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2012 Fiscal Year Final Research Report

Regulation mechanism of expression of drug-metabolizing enzymes,UGT1A1 and CYP3A4,at cell-cycle check-point

Research Project

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Project/Area Number 22590068
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionUniversity of Shizuoka

Principal Investigator

SUGATANI Junko  静岡県立大学, 薬学部, 教授 (30098131)

Project Period (FY) 2010 – 2012
Keywordsサイクリン依存性キナーゼ / 薬物代謝酵素 / 転写調節 / 核内受容体 / シグナル伝達 / CDK2 / 細胞周期
Research Abstract

We have found that CDK inhibitor roscovtine markedly stimulated the expression of UGT1A1 mRNA and protein, whereas it slightly stimulated the expression of CYP1A1, CYP2B6, and CYP3A4 mRNAs and proteins in HepG2 cells. PXR-mediated transacriptional activity of the reporter gene in the absence of PXR ligand rifampicin by roscovitine was more prominently enhanced, compared with the basal-, CAR-, and AhR/ARNT-mediated transacriptional activities. Phosphomimetic mutations at positions T57, T290, S350, and T408 attenuated the induction of UGT1A1 and CYP3A4 mRNAs by roscovitine, while the residues T57, T290, S305, and T408 were involved in the suppression for rifampicin stimulation. Transfection with anti-CDK2 siRNA but not anti-CDK1 and CDK5siRNAs led to stimulated expression of UGT1A1. Phosphomimetic mutant at S350 of PXR was detected in the nucleus, and co-transfection with co-activator SRC-2but not SRC-1 recovered the PXR activity. Immunoprecipitation analysis revealed the binding of PXR with HDAC1 in the nucleus. T290D mutant YFP-PXR fusion proteins retained in the cytoplasm and were not translocated to the nucleus of the cells stimulated with roscovitine. These results indicate that phosphorylation at positions T290 retained PXR protein in the cytoplasm, and that roscovitine stimulated expression of UGT1A1 and CYP3A4 through inhibiting CDK2, which phosphorylated PXR at S350 to suppress the transactivation in the nucleus, that is, the binding of PXR with RXR and the deacetylation of PXR.

  • Research Products

    (16 results)

All 2013 2012 2011 2010 Other

All Journal Article (5 results) (of which Peer Reviewed: 5 results) Presentation (9 results) Book (1 results) Remarks (1 results)

  • [Journal Article] Function, genetic polymorphism, and transcriptional regulation of human UDP-glucuronosyl transferase (UGT) 1A1.2013

    • Author(s)
      Sugatani J
    • Journal Title

      Drug Metab. Pharmacokinet.

      Volume: 28(2) Pages: 83-92

    • DOI

      DOI:10.2133/dmpk.DMPK-12-RV-096

    • Peer Reviewed
  • [Journal Article] Effects of dietary inulin, statin, and their co-treatment on hyperlipidemia, hepatic steatosis and changes in drug-metabolizing enzymes in rats fed a high-fat and high-sucrose diet.2012

    • Author(s)
      Sugatani J, Sadamitsu S, Wada T, Yamazaki Y, Ikari A, Miwa M
    • Journal Title

      Nutr. Metab.

      Volume: 9 Pages: 23

    • DOI

      DOI:10.1186/1743-7075-9-23 (21pages)

    • Peer Reviewed
  • [Journal Article] Regulation of pregnane X receptor (PXR) function and UGT1A1 gene expression by posttranslational modification of PXR protein.2012

    • Author(s)
      Sugatani J, Uchida T, Kurosawa M, Yamaguchi M, Yamazaki Y, Ikari A, Miwa M
    • Journal Title

      Drug Metab. Dispos

      Volume: 40(10) Pages: 2031-2040

    • DOI

      DOI:10.1124/dmd.112.046748

    • Peer Reviewed
  • [Journal Article] Nutritional status affects fluvastatin-nduced hepatotoxicity and myopathy in rats.2010

    • Author(s)
      Sugatani J, Sadamitsu S, Kurosawa M, Ikushiro S, Sakaki T, Ikari A, Miwa M
    • Journal Title

      Drug Metab. Dispos.

      Volume: 38 Pages: 1655-1664

    • DOI

      DOI:10.1124/dmd.110.034090

    • Peer Reviewed
  • [Journal Article] Induction of UGT1A1 and CYP2B6 by an antimitogenic factor in HepG2 cells is mediated through suppression of cyclin-dependent kinase 2.2010

    • Author(s)
      Sugatani J, Osabe M, Kurosawa M, Kitamura N,Ikari A, Miwa M
    • Journal Title

      Drug Metab. Dispos.

