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Role of microRNA on drug-induced hepatotoxocity

Research Project

Project/Area Number 18390049
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical pharmacy
Research InstitutionKanazawa 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 *help
¥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。

Report

(4 results)
  • 2008 Annual Research Report   Final Research Report ( PDF )
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • Research Products

    (51 results)

All 2009 2008 2007 2006 Other

All Journal Article (28 results) (of which Peer Reviewed: 22 results) Presentation (17 results) Book (4 results) Remarks (2 results)

  • [Journal Article] Mitabolic activation of benzodiazepine by CYP3A42009

    • 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

    • Related Report
      2008 Final Research Report
    • 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

    • Related Report
      2008 Annual Research Report
    • 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)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulatiion of insulin-like growth factor binding protein-1 and lipoprotein lipase by aryl hydrocarbon receptor2008

    • Author(s)
      Keiichi Minami, Miki Nakajima, Yuto Fujiki, Miki Katoh, Frank J. Gonzalez, Tsuyoshi Yokoi
    • Journal Title

      J.Tox.Sci 33

      Pages: 405-413

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Post-transcriptional regulation of human pregnane X receptor by microRNA affects the expression of cytochrome P450 3A42008

    • Author(s)
      Shingo Takagi, Miki Nakajima, Takuya Mohri, Tsuyoshi Yokoi
    • Journal Title

      J.Biol.Chem 283

      Pages: 9674-9680

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Human cytochrome P450 2A13 efficiently metabolizes chemicals in air pollutants : naphthalene, styrene, and toluene2008

    • Author(s)
      Tatsuki Fukami, Miki Katoh, Tsuyoshi Yokoi, Miki Nakajima
    • Journal Title

      Chem.Res.Toxicol 21

      Pages: 720-725

    • Related Report
      2008 Final Research Report
    • 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

    • Related Report
      2008 Annual Research Report
    • 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

    • Related Report
      2008 Annual Research Report
    • 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

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Glucuronidation of thyroxine in human liver, jejunum, and kidney microsomes2007

    • Author(s)
      Hiroyuki Yamanaka, Miki Nakajima, Miki Katoh, Tsuyoshi Yokoi
    • Journal Title

      Drug Metab. Dispos 35

      Pages: 1642-7648

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Knockdown of γ-glutamylsysteine synthetase in rat causes acetaminophen-induced hepatotoxicity2007

    • 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

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Change of drug excretory pathway by CCl4-induced liver dysfunction in rat2007

    • Author(s)
      Hirotoshi Okumura, Miki Katoh, Keiichi Minami, Miki Nakajima, Tsuyoshi Yokoi
    • Journal Title

      Biochem.Pharmacol 74

      Pages: 488-495

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Change of drug excretory pathway by CC14-induced liver dysfunction in rat2007

    • Author(s)
      H. Okumura, et. al.
    • Journal Title

      Biochememical Pharmacology 74

      Pages: 488-495

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Glucuronidation of thyroxine in human liver, jejunum, and kidney microsomes2007

    • Author(s)
      H. Yamanaka, et. al.
    • Journal Title

      Drug Metabolism and Disposition 35

      Pages: 1642-1648

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Knock down of γ-glutamylcysteine synthetase in rat causes acetaminophen-induced hepatotoxicity2007

    • Author(s)
      S. Akai, et. al.
    • Journal Title

      Journal of Biological Chemistry 282

      Pages: 23996-24003

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Induction of human CYP2A6 is mediated by the pregnane X receptor with peroxisome proliferator-activated receptor-γ coactivator 1α2006

    • 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

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] MicroRNA regulates the expression of human CYP1B12006

    • Author(s)
      Yuki Tsuchiya, Miki Nakajima, Shingo Takagi, Takao Taniya, Tsuyoshi Yokoi
    • Journal Title

      Cancer Res 66

      Pages: 9090-9098

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Dephosphorylation of ribosomal P0 protein in response to troglitazone-induced cytotoxicity2006

    • Author(s)
      Rawiwan Maniratanachote, Keiichi Minami, Miki Katoh, Miki Nakajima, Tsuyoshi Yokoi
    • Journal Title

      Toxicol. Lett 166

      Pages: 189-199

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Kinetic analyses for species differences in P-glycoprotein-mediated drug transport2006

    • Author(s)
      Miki Katoh, Naoto Suzuyama, ToshiyukiTakeuchi, Sumie Yoshitomi, Satoru Asahi, Tsuyoshi Yokoi
    • Journal Title

      J.Pharm.Sci 95

      Pages: 2673-2683

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Binding of steroidogenic factor-1 to the regulatory region might not be critical for transcriptional regulation of human CYP1B1 gene2006

    • 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

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Gene expression analyses for hepatotoxicity in thioacetamide administered rat by DNA microarrays2006

    • Author(s)
      Keiichi Minami, Rawiwan Maniratanachote, Miki Katoh, Miki Nakajima, Tsuyoshi Yokoi
    • Journal Title

