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

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K15148
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Environmental and hygienic pharmacy
• Research Institution: Kyushu 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
• 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

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.

Free Research Field

衛生薬学、薬物代謝

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。