Role of microRNA on drug-induced hepatotoxocity

• Project/Area Number: 18390049
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kanazawa University
• Principal Investigator: YOKOI Tsuyoshi Kanazawa University, 薬学系, 教授 (70135226)
• Co-Investigator(Kenkyū-buntansha): KATOH Miki 金沢大学, 薬学系, 助教 (70345594)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥17,740,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥2,640,000); Fiscal Year 2008: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2007: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2006: ¥6,300,000 (Direct Cost: ¥6,300,000)
• Keywords: チトクロムP450 / マイクロRNA / 薬物誘導性肝障害 / miR-27b / miR-148a / CYP3A4 / miR-125b / miR-378 / PXR / チトクロームP450 / CYP1B1 / CYP24 / miR-22 / 細胞毒性

Research Abstract

本研究は、近年急速に様々な機能が明らかにされつつあるマイクロRNAの薬物代謝および薬物誘導性肝障害における役割を明らかにすることを目的とした。本研究において、(1)チオアセタミド等の投与による肝障害モデルラットにおいて、miR-21が保護作用に働くことを見出した。(2)環境化学物質や薬物の毒性を高めるCYP1B1は、miR-27bが誘導および恒常的発現に関与していることを見出した。(3)臨床で使用される薬の半分以上の代謝に関与するCYP3A4は、PXRという転写因子がmiR-148aによって制御されることがCYP3A4の活性の個体差に大きな影響を及ぼしていることを明らかにした。さらに、(4)細胞の増殖制御の役割を担っている活性型ビタミンD3の代謝酵素に、転写後調節にmiR-125bが関わっていることを明らかにした。以上、肝障害を初めとする副作用の発現に関わる多くの代謝酵素について、マイクロRNAの関与を明示することができた。

Research Products

• [Journal Article] Mitabolic activation of benzodiazepine by CYP3A4 (2009)
  • Author(s): Katsuhiko Mizuno, Miki Katoh, Hirotoshi Okumura, Nao Nakagawa, Toru Negishi, Takanori Hashizume, Miki Nakajima, Tsuyoshi Yokoi
  • Journal Title: Drug Metab. Dispos 37 Pages: 345-351
  • Peer Reviewed
• [Journal Article] Mitabolic activation of benzodiazepine by CYP3A4. (2009)
  • Author(s): K. Mizuno, et al.
  • Journal Title: Drug Metabolism and Disposition 37 Pages: 345-351
  • Peer Reviewed
• [Journal Article] MicroRNA regulates human vitamin D receptor. (2009)
  • Author(s): T. Mohri, et al.
  • Journal Title: International Journal of Cancer (in press)
  • Peer Reviewed
• [Journal Article] Regulatiion of insulin-like growth factor binding protein-1 and lipoprotein lipase by aryl hydrocarbon receptor (2008)
  • Author(s): Keiichi Minami, Miki Nakajima, Yuto Fujiki, Miki Katoh, Frank J. Gonzalez, Tsuyoshi Yokoi
  • Journal Title: J.Tox.Sci 33 Pages: 405-413
  • Peer Reviewed
• [Journal Article] Post-transcriptional regulation of human pregnane X receptor by microRNA affects the expression of cytochrome P450 3A4 (2008)
  • Author(s): Shingo Takagi, Miki Nakajima, Takuya Mohri, Tsuyoshi Yokoi
  • Journal Title: J.Biol.Chem 283 Pages: 9674-9680
  • Peer Reviewed
• [Journal Article] Human cytochrome P450 2A13 efficiently metabolizes chemicals in air pollutants : naphthalene, styrene, and toluene (2008)
  • Author(s): Tatsuki Fukami, Miki Katoh, Tsuyoshi Yokoi, Miki Nakajima
  • Journal Title: Chem.Res.Toxicol 21 Pages: 720-725
  • Peer Reviewed
• [Journal Article] Post-transcriptional regulation of human pregnane X receptor by microRNA affects the expression of cytochrome P450 3A4. (2008)
  • Author(s): S. Takagi, et al.
  • Journal Title: Journal of Bioloogical Chemistry 283 Pages: 9674-9680
  • Peer Reviewed
• [Journal Article] Human cytochrome P450 2Al3 efficiently metabolizes chemicals in air pollutants : naphthalene, styrene, and toluene. (2008)
  • Author(s): T. Fukami, et al.
