Creation of CYP3A- and P-glycoprotein-humanized mouse and its application to the study of drug metabolism and disposition

CYP3A和P-糖蛋白人源化小鼠的构建及其在药物代谢和处置研究中的应用

• 批准号: 21390040
• 负责人: CHIBA Kan
• 金额: $ 11.32万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21390040/
• 关键词: 薬物代謝; 応用動物; ヒトの薬物動態・代謝予測系; 薬学

CYP3A is the most important subfamily of cytochrome P450s in humans, which metabolizes around 50% of therapeutic agents. We have created humanized mouse (CYP3A-HAC mouse) which carries human CYP3A instead of mouse Cyp3a, using human artificial chromosome system, This mouse shows similar characteristics as human for the tissue- and stage-specific expression of CYP3A genes and metabolism of various therapeutic agents. Thus, this mouse is considered to be valuable for the prediction of human drug metabolism. As for P-glycoprotein- and pregnane X receptor-humanized mice, they have also been developed and their function and valuableness for the prediction of human drug metabolism are undertaken.

CYP3A 是人类细胞色素 P450 最重要的亚家族，代谢约 50% 的治疗药物。我们利用人类人工染色体系统创建了携带人类CYP3A而不是小鼠Cyp3a的人源化小鼠（CYP3A-HAC小鼠），该小鼠在CYP3A基因的组织和阶段特异性表达以及各种治疗剂的代谢方面表现出与人类相似的特征。因此，这种小鼠被认为对于预测人类药物代谢有价值。至于P-糖蛋白和孕烷X受体人源化小鼠，也已开发出来，并对其功能和预测人类药物代谢的价值进行了研究。

项目成果

Trans-chromosomic mice containing a human CYP3A cluster for prediction of xenobiotic metabolism in humans

• DOI: 10.1093/hmg/dds468
• 发表时间: 2013-02-01
• 期刊: HUMAN MOLECULAR GENETICS
• 影响因子: 3.5
• 作者: Kazuki, Yasuhiro;Kobayashi, Kaoru;Oshimura, Mitsuo
• 通讯作者: Oshimura, Mitsuo

Sex-dependent differences of CYP3A expression in CYP3A-HAC mice

CYP3A-HAC 小鼠中 CYP3A 表达的性别依赖性差异

• 发表时间: 2011
• 作者: Endo M;et al.
• 通讯作者: et al.

Species Differences in Mechanism-Based Inactivation of CYP3A in Humans, Rats and Mice

• DOI: 10.2133/dmpk.25.93
• 发表时间: 2010-01-01
• 期刊: DRUG METABOLISM AND PHARMACOKINETICS
• 影响因子: 2.1
• 作者: Aueviriyavit, Sasitorn;Kobayashi, Kaoru;Chiba, Kan
• 通讯作者: Chiba, Kan

(2) FUNCTIONAL EXPRESSION OF HUMAN CYP3A ISOFORMS IN CYP3A-HAC MICE AND INHIBITION OF CYP3A VIA MECHHANISM -BASED INACTIVATION(ポスター発表) 9th Interntional ISSX Meeting ・Istanbul Turkey・

(2) CYP3A-HAC MICE 中人类 CYP3A 异构体的功能表达以及通过基于机制的失活抑制 CYP3A（海报展示）第 9 届国际 ISSX 会议·土耳其伊斯坦布尔·

• 发表时间: 2010
• 作者: Mio Watanabe;Sasitorn Aueviriyavit;Kaoru Kobayashi;Nahoko Iuchi;Yasuhiro kazuki,Mitsuo Oshimura and Kan Chiba HUMANIZED CYP3A MICE
• 通讯作者: Yasuhiro kazuki,Mitsuo Oshimura and Kan Chiba HUMANIZED CYP3A MICE

Humanized CYP3A Mice : (2) Functional Expression of Human CYP3A Isoforms in CYP 3A-HAC Mice and Inhibition of CYP3A via Mechanism-Based Inactivation

人源化 CYP3A 小鼠：(2) CYP3A-HAC 小鼠中人 CYP3A 亚型的功能表达以及基于机制的失活对 CYP3A 的抑制

• 发表时间: 2010
• 作者: Watanabe M.;et al.
• 通讯作者: et al.