • Place of Presentation
      鹿児島市
    • Year and Date
      2016-12-03
    • Related Report
      2016 Research-status Report
  • [Presentation] Comprehensive characterization of mouse hepatic UDP-glucuronosyltransferases belonging to 2B subfamily: major participation of Ugt2b36 in morphine and diclofenac glucuronidation.2016

    • Author(s)
      Ayumi Kurita, Yuu Miyauchi, Peter I. Mackenzie, Hideyuki Yamada, Yuji Ishii
    • Organizer
      日本薬物動態学会第31年会
    • Place of Presentation
      松本市
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
  • [Remarks] 九州大学大学院薬学研究院大学院薬学府薬学部

    • URL

      http://www.phar.kyushu-u.ac.jp

    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2023-03-23  

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