  • Journal Title: Chemical Research in Toxicology 21 Pages: 720-725
  • Peer Reviewed
• [Journal Article] Regulatiion of insulin-like growth factor binding protein-1 and lipoprotein lipase by aryl hydrocarbon receptor. (2008)
  • Author(s): K. Minami, et al.
  • Journal Title: Journal of Toxicological Science 33 Pages: 405-413
  • Peer Reviewed
• [Journal Article] Glucuronidation of thyroxine in human liver, jejunum, and kidney microsomes (2007)
  • Author(s): Hiroyuki Yamanaka, Miki Nakajima, Miki Katoh, Tsuyoshi Yokoi
  • Journal Title: Drug Metab. Dispos 35 Pages: 1642-7648
  • Peer Reviewed
• [Journal Article] Knockdown of γ-glutamylsysteine synthetase in rat causes acetaminophen-induced hepatotoxicity (2007)
  • Author(s): Sho Akai, Hiroko Hosomi, Keiichi Minami, Koichi Tsuneyama, Miki Katoh, Miki Nakajima, Tsuyoshi Yokoi
  • Journal Title: J.Biol.Chem 282 Pages: 23996-24003
  • Peer Reviewed
• [Journal Article] Change of drug excretory pathway by CCl4-induced liver dysfunction in rat (2007)
  • Author(s): Hirotoshi Okumura, Miki Katoh, Keiichi Minami, Miki Nakajima, Tsuyoshi Yokoi
  • Journal Title: Biochem.Pharmacol 74 Pages: 488-495
  • Peer Reviewed
• [Journal Article] Change of drug excretory pathway by CC14-induced liver dysfunction in rat (2007)
  • Author(s): H. Okumura, et. al.
  • Journal Title: Biochememical Pharmacology 74 Pages: 488-495
  • Peer Reviewed
• [Journal Article] Glucuronidation of thyroxine in human liver, jejunum, and kidney microsomes (2007)
  • Author(s): H. Yamanaka, et. al.
  • Journal Title: Drug Metabolism and Disposition 35 Pages: 1642-1648
  • Peer Reviewed
• [Journal Article] Knock down of γ-glutamylcysteine synthetase in rat causes acetaminophen-induced hepatotoxicity (2007)
  • Author(s): S. Akai, et. al.
  • Journal Title: Journal of Biological Chemistry 282 Pages: 23996-24003
  • Peer Reviewed
• [Journal Article] Induction of human CYP2A6 is mediated by the pregnane X receptor with peroxisome proliferator-activated receptor-γ coactivator 1α (2006)
  • Author(s): Masahiro Ito, Miki Nakajima, Eriko Higashi, Rhoko Yoshida, Kiyoshi Nagata, Yasushi Yamazoe, Tsuyoshi Yokoi
  • Journal Title: J.Pharmacol.Exp.Ther 319 Pages: 693-702
  • Peer Reviewed
• [Journal Article] MicroRNA regulates the expression of human CYP1B1 (2006)
  • Author(s): Yuki Tsuchiya, Miki Nakajima, Shingo Takagi, Takao Taniya, Tsuyoshi Yokoi
  • Journal Title: Cancer Res 66 Pages: 9090-9098
  • Peer Reviewed
• [Journal Article] Dephosphorylation of ribosomal P0 protein in response to troglitazone-induced cytotoxicity (2006)
  • Author(s): Rawiwan Maniratanachote, Keiichi Minami, Miki Katoh, Miki Nakajima, Tsuyoshi Yokoi
  • Journal Title: Toxicol. Lett 166 Pages: 189-199
  • Peer Reviewed
• [Journal Article] Kinetic analyses for species differences in P-glycoprotein-mediated drug transport (2006)
  • Author(s): Miki Katoh, Naoto Suzuyama, ToshiyukiTakeuchi, Sumie Yoshitomi, Satoru Asahi, Tsuyoshi Yokoi
  • Journal Title: J.Pharm.Sci 95 Pages: 2673-2683
  • Peer Reviewed
• [Journal Article] Binding of steroidogenic factor-1 to the regulatory region might not be critical for transcriptional regulation of human CYP1B1 gene (2006)
  • Author(s): Yuki Tsuchiya, Miki Nakajima, Shingo Takagi, Miki Katoh, Wenchao Zheng, Colin R Jefcoate, Tsuyoshi Yokoi
  • Journal Title: J.Biochem 139 Pages: 527-534
  • NAID: 10018846913
  • Peer Reviewed
• [Journal Article] Gene expression analyses for hepatotoxicity in thioacetamide administered rat by DNA microarrays (2006)
