Role of nuclear receptors PXR and CAR under the energy surplus condition such as obesity

• Project/Area Number: 19790114
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Medical pharmacy
• Research Institution: Tohoku University
• Principal Investigator: YOSHINARI Kouichi Tohoku University, 大学院・薬学研究科, 准教授 (60343399)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,690,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥390,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: 薬物代謝学 / 核内受容体 / 転写調節 / エネルギー代謝 / コレステロール合成酵素 / DHCR24 / SREBP / HNF4 / レポーターアッセイ / コレステロール / 薬物代謝酵素 / 肝臓 / マウス

Research Abstract

本研究では、薬物応答性の核内受容体CARおよびPXRはコレステロール合成に関わる酵素の遺伝子発現調節を正に調節すること、また、マウスの主要な薬物代謝酵素Cyp3a11の発現はコレステロール欠乏により活性化される転写因子SREBPにより抑制的に制御されることが明らかとなった。これらの結果は、脂質代謝と薬物代謝の間に転写調節因子を介したクロストークが存在することを示唆している。

Research Products

• [Journal Article] Unveiling a new essential cis-element for the transactivation of the CYP3A4 gene by xenobiotics (2009)
  • Author(s): T. Toriyabe, K. Nagata, T. Takada, Y. Aratsu, T. Matsubara, K Yoshinari, and Y. Yamazoe
  • Journal Title: Mol Pharmacol 75 Pages: 677-684
  • Peer Reviewed
• [Journal Article] Role of enzymatic N-hydroxylation and reduction in flutamide metabolite-induced liver toxicity (2009)
  • Author(s): M. Ohbuchi, M. Miyata, D. Nagai, M. Shimada, K. Yoshinari, and Y. Yamazoe
  • Journal Title: Drug Metab Dispos 37 Pages: 97-105
  • Peer Reviewed
• [Journal Article] Unveiling a new essential cis-element for the transactivation of the CYP3A4 gene by xenobiotics (2009)
  • Author(s): T. Toriyabe, et.al.
  • Journal Title: Mol Pharmacol 75 Pages: 677-684
  • Peer Reviewed
• [Journal Article] Role of enzymatic N-hydroxylation and reduction in flutamide metabolite-induced liver toxicity (2009)
  • Author(s): M. Ohbuchi, et.al.
  • Journal Title: Drug Metab Dispos 37 Pages: 97-105
  • Peer Reviewed
• [Journal Article] Bile acid-induced elevated oxidative stress in the absence of farnesoid X receptor (2008)
  • Author(s): M. Nomoto, M. Miyata, S. Yin, Y. Kurata, M. Shimada, K. Yoshinari, F. J. Gonzalez, K. Suzuki, S. Shibasaki, T. Kurosawa, and Y. Yamazoe
  • Journal Title: Biol Pharm Bull 32 Pages: 172-178
  • NAID: 110007042166
  • Peer Reviewed
• [Journal Article] Involvement of ST1B subfamily of cytosolic sulfotransferase in kynurenine metabolism to form natriuretic xanthurenic acid sulfate (2008)
  • Author(s): L. Senggunprai, K. Yoshinari, M. Shimada, and Y. Yamazoe
  • Journal Title: J Pharmacol Exp Ther 327 Pages: 789-798
  • Peer Reviewed
• [Journal Article] Role of vitamin D receptor in the lithocholic acid-mediated CYP3A induction in vitro and in vivo (2008)
  • Author(s): T. Matsubara, K. Yoshinari, K. Aoyama, M. Sugawara, Y. Sekiya, K. Nagata, and Y. Yamazoe
  • Journal Title: Drug Metab Dispos 36 Pages: 2058-2063
  • Peer Reviewed
• [Journal Article] Omeprazole transactivates human CYP1A1 and CYP1A2 expression through the common regulatory region containing multiple xenobiotic-responsive elements (2008)
  • Author(s): K. Yoshinari, R. Ueda, K. Kusano, T. Yoshimura, K. Nagata, and Y. Yamazoe
  • Journal Title: Biochem Pharmacol 76 Pages: 139-145
  • Peer Reviewed
• [Journal Article] Bile acid-induced elevated oxidative stress in the absence of farnesoid X receptor. (2008)
  • Author(s): M. Nomoto, et.al.
  • Journal Title: Biol Pharm Bull 32 Pages: 172-178
  • Peer Reviewed
• [Journal Article] Involvement of ST1B subfamily of cytosolic sulfotransferase in kynurenine metabolism to form natriuretic xanthurenic acid sulfate (2008)
  • Author(s): L. Senggunprai, et.al.
  • Journal Title: J Pharmacol Exp Ther 327 Pages: 789-798
  • Peer Reviewed