      Volume: 38 Pages: 177-186

    • DOI

      DOI:10.1124/dmd.109.029785

    • Peer Reviewed
  • [Presentation] 翻訳後に修飾された核内受容体PXRのUGT1A1発現におよぼす影響2012

    • Author(s)
      内田貴啓、服部芳規、黒澤雅俊、山口賢彦、山崎泰広、五十里彰、菅谷純子
    • Organizer
      第85回日本生化学会大会プログラム、p.147
    • Place of Presentation
      福岡
    • Year and Date
      2012-12-16
  • [Presentation] Regulation of PXR function and UGT1A1 gene expression by post-translational modification of PXR protein.2012

    • Author(s)
      Takahiro Uchida, Yoshiki Hattori, Masahiko Yamaguchi, Yasuhiro Yamazaki, Akira Ikari, Junko Sugatani
    • Organizer
      The 1stInternational Conference on Pharma-Food (ICPF 2012) Abstract, p. 118
    • Place of Presentation
      Shizuoka
    • Year and Date
      2012-11-16
  • [Presentation]2012

    • Author(s)
      Junko Sugatani
    • Organizer
      Regulation of PXR function by post-translational modification. 19th International Symposium on Microsomes and Drug Oxidations (MDO) and 12th European Regional ISSX Meeting Abstracts、p. 15、p. 147
    • Place of Presentation
      Noordwijk aan Zee, the Netherlands
    • Year and Date
      2012-06-20
  • [Presentation] 核内受容体PXRのリガンド結合部位を介した活性化制御機構について2012

    • Author(s)
      菅谷純子、内田貴啓、黒澤雅俊、山崎泰広、五十里彰、三輪匡男
    • Organizer
      第132年会日本薬学会講演要旨集、p.203
    • Place of Presentation
      札幌
    • Year and Date
      2012-03-29
  • [Presentation] Cyclin-dependent kinase 2 down-regulates expression of drug-metabolizing enzymes UGT1A1 and CYP3A4 through phosphorylation of nuclear receptor PXR in S phase.2011

    • Author(s)
      内田貴啓、黒澤雅俊、平川城太朗、山崎泰広、五十里彰、三輪匡男、菅谷純子
    • Organizer
      第34回日本分子生物学会年会プログラム、p.360
    • Place of Presentation
      横浜
    • Year and Date
      2011-12-16
  • [Presentation] Nutritional status influences basal and drug-induced expression of drug-metabolizing enzymes and transporters and drug-adverse effects.2011

    • Author(s)
      Junko Sugatani
    • Organizer
      第26回日本薬物動態学会講演要旨集p.189
    • Place of Presentation
      広島
    • Year and Date
      2011-11-18
  • [Presentation] 核内受容体PXRを介したUGT1A1発現調節機構の解析2011

    • Author(s)
      内田貴啓、黒澤雅俊、山崎泰広、五十里彰、三輪匡男、菅谷純子
    • Organizer
      第131年回日本薬学会講演要旨集3、p.173
    • Place of Presentation
      静岡
    • Year and Date
      2011-03-30
  • [Presentation] CDKシグナル伝達系を介した核内受容体CAR発現調節機序の解明2010

    • Author(s)
      黒澤雅俊、内田貴啓、五十里彰、三輪匡男、菅谷純子
    • Organizer
      第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
    • Place of Presentation
      神戸
    • Year and Date
      2010-12-07
  • [Presentation] Transcriptional regulation of human UDP-glucoronosyl transferase UGT1A1 gene expression and the alteration in its protein expression by intracellular factors controlling cell proliferation.2010

    • Author(s)
      菅谷純子
    • Organizer
      第25回日本薬物動態学会講演要旨集p.178
    • Place of Presentation
      東京
    • Year and Date
      2010-10-08
  • [Book] Transcriptional regulation of human bilirubin: UDP-glucuronosyl transferase UGT1A1gene and implication of defects in the UGT1A1gene promoter in "Bilirubin: Chemistry, Regulation and Disorder" (Jakub F. Novotny and Florian Sedlacek eds)2011

    • Author(s)
      Junko Sugatani and Masao Miwa
    • Total Pages
      8.1-8.27
    • Publisher
      NOVA Science Publishers
  • [Remarks]

    • URL

      http://w3pharm.u-shizuoka-ken.ac.jp/~rinsho/

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Published: 2014-08-29  

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