  • Author(s): Keiichi Minami, Rawiwan Maniratanachote, Miki Katoh, Miki Nakajima, Tsuyoshi Yokoi
  • Journal Title: Mut. Res 603 Pages: 64-73
  • Peer Reviewed
• [Journal Article] Induction of human CYP2A6 is mediated by the pregnene X receptor with peroxisome proliferator-activated receptor-γ coactivator 1 α (2006)
  • Author(s): Masahiro Itoh
  • Journal Title: J.Pharmacol. Exp. Ther. 319 Pages: 693-702
• [Journal Article] MicroRNA regulates the expression of human CYP1B1. (2006)
  • Author(s): Yuki Tsuchiya
  • Journal Title: Cancer Res. 66 Pages: 9090-9098
• [Journal Article] Dephosphorylation of ribosomal PO protein in response to troglitazaone-induced cytotoxicity. Toxicol. (2006)
  • Author(s): Rawiwan Maniratanachote
  • Journal Title: Toxiclo. Lett. 166 Pages: 189-199
• [Journal Article] Kinetic analyses for species differences in P-glycoprotein-mediated drug transport. (2006)
  • Author(s): Miki Katoh
  • Journal Title: J.Pharm.Sci. 95 Pages: 2673-2683
• [Journal Article] Simultaneous measurement of gene expression for hepatotoxicity in thioacetamide-administered rats by DNA microarrays. (2006)
  • Author(s): Keiichi Minami
  • Journal Title: Mutat. Res. 603 Pages: 64-73
• [Journal Article] Binding of steroidogenic factor-1 to the regulatory region might not be critical for transcriptional regulation of human CYP1B1 gene. (2006)
  • Author(s): Yuki Tsuchiya
  • Journal Title: J.Biockem. 139 Pages: 527-534
• [Journal Article] MicroRNA regulates human vitamin D receptorr
  • Author(s): Takuya Mohri, Miki Nakajima, Shingo Takagi, Tsuyoshi Yokoi
  • Journal Title: Int J Cance in press
  • Peer Reviewed
• [Presentation] microRNAによるヒトVDRの発現制御 (2008)
  • Author(s): 茂利拓也、中島美紀、高木信伍、横井毅
  • Organizer: 第23回日本薬物動態学会年会
  • Place of Presentation: 熊本
• [Presentation] 薬物代謝酵素と核内レセプターのmicroRNAによる発現調節 (2008)
  • Author(s): 中島美紀、高木信伍、駒形小夜香、茂利拓也、土屋祐樹、横井毅
  • Organizer: 第23回日本薬物動態学会年会, シンポジウム
  • Place of Presentation: 熊本
• [Presentation] CYP enzymes and cancer : regulation by steroids and miRNA (2008)
  • Author(s): Tsuyoshi Yokoi, Miki Nakajima
  • Organizer: 9th Advanced Course on "Steroid Enzymes and Cancer"
  • Place of Presentation: Erice, Italy.
• [Presentation] 反応性代謝物を考慮した肝障害性予測試験系 (2008)
  • Author(s): 横井毅
  • Organizer: 日本薬物動態学会第22回ワークショップ招待講演
  • Place of Presentation: 東京
• [Presentation] CYP enzymes and cancer : regulation by steroids and miRNA. (2008)
  • Author(s): T. Yokoi, et al.
  • Organizer: 9th Advanced Course on "Steroid Enzymesand Cancer"
  • Place of Presentation: Erice, Italy
• [Presentation] Micro RNAs regulate the expression of human cytochrome P450 1B1 and P450 3A4 (2008)
  • Author(s): T. Yokoi, et al.
  • Organizer: Plenary Session on 17^<th> International Symposioum on Microsomes and Drug Oxidations
  • Place of Presentation: New York, USA
• [Presentation] 薬物代謝酵素の核内レセプターのmicroRNAによる発現調節 (2008)
  • Author(s): 中島美紀, 他
  • Organizer: 第23回日本薬物動態学会年会
  • Place of Presentation: 熊本
• [Presentation] micro RNAによるヒトVDRの発現制御 (2008)
  • Author(s): 茂利拓也, 他
  • Organizer: 第23回日本薬物動態学会年会
  • Place of Presentation: 熊本
• [Presentation] Human CYP1B1 is regulated by microRNA, miR-27b (2007)
  • Author(s): Tsuyoshi Yokoi, Shingo Takagi, Yuki Tsuchiya, Miki Katoh, Takao Taniya, Miki Nakajima
  • Organizer: 15th International Conference on cytochrome P450
  • Place of Presentation: Bled, Slovenia
• [Presentation] MicroRNA post-transcriptionally regulates human PXR affecting the expression level of CYP3A4 (2007)
  • Author(s): S. Takagi, et. al.
