Studies for physiological functions of human CYP3A enzymes and their clinical applications

• Project/Area Number: 15K08067
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Chiba University
• Principal Investigator: Kobayashi Kaoru 千葉大学, 大学院薬学研究院, 准教授 (30255864)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: CYP3A / テストステロン / ノックアウトマウス / 前立腺 / コレステロール / ヒト化動物

Outline of Final Research Achievements

Results of this study showed that remarkable increase in free testosterone in plasma enhanced androgen response in the prostate of Cyp3a-knockout (KO) mice. Increased testosterone levels activated the androgen receptor (AR), resulting in stimulation of cholesterol synthesis in the prostates of Cyp3a-KO mice. In addition, KO of Cyp3a genes enhanced the synthesis of cholesterol in the liver via activation of SREBP-2 by reduction of 25-hydroxycholesterol. These findings suggest that CYP3A is a regulator for androgen response in the prostate and for synthesis of cholesterol in the liver.

Research Products

• [Journal Article] Evaluation of 4β-hydroxy- cholesterol and 25-hydroxycholesterol as endogenous biomarkers of CYP3A4: study with CYP3A-humanized mic (2018)
  • Author(s): Nitta S, Hashimoto M, Kazuki Y, Takehara S, Suzuki H, Oshimura M, Chiba K, Kobayashi K.
  • Journal Title: AAPS J. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Cyp3a deficiency enhances androgen receptor activity and cholesterol synthesis in the mouse prostate. (2016)
  • Author(s): Hashimoto M, Kobayashi K, Yamazaki M, Kazuki Y, Takehara S, Oshimura M, Chiba K.
  • Journal Title: J Steroid Biochem Mol Biol. Volume: 163 Pages: 121-8
  • DOI: 10.1016/j.jsbmb.2016.04.018
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 異物代謝酵素CYP3Aの生理機能 (2017)
  • Author(s): 小林カオル
  • Organizer: 日本薬物動態学会第32回年会
  • Invited
• [Presentation] Cytochrome P450 3Aの生理的機能：肝コレステロール合成と前立腺アンドロゲン制御における役割 (2016)
  • Author(s): 橋本真里、小林カオル、香月康宏、押村光雄、千葉寛
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-26
• [Presentation] Effect of human CYP3A genes transferred into Cyp3a-KO mouse on cholesterol synthesis in the liver (2015)
  • Author(s): Mana Yamazaki, Kaoru Kobayashi, Yasuhiro Kazuki, Shoko Takehara, Mari Hashimoto, Mitsuo Oshimura and Kan Chiba
  • Organizer: 日本薬物動態学会第30回年会
  • Place of Presentation: 東京
  • Year and Date: 2015-11-12
• [Remarks] 千葉大学大学院薬学研究院薬物学研究室
  • URL: http://www.p.chiba-u.jp/lab/yakubutu/index.html