      Mut. Res 603

      Pages: 64-73

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Induction of human CYP2A6 is mediated by the pregnene X receptor with peroxisome proliferator-activated receptor-γ coactivator 1 α2006

    • Author(s)
      Masahiro Itoh
    • Journal Title

      J.Pharmacol. Exp. Ther. 319

      Pages: 693-702

    • Related Report
      2006 Annual Research Report
  • [Journal Article] MicroRNA regulates the expression of human CYP1B1.2006

    • Author(s)
      Yuki Tsuchiya
    • Journal Title

      Cancer Res. 66

      Pages: 9090-9098

    • Related Report
      2006 Annual Research Report
  • [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

    • Related Report
      2006 Annual Research Report
  • [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

    • Related Report
      2006 Annual Research Report
  • [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

    • Related Report
      2006 Annual Research Report
  • [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

    • Related Report
      2006 Annual Research Report
  • [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

    • Related Report
      2008 Final Research Report
    • 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
    • Related Report
      2008 Final Research Report
  • [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
    • Related Report
      2008 Final Research Report
  • [Presentation] CYP enzymes and cancer : regulation by steroids and miRNA2008

    • Author(s)
      Tsuyoshi Yokoi, Miki Nakajima
    • Organizer
      9th Advanced Course on "Steroid Enzymes and Cancer"
    • Place of Presentation
      Erice, Italy.
    • Related Report
      2008 Final Research Report
  • [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
    • Related Report
      2008 Annual Research Report
  • [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
    • Related Report
      2008 Annual Research Report
  • [Presentation] Micro RNAs regulate the expression of human cytochrome P450 1B1 and P450 3A42008

    • 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
    • Related Report
      2008 Annual Research Report
  • [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
    • Related Report
      2008 Annual Research Report
  • [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
    • Related Report
      2008 Annual Research Report
  • [Presentation] Human CYP1B1 is regulated by microRNA, miR-27b2007

    • 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
    • Related Report
      2008 Final Research Report
  • [Presentation] MicroRNA post-transcriptionally regulates human PXR affecting the expression level of CYP3A42007

    • Author(s)
      S. Takagi, et. al.
    • Organizer
      8th International ISSX meeting
    • Place of Presentation
      Sendai, Japan
    • Related Report
      2007 Annual Research Report
  • [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
    • Related Report
      2008 Final Research Report
  • [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
    • Related Report
      2008 Final Research Report
  • [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
    • Related Report
      2008 Final Research Report
  • [Presentation] Human CYP1B1 is regulated by microRNA, miR-27b2006

    • 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
    • Related Report
      2008 Final Research Report
  • [Presentation] Regulation of insulin-like growth factor binding protein-1 and lipoprotein lipase via aryl hydrocarbon receptor2006

    • 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
    • Related Report
      2008 Final Research Report
  • [Presentation] Human cytochrome P450 CYP1B1 is a target of microRNA, miR-27b2006

    • 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
    • Related Report
      2008 Final Research Report
  • [Presentation] Ribosomal protein P0 dephosphorylation associated with troglitazone-induced cytotoxicity2006

    • Author(s)
      Rawiwan Maniratanachote, Miki Katoh, Mik Nakajima, Tsuyoshi Yokoi
    • Organizer
      The 1^<st> Asia Pacific ISSX Meeting
    • Place of Presentation
      Jeju, Korea
    • Related Report
      2008 Final Research Report
  • [Book] Mechanism of Adverse Drug Reaction (共著)2009

    • Author(s)
      Tsuyoshi Yokoi(in press)
    • Publisher
      Springer
    • Related Report
      2008 Annual Research Report
  • [Book] In Hepatotoxicity : From Genomics to in vitro and in vivo2007

    • Author(s)
      Rawiwan Maniratanachote, and Tsuyoshi Yokoi : Amechanistic view of troglitazone hepatotoxicity
    • Publisher
      S.C. Sahu Ed. John Wiley & Sons, Ltd. Pp
    • Related Report
      2008 Final Research Report
  • [Book] A mechanistic view of troglitazone hepatotoxicity.2007

    • Author(s)
      Rawiwan Maniratanachote, and Tsuyoshi Yokoi
    • Total Pages
      682
    • Publisher
      John Wiley & Sons, Ltd
    • Related Report
      2007 Annual Research Report
  • [Book] In Mechanism of Adverse Drug Reaction, Handbook of Expreimental Pharmacology, Springer

    • Author(s)
      Tsuyoshi Yokoi : Troglitazone
    • Publisher
      J. Uetrecht (in press)
    • Related Report
      2008 Final Research Report
  • [Remarks]

    • URL

      http://www.p.kanazawa-u.ac.jp/~taisha/

    • Related Report
      2008 Annual Research Report
  • [Remarks]

    • URL

      http://www.p.kanazawa-u.ac.jp/~taisha/

    • Related Report
      2007 Annual Research Report

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Published: 2006-04-01   Modified: 2016-04-21  

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