Chain Reaction of Drug Metabolism -A Comprehensive Study on the Cooperative and Competitive Drug Metabolism by CYP Isoforms

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390011
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Physical pharmacy
• Research Institution: Osaka University
• Principal Investigator: UNO Tadayuki 大阪大学, 薬学研究科(研究院), 教授 (00183020)
• Co-Investigator(Kenkyū-buntansha): AOYAMA Hiroshi 大阪大学, 大学院・薬学研究科, 准教授 (60291910) ; YAMASHITA Taku 大阪大学, 大学院・薬学研究科, 招聘准教授 (70398246)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 薬物代謝

Research Abstract

Cytochrome P450s (CYPs) play a key role in human drug metabolism, and five CYP isoforms can metabolize more than 90% of clinical drugs in the market. In this study, we focused on a chain reaction of drug metabolism played by five isoforms. Although an anti-depressant amitriptyline is mainly metabolized by CYP1A2, 2C19, and 2D6, its metabolite nortriptyline, which is structurally similar to amitriptyline, was found to be poorly metabolized by these isoforms. On the other hand, CYP2C9 is a poor metabolizer of amitriptyline although it is homologous with 2C19 in amino acid sequence and three dimensional structure. We revealed that the drug specificity is regulated by the basicity of an amino acid residue at position 72.

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): Tamer Zekry Attia, Taku Yamashita, Mohamed Abdelkhalek Hammad, Akinori Hayasaki, Takumi Sato, Masayoshi Miyamoto, Yuki Yasuhara, Takashi Nakamura, Yusuke Kagawa, Hirofumi Tsujino, Mahmoud Ahmed Omar, Osama Hassan Abdelmageed, Sayed Mohamed Derayea, Tadayuki Uno
  • Journal Title: Chem. Pharm. Bull Volume: 62巻 Pages: 176-181
  • DOI: 10.1248/cpb.c13-00800
  • Peer Reviewed
• [Journal Article] Comparison of Cytochrome P450 Mediated Metabolism of Three Central Nervous System Acting Drugs (2012)
  • Author(s): Tamer Zekry Attia, Taku Yamashita, Masayoshi Miyamoto, Atsushi Koizumi, Yuki Yasuhara, Jun-ichi Node, Yumi Erikawa, Yumi Komiyama, Chiaki Horii, Mayu Yamada, Mahmoud Ahmad Omar, Osama Hassan Abdelmageed, Sayed Mohamed Derayea, Tadayuki Uno
  • Journal Title: Chem. Pharm. Bull Volume: 60巻 Pages: 1544-1549
  • DOI: 10.1248/cpb.c12-00719
  • Peer Reviewed
• [Presentation] Molecular Analysis of Human Drug Metabolizing Enzyme, Cytochrome P450 (2013)
  • Author(s): Tadayuki Uno
  • Organizer: The Eighth Indochina Conference on Pharmaceutical Sciences
  • Place of Presentation: Ho Chi Minh City, Vietnam
  • Year and Date: 2013-12-05
  • Invited
• [Presentation] CYP3A4における薬物結合様式の分光学的解析 (2013)
  • Author(s): 倉橋 拓也, 小泉 温史, 山下 沢, 宇野 公之
  • Organizer: 第23回金属の関与する生体関連反応シンポジウム
  • Place of Presentation: 西東京
  • Year and Date: 2013-06-21
• [Presentation] サイトグロビンの配位子結合性に対する両末端ドメインの影響 (2013)
  • Author(s): 花井 舜平, 辻野 博文, 宇野 公之
  • Organizer: 第23回金属の関与する生体関連反応シンポジウム
  • Place of Presentation: 西東京
  • Year and Date: 2013-06-21
• [Presentation] Effect of Single Nucleotide Polymorphisms(SNPs) on the Activation of Procarcinogens in Human CYP1A2 (2012)
  • Author(s): Tadayuki Uno, Jun-ichi Node, Sakiko Morita, Akihide Tsujimoto, Taku Yamashita, Hiroshi Aoyama
  • Organizer: Seventh International Conference on Porphyrins and Phthalocyanines
  • Place of Presentation: Jeju, Korea
  • Year and Date: 2012-07-05
• [Presentation] Effects of Single Nucleotide Polymorphisms (SNPs) on Drug Metabolism in Human CYP2C9 (2012)
  • Author(s): Tadayuki Uno, Yumi Erikawa, Masayoshi Miyamoto, Yuki Yasuhara, Taku Yamashita, Hiroshi Aoyama
  • Organizer: Seventh International Conference on Porphyrins and Phthalocyanines
  • Place of Presentation: Jeju, Korea
  • Year and Date: 2012-07-05
• [Presentation] Effects of Single Nucleotide Polymorphisms (SNPs) on the Interaction of Human CYP reductase with CYP2C19 and Its Drug Metabolizing Properties (2012)
  • Author(s): 宮本 正芳, 飯賀 由実子, 松本 麻希, 安原 由樹, 青山 浩, 山下 沢, 宇野 公之
  • Organizer: 第22回金属の関与する生体関連反応シンポジウム
  • Place of Presentation: 金沢
  • Year and Date: 2012-05-31
• [Presentation] The role of lipid membrane in the course of drug metabolism by cytochrome P450 (2012)
  • Author(s): 宇野 公之, 安原 由樹, 宮本 正芳, 山田 麻由, 山下 沢, 青山 浩
  • Organizer: 第22回金属の関与する生体関連反応シンポジウム
  • Place of Presentation: 金沢
  • Year and Date: 2012-05-31
• [Presentation] Effects of SNPs on the metabolism of Amitriptyline in CYP2D6 (2012)
  • Author(s): 宇野 公之, 堀井 千明, 山田 麻由, 上村 真司, 青山 浩, 山下 沢
  • Organizer: 第22回金属の関与する生体関連反応シンポジウム
  • Place of Presentation: 金沢
  • Year and Date: 2012-05-31
• [Presentation] Three Cytochrome P450s Responsible for the Metabolism of Amitriptyline and Imipramine (2011)
  • Author(s): Tadayuki Uno, Mayu Yamada, Shinji Uemura, Sakiko Morita, Maki Matsumoto, Hiroshi Aoyama, Taku Yamashita
  • Organizer: 15th International Conference on Biological Inorganic Chemistry
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2011-08-08
• [Presentation] Effect of Single Nucleotide Polymorphisms (SNPs) on the Drug Binding and Metabolizing Properties of Human CYP2C19 (2011)
  • Author(s): Tadayuki Uno, Masayoshi Miyamoto, Yumiko Iiga, Maki Matsumoto, Hiroshi Aoyama, Taku Yamashita
  • Organizer: 15th International Conference on Biological Inorganic Chemistry
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2011-08-08