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

药物代谢的连锁反应——CYP亚型协同和竞争药物代谢的综合研究

• 批准号: 23390011
• 负责人: UNO Tadayuki
• 金额: $ 11.9万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23390011/
• 关键词: 薬物代謝; シトクロムＰ４５０; 一塩基多型; 共鳴ラマン分光; シトクロムP450; X線結晶構造解析

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.

细胞色素P450在人体药物代谢中起着关键作用，目前市面上90%以上的临床药物都能被5种细胞色素P450亚型代谢。在这项研究中，我们重点研究了药物代谢的五种异构体所起的连锁反应。虽然抗抑郁药阿米替林主要由CYP1A2、2C19和2D6代谢，但其结构类似于阿米替林的代谢物去甲替林在这些异构体中的代谢较差。另一方面，尽管在氨基酸序列和三维结构上与2C19具有同源性，但CYP2C9是阿米替林的不良代谢物。我们发现药物的特异性受第72位氨基酸残基的碱性调节。

项目成果

Roles of Terminal Domains in the Ligand Binding Properties of Cytoglobin

末端结构域在细胞珠蛋白配体结合特性中的作用

• 发表时间: 2013
• 作者: 花井舜平;辻野博文;山下沢;宇野公之
• 通讯作者: 宇野公之

Effects of Single Nucleotide Polymorphisms (SNPs) on the Interaction of Human CYP reductase with CYP2C19 and Its Drug Metabolizing Properties

单核苷酸多态性（SNP）对人CYP还原酶与CYP2C19相互作用及其药物代谢特性的影响

• 发表时间: 2012
• 作者: 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
• 通讯作者: 宇野 公之

Effect of Single Nucleotide Polymorphisms (SNPs) on the Drug Binding and Metabolizing Properties of Human CYP2C19

单核苷酸多态性 (SNP) 对人 CYP2C19 药物结合和代谢特性的影响

• 发表时间: 2008
• 作者: 宇野公之;飯賀由実子;Sayed Ali;佐々木隆一;富杉佳計;青山浩
• 通讯作者: 青山浩

Molecular Analysis of Human Drug Metabolizing Enzyme, Cytochrome P450

人类药物代谢酶细胞色素 P450 的分子分析

• 发表时间: 2013
• 作者: Miyazaki;K.;Tadayuki Uno
• 通讯作者: Tadayuki Uno

Spectroscopic Characterization of Drug Binding to Cytochrome P450 3A4

药物与细胞色素 P450 3A4 结合的光谱表征

• 发表时间: 2013
• 作者: 倉橋拓也;小泉温史;山下沢;宇野公之
• 通讯作者: 宇野公之