The Elucidation on mechanism of drug metabolism by a statistic and dynamics approaches.

2013 Fiscal Year Final Research Report

• Project/Area Number: 23790045
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Physical pharmacy
• Research Institution: Osaka University
• Principal Investigator: YAMASHITA Taku 大阪大学, 薬学研究科(研究院), 招聘准教授 (70398246)
• Project Period (FY): 2011 – 2012
• Keywords: シトクロムP450 / 代謝活性 / 時間分解スペクトル測定 / 基質認識 / 結合親和性 / 薬物代謝 / 部位特異的変異

Research Abstract

The result in the last fiscal year suggested that tricyclic antidepressants could be interesting targets which should be investigated on several CYP isoforms. Especially, CYP2C9 and 2C19 had been reported that the two isoforms metabolized opposite properties of substrates in each. In this work, we focused on two reciprocal residues on positions 72 and 241, and two mutants were prepared, respectively; i.e., K72E and K241E for CYP2C9 and E72K and E241K for CYP2C19. These mutants and wild-types on CYP2C9 and 2C19 were evaluated on binding affinities and metabolic activities on three tricyclic antidepressants; amitriptyline, imipramine, and dothiepin. The estimated values implied that an amino acid located on position 72 could contribute to recognize property of substrate, mainly on basic drugs.

Research Products

• [Journal Article] Effect of cytochrome P450 2C19 and 2C9 amino acid residues 72 and 241 on metabolism of tricyclic antidepressant drugs (2014)
  • Author(s): T. Z. Attia, T. Yamashita, M. A. Hammad, A. Hayasaki, T. Sato, M. Miyamoto, Y. Yasuhara, T. Nakamura, Y. Kagawa, H. Tsujino, M. A. Omar, O. H. Abdelmageed, S. M. Derayea, and T. Uno
  • Journal Title: Chem. Pharm. Bull Volume: 62(2) Pages: 176-81
• [Journal Article] Comparison of cytochrome p450 mediated metabolism of three central nervous system acting drugs (2012)
  • Author(s): T. Z. Attia, T. Yamashita, M. Miyamoto, A. Koizumi, Y. Yasuhara, J. Node, Y. Erikawa, Y. Komiyama, C. Horii, M. Yamada, M. A. Omar, O. H. Abdelmageed, S. M. Derayea, and T. Uno
  • Journal Title: Chem. Pharm. Bull Volume: 60(12) Pages: 1544-9
• [Presentation] Contribution of oppositely charged residues to the drug metabolism of cytochrome P450 2C9 and 2C19 (2014)
  • Author(s): 山下沢、T.Z.Attia、M. A. Hammad、佐藤匠、早崎瑛紀、宮本正芳、安原由樹、中村隆志、辻野博文、宇野公之
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
  • Year and Date: 20140300
• [Presentation] Comparison of Cytochrome P450 Mediated Metabolism of Three CNS Acting Drugs (2012)
  • Author(s): T. Yamashita, T. Z. Attia, M. Miyamoto, A. Koizumi, Y. Yasuhara, J. Node, Y. Erikawa, Y. Komiyama, C. Horii, M. Yamada, M. A. Omar, O. H. Abdelmageed, S. M. Derayea, and T. Uno
  • Organizer: 50th Anniversary Symposium on Cytochrome P450
  • Place of Presentation: 福岡
  • Year and Date: 20121200