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

• Project/Area Number: 21390040
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Chiba University
• Principal Investigator: CHIBA Kan 千葉大学, 大学院・薬学研究院, 教授 (40159033)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Kaoru 千葉大学, 大学院・薬学研究院, 准教授 (30255864) ; FURIHATA Tomomi 千葉大学, 大学院・薬学研究院, 助教 (80401008) ; 香月 康宏 鳥取大学, 医学研究科, 助教 (90403401)
• Co-Investigator(Renkei-kenkyūsha): KAZUKI Yasuhiro 鳥取大学, 大学院・医学研究科, 助教 (90403401)
• Project Period (FY): 2009 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2012: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2011: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2010: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2009: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
• Keywords: 薬物代謝 / 応用動物 / ヒトの薬物動態・代謝予測系 / 薬学

Research Abstract

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.

Research Products

• [Journal Article] Trans-chromosomic mice containing a human CYP3A cluster for prediction of xenobiotic metabolism in humans (2013)
  • Author(s): Kazuki Y, Kobayashi K, Aueviriyavit S, Oshima T, Kuroiwa Y, Tsukazaki Y, Senda N, Kawakami H, Ohtsuki S, Abe S, Takiguchi M, Hoshiya H, Kajitani N, Takehara S, Kubo K, Terasaki T, Chiba K, Tomizuka K, Oshimura M.
  • Journal Title: Hum Mol Genet Volume: 22(3) Pages: 578-92
  • Peer Reviewed
• [Journal Article] Trans-chromosomic mice containing a human CYP3A cluster for prediction of xenobiotic metabolism in humans (2013)
  • Author(s): Kazuki Y
  • Journal Title: Hum Mol Genet. Volume: 22 Issue: 3 Pages: 578-92
  • DOI: 10.1093/hmg/dds468
  • Peer Reviewed
• [Journal Article] Species differences in mechanism-based inactivation of CYP3A in humans, rats and (2010)
  • Author(s): Aueviriyavit S, Kobayashi K, Chiba K.
  • Journal Title: Drug Metab Pharmacokinet Volume: 25(1) Pages: 93-100
  • Peer Reviewed
• [Journal Article] Species differences in mechanism-based inactivation of CYP3A in humans, rats and mice (2010)
  • Author(s): Aueviriyarit, et al.
  • Journal Title: Drug Metab Pharmacokinet 25 Pages: 93-100
  • Peer Reviewed
• [Presentation] Effect of dietary cholesterol on expression and activity of human CYP3A4 in humanized CYP3A (CYP3A-HAC) mice (2012)
  • Author(s): Mari Hashimoto
  • Organizer: 第27回日本薬物動態学会年会
  • Place of Presentation: 千葉
• [Presentation] Humanized model mice containing P-450-related genes using a novel mouse artificial chromosome (2011)
  • Author(s): Kazuki, et al.
  • Organizer: 日本薬物動態学会第26年会
  • Place of Presentation: 広島
• [Presentation] Sex-dependent differences of CYP3A expression in CYP3A-HAC mice (2011)
  • Author(s): Endo M, et al.
  • Organizer: 日本薬物動態学会第26年会
  • Place of Presentation: 広島
• [Presentation] ヒト、マウス及びラットにおけるPXR活性化と肝CYP3A誘導の関連性 (2011)
  • Author(s): 稲葉明日実, 他
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
• [Presentation] (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・ (2010)
  • Author(s): Mio Watanabe, Sasitorn Aueviriyavit, Kaoru Kobayashi, Nahoko Iuchi, Yasuhiro kazuki,Mitsuo Oshimura and Kan Chiba HUMANIZED CYP3A MICE
• [Presentation] Humanized CYP3A Mice : (2) Functional Expression of Human CYP3A Isoforms in CYP 3A-HAC Mice and Inhibition of CYP3A via Mechanism-Based Inactivation (2010)
  • Author(s): Watanabe M., et al.
  • Organizer: 9th International ISSX Meeting
  • Place of Presentation: Istanbul