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

用统计学和动力学方法阐明药物代谢机制。

• 批准号: 23790045
• 负责人: YAMASHITA Taku
• 金额: $ 2.83万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23790045/
• 关键词: 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; 薬物代謝酵素; CYP; 2C19; 2C9; 国際研究者交流; フランス; CPR; 時間分解測定; シミュレーション; 共鳴ラマン分光法

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.

上一财政年度的结果表明，三环抗抑郁药可能是一个有趣的目标，应该在几个CYP异构体上进行研究。特别是CYP2C9和2C19，据报道，这两种亚型代谢的底物性质相反。在这项工作中，我们重点研究了72位和241位的两个互反残基，分别制备了两个突变体；即CYP2C9的K72E和K241E， CYP2C19的E72K和E241K。观察CYP2C9和2C19突变体和野生型对3种三环类抗抑郁药的结合亲和力和代谢活性；阿米替林，丙咪嗪和多硫平。估计值表明，位于72位的氨基酸有助于识别底物的性质，主要是对基本药物的识别。

项目成果

Comparison of cytochrome p450 mediated metabolism of three central nervous system acting drugs.

细胞色素p450介导的三种中枢神经系统作用药物代谢的比较。

• DOI: 10.1248/cpb.c12-00719
• 发表时间: 2012
• 期刊: Chemical & pharmaceutical bulletin
• 影响因子: 1.7
• 作者: Tamer Z. Attia;Taku Yamashita;Masayoshi Miyamoto;A. Koizumi;Y. Yasuhara;J. Node;Y. Erikawa;Y. Komiyama;C. Horii;Mayu Yamada;Mahmoud A Omar;O. Abdelmageed;S. M. Derayea;T. Uno
• 通讯作者: T. Uno

Effect of Cytochrome P450 2C19 and 2C9 Amino Acid Residues 72 and 241 on Metabolism of Tricyclic Antidepressant Drugs

• DOI: 10.1248/cpb.c13-00800
• 发表时间: 2014-02-01
• 期刊: CHEMICAL & PHARMACEUTICAL BULLETIN
• 影响因子: 1.7
• 作者: Attia, Tamer Zekry;Yamashita, Taku;Uno, Tadayuki
• 通讯作者: Uno, Tadayuki

Contribution of oppositely charged residues to the drug metabolism of cytochrome P450 2C9 and 2C19

带相反电荷的残基对细胞色素 P450 2C9 和 2C19 药物代谢的贡献

• 发表时间: 2014
• 作者: 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
• 通讯作者: 宇野公之

Comparison of Cytochrome P450 Mediated Metabolism of Three CNS Acting Drugs

细胞色素P450介导的三种中枢神经系统药物代谢的比较

• 发表时间: 2012
• 作者: 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
• 通讯作者: and T. Uno