• [Journal Article] Umeprazole transactivates human CYP1A1 and CYP1A2 expression through the common regulatory region containing multiple xenobiotic-responsive elements (2008)
  • Author(s): K. Yoshinari, et.al.
  • Journal Title: Biochem Pharmacol 76 Pages: 139-145
  • Peer Reviewed
• [Journal Article] Role of vitamin D receptor in the lithocholic acid-mediated CYP3A induction in vitro and in vivo (2008)
  • Author(s): T. Matsubara, et.al
  • Journal Title: Drug Metab Dispos 36 Pages: 2058-2063
  • Peer Reviewed
• [Journal Article] ME3738 protects against lithocholic acid-induced hepatotoxicity, which is associated with enhancement of biliary bile acid and cholesterol output (2007)
  • Author(s): M. Nomoto, M. Miyata, M. Shimada, K. Yoshinari, F.J. Gonzalez, S. Shibasaki, T. Kurosawa, Y. Shindo, and Y. Yamazoe
  • Journal Title: Eur J Pharmacol 574 Pages: 192-200
  • Peer Reviewed
• [Journal Article] Role of human hepatocyte nuclear factor 4a in the expression of drug-metabolizing enzymes and transporters in human hepatocytes assessed by use of small interfering RNA (2007)
  • Author(s): Y. Kamiyama, T. Matsubara, K. Yoshinari, K. Nagata, H. Kamimura, and Y. Yamazoe
  • Journal Title: Drug Metab Pharmacokinet 22 Pages: 287-298
  • Peer Reviewed
• [Journal Article] Assessment of human pregnane X receptor-involvement in pesticide-mediated activation of CYP3A4 gene (2007)
  • Author(s): T. Matsubara, W. Noracharttiyapot, T. Toriyabe, K. Yoshinari, K. Nagata, and Y. Yamazoe
  • Journal Title: Drug Metab Dispos 35 Pages: 728-733
  • Peer Reviewed
• [Journal Article] ME3738 protects against lithocholic acid-induced hepatotoxicity, which is associated with enhancement of biliary bile acid and cholesterol output. (2007)
  • Author(s): M Nomoto, M Miyata, M Shimada, K Yoshinari, FJ Gonzalez, S Shibasaki, T Kurosawa, Y Shindo, Y Yamazoe
  • Journal Title: European Journal of Pharmacology 574 Pages: 192-200
  • Peer Reviewed
• [Journal Article] Role of human hepatocyte nuclear factr 4a in the expression of drug-metabolizing enzymes and transporters in human hepatocytes assessed by use of small interfering RNA. (2007)
  • Author(s): Y Kamiyama, T Matsubara, K Yoshinari, K Nagata, H Kamimura, Y Yamazoe
  • Journal Title: Drug Metabolism and Pharmacokinetics 22 Pages: 287-298
  • Peer Reviewed
• [Journal Article] Assessment of human pregnane X receptor-involvement in pesticide-mediated activation of CYP3A4 gene. (2007)
  • Author(s): T Matsubara, W Noracharttiyapot, T Toriyabe, K Yoshinari, K Nagata, Y Yamazoe
  • Journal Title: Drug Metabolism and Disposition 35 Pages: 728-733
  • Peer Reviewed
• [Presentation] 薬物応答性核内受容体と医薬品副作用 (2009)
  • Author(s): 吉成浩一
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-28
• [Presentation] リトコール酸によるCYP3A誘導におけるビタミンD受容体の役割 (2008)
  • Author(s): 松原勤、吉成浩一、青山和誠、菅原実香、関谷裕次、永田清、山添康
  • Organizer: 第23回日本薬物動態学会年会
  • Place of Presentation: 熊本
  • Year and Date: 2008-10-31
• [Presentation] 外来異物によるCYP3A4遺伝子の転写活性化に必須な新規シスエレメント (2008)
  • Author(s): 鳥谷部貴祥、高田智成、荒津佑輔、松原勤、吉成浩一、永田清、山添康
  • Organizer: 第23回日本薬物動態学会年会
  • Place of Presentation: 熊本
  • Year and Date: 2008-10-31
• [Presentation] CARによるヒトCYP1A1およびCYP1A2遺伝子の転写活性化 (2008)
  • Author(s): 依田典朗、吉成浩一、山添康
  • Organizer: 第23回日本薬物動態学会年会
  • Place of Presentation: 熊本
  • Year and Date: 2008-10-30
• [Presentation] 食餌中の糖・脂質レベルが肝チトクロムP450発現レベルに及ぼす影響 (2008)
  • Author(s): 菅原実香、吉成浩一、山添康
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-26
• [Presentation] Role of vitamin D receptor in the lithocholic acid-mediated CYP3A induction (2008)
  • Author(s): Tsutomu Matsubara, Kouichi Yoshinari, Kazunobu Aoyama, Mika Sugawara, Yuji Sekiya, Kiyoshi Nagata, Yasushi Yamazoe
  • Organizer: ISSX 15th North American Regional Meeting
  • Place of Presentation: San Diego, USA