  • Organizer: 8th International ISSX meeting
  • Place of Presentation: Sendai, Japan
• [Presentation] 薬物排泄に及ぼす肝障害の影響 (2006)
  • Author(s): 奥村浩敏、加藤美紀、南圭一、中島美紀、横井毅
  • Organizer: 日本薬学会北陸支部会
  • Place of Presentation: 金沢
  • Year and Date: 2006-07-08
• [Presentation] ヒトCYP1B1遺伝子の発現はmicroRNAにより制御される (2006)
  • Author(s): 高木信吾、土屋佑樹、中島美紀、加藤美紀、谷屋隆雄、横井毅
  • Organizer: 日本薬学会北陸支部会
  • Place of Presentation: 金沢
  • Year and Date: 2006-07-08
• [Presentation] Metabolic activation and drug induced hepatotoxicity-the troglitazone case- (2006)
  • Author(s): Tsuyoshi Yokoi
  • Organizer: 第21回日本薬物動態学会年会
  • Place of Presentation: シンポジウム, 東京
• [Presentation] Human CYP1B1 is regulated by microRNA, miR-27b (2006)
  • Author(s): Shingo Takagi, Yuki Tsuchiya, Miki Nakajima, Miki Katoh, Takao Taniya, Tsuyoshi Yokoi
  • Organizer: 第21回日本薬物動態学会年会
  • Place of Presentation: シンポジウム, 東京
• [Presentation] Regulation of insulin-like growth factor binding protein-1 and lipoprotein lipase via aryl hydrocarbon receptor (2006)
  • Author(s): Keiichi Minami, Miki Nakajima, Yuto Fujiki, Miki Katoh, Frank J. Gonzalez, Tsuyoshi Yokoi
  • Organizer: 20^<th> IUBMB International Congress of Biochemistry and Molecular Biology and 11^<th> FAOBMB Congress
  • Place of Presentation: Kyoto, Japan
• [Presentation] Human cytochrome P450 CYP1B1 is a target of microRNA, miR-27b (2006)
  • Author(s): Yuki Tsuchiya, Shingo Takagi, Miki Nakajima, Miki Katoh, Takao Taniya, Tsuyoshi Yokoi
  • Organizer: 20^<th> IUBMB International Congress of Biochemistry and Molecular Biology and 11^<th> FAOBMB Congress
  • Place of Presentation: Kyoto, Japan
• [Presentation] Ribosomal protein P0 dephosphorylation associated with troglitazone-induced cytotoxicity (2006)
  • Author(s): Rawiwan Maniratanachote, Miki Katoh, Mik Nakajima, Tsuyoshi Yokoi
  • Organizer: The 1^<st> Asia Pacific ISSX Meeting
  • Place of Presentation: Jeju, Korea
• [Book] Mechanism of Adverse Drug Reaction (共著) (2009)
  • Author(s): Tsuyoshi Yokoi(in press)
  • Publisher: Springer
• [Book] In Hepatotoxicity : From Genomics to in vitro and in vivo (2007)
  • Author(s): Rawiwan Maniratanachote, and Tsuyoshi Yokoi : Amechanistic view of troglitazone hepatotoxicity
  • Publisher: S.C. Sahu Ed. John Wiley & Sons, Ltd. Pp
• [Book] A mechanistic view of troglitazone hepatotoxicity. (2007)
  • Author(s): Rawiwan Maniratanachote, and Tsuyoshi Yokoi
  • Total Pages: 682
  • Publisher: John Wiley & Sons, Ltd
• [Book] In Mechanism of Adverse Drug Reaction, Handbook of Expreimental Pharmacology, Springer
  • Author(s): Tsuyoshi Yokoi : Troglitazone
  • Publisher: J. Uetrecht (in press)
• [Remarks]
  • URL: http://www.p.kanazawa-u.ac.jp/~taisha/
• [Remarks]
  • URL: http://www.p.kanazawa-u.ac.jp/~taisha/