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（CYPS）在人类药物代谢中起关键作用，五种CYP同工型可以代谢市场中90％以上的临床药物。在这项研究中，我们专注于五种同工型发挥的药物代谢的链反应。尽管抗抑制剂的阿米替林主要由CYP1A2、2C19和2D6代谢，但其代谢物诺特替林在结构上与阿米替林的代谢物诺特替林被认为是由这些同工型的不良代谢。另一方面，CYP2C9是阿米替林的不良代谢剂，尽管它在氨基酸序列和三维结构中与2C19同源。我们透露，药物特异性受位置72处的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

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

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 Activation of Procarcinogens in Human CYP1A2

单核苷酸多态性（SNP）对人CYP1A2原致癌物激活的影响

• 发表时间: 2012
• 作者: Tadayuki Uno;Jun-ichi Node;Sakiko Morita;Akihide Tsujimoto;Taku Yamashita;Hiroshi Aoyama
• 通讯作者: Hiroshi Aoyama

CYP3A4における薬物結合様式の分光学的解析

CYP3A4药物结合模式的光谱分析

• 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