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Intrahepatic imaging and molecular analysis of MRP2 localization regulated by the intracellular redox status

Research Project

Project/Area Number 18390012
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Physical pharmacy
Research InstitutionChiba University

Principal Investigator

HORIE Toshiharu  Chiba University, Graduate school of pharmaceutical sciences, Professor (90120154)

Co-Investigator(Kenkyū-buntansha) SHITARA Yoshihisa  Chiba University, Graduate school of pharmaceutical sciences, Lecturer (00306656)
SEKINE Shuichi  Chiba University, Graduate school of pharmaceutical sciences, Assistant Professor (70401007)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥14,020,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2007: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2006: ¥9,600,000 (Direct Cost: ¥9,600,000)
KeywordsBiophysical / Signal transduction / Drug reactivity / Protein / 蛋自質
Research Abstract

Oxidative stress is known to be a common feature of cholestatic syndrome. We have described the internalization of multidrug resistance-associated protein 2 (Mrp2), a biliary transporter involved in bile-salt independent bile flow, under acute oxidative stress and a series of signaling pathways finally leading to the activation of novel protein kinase C (nPKC) were involved in this mechanism; however, it has been unclear whether the internalized Mrp2 localization was re-localized to the canalicular membrane when the intracellular redox status was recovered from oxidative stress. In this research, we demonstrated that decreased canalicular expression of Mrp2 induced by tertiary-butyl hydroperoxide (t-BHP) was recovered to the canalicular membrane by the replenishment of GSH by GSH-ethyl ester, a cell-permeable form of GSH. Moreover, pretreatment of isolated rat hepatocytes with colchicine and protein kinase A (PKA) inhibitor did not affect the t-BHP induced Mrp2 internalization process, but did prevent the Mrp2 recycling process induced by GSH replenishment. Moreover, intracellular cAMP concentration similarly changed with the change of intracellular GSH content. Taken together, our data clearly indicate that the redox-sensitive balance of PKA/PKC activation regulates the reversible Mrp2 localization in two different pathways, the microtubule-independent internalization pathway and -dependent recycling pathway of Mrp2.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (29 results)

All 2008 2007 2006 Other

All Journal Article (16 results) (of which Peer Reviewed: 8 results) Presentation (10 results) Book (1 results) Remarks (2 results)

  • [Journal Article] Down-regulation of hepatic cytochrome P450 enzymes in rats with trinitrobenzene sulfonic acid-induced colitis.2008

    • Author(s)
      Masubuchi Y, Enoki K, Horie T.
    • Journal Title

      Drug Metab Dispos. 36(3)

      Pages: 597-603

    • NAID

      130005024164

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Down-regulation of hepatic cytochrome P450 enzymes in rats with trinitrobenzene sulfonic acid-induced colitis2008

    • Author(s)
      Masubuchi Y, Enoki K, Horie T.
    • Journal Title

      Drug Metab Dispos. 36 (3)

      Pages: 597-603

    • NAID

      130005024164

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Down-regulation of hepatic cytochrome P450 enzymes in ratswith trinitrobenzene sulfonic acid-induced colitis2008

    • Author(s)
      Masubuchi Y, Enoki K, Horie T.
    • Journal Title

      Drug Metab Dispos 36(3)

      Pages: 597-603

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dimerumic acid protected oxidative stress-induced cytotoxicity in isolated rat hepatocytes.2007

    • Author(s)
      Yamashiro JI, Shiraishi S, Fuwa T, Horie T.
    • Journal Title

      Cell Biol Toxicol. (Epub ahead of print)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs.2007

    • Author(s)
      Masubuchi Y, Horie T.
    • Journal Title

      Crit Rev Toxicol. 37(5)

      Pages: 389-412

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Down-regulation of hepatic transporters for BSP in rats with indomethacin-induced intestinal injury.2007

    • Author(s)
      Fujiyama N, Shitara Y, Ito K, Masubuchi Y, Horie T.
    • Journal Title

      Biol Pharm Bull. 30(3)

      Pages: 556-61

    • NAID

      110006239203

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Dimerumic acid protected oxidative stress-induced cytotoxicity in isolated rat hepatocytes2007

    • Author(s)
      Yamashiro JI, Shiraishi S, Fuwa T, Horie T.
    • Journal Title

      Cell Biol Toxicol. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs2007

    • Author(s)
      Masubuchi Y, Horie T.
    • Journal Title

      Crit Rev Toxicol. 37 (5)

      Pages: 389-412

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Down-regulation of hepatic transporters for BSP in rats with indomethacin-induced intestinal injury2007

    • Author(s)
      Fujiyama N, Shitara Y, Ito K, Masubuchi Y, Horie T.
    • Journal Title

      Biol Pharm Bull. 30 (3)

      Pages: 556-561

    • NAID

      110006239203

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Drug-drug interactions in pharmaceutical development2007

    • Author(s)
      Shitara Y, Horie T, Sugiyama Y.
    • Journal Title

      John Wiley and Sons 244

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Dimerumic acid protected oxidative stress-induced cytotoxicity in isolated rat hepatocytes2007

    • Author(s)
      Yamashiro JI, Shiraishi S, Fuwa T, Horie T.
    • Journal Title

      Cell Biol Toxicol [Epub ahead of print]

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs2007

    • Author(s)
      Masubuchi Y, Horie T.
    • Journal Title

      Crit Rev Toxicol 37(5)

      Pages: 389-412

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Down-regulation of hepatic transporters for BSP in rats withindomethacin-induced intestinal injury2007

    • Author(s)
      Fujiyama N, Shitara Y, Ito K, Masubuchi Y, Horie T.
    • Journal Title

      Biol Pharm Bull 30(3)

      Pages: 556-561

    • NAID

      110006239203

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Down-regulation of hepatic transporters for BSP in rats with indomethacin-induced intestinal injury.2007

    • Author(s)
      Fujiyama N, Shitara Y, Ito K, Masubuchi Y, Horie T
    • Journal Title

      Biol Pharm Bull. 30(3)

      Pages: 556-61

    • NAID

      110006239203

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Oxidative stress and Mrp2 internalization.2006

    • Author(s)
      Sekine S, Ito K, Horie T.
    • Journal Title

      Free Radic Biol Med. 40(12)

      Pages: 2166-74

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Functional analysis of mouse and monkey multidrug resistance-associated protein 2(Mrp2).2006

    • Author(s)
      Ninomiya M, Ito K, Hiramatsu R, Horie T
    • Journal Title

      Drug Metab Dispos. 34(12)

      Pages: 2056-63

    • Related Report
      2006 Annual Research Report
  • [Presentation] 小腸上皮Mrp2の膜局在と膜裏打ち蛋白質Ezrinのリン酸化状態との関連2007

    • Author(s)
      中埜貴文, 関根秀一, 伊藤晃成, 堀江利治
    • Organizer
      日本薬学会第126年会
    • Place of Presentation
      富山
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Mrp2 localization is reversibly regulated by protein kinases.2007

    • Author(s)
      Shuichi Sekine, Kousei Ito, Toshiharu Horie
    • Organizer
      8th International ISSX
    • Place of Presentation
      仙台
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Tha phosphorylation status of ezrin regulates Mrp2 localization in rat intestine2007

    • Author(s)
      Takahumi Nakano, Shuichi Sekine, Kousei Ito, Toshiharu Horie
    • Organizer
      8th International ISSX
    • Place of Presentation
      仙台
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] PKA/PKC活性化平衡の変動によるMrp2の可逆的膜動輸送制御について2007

    • Author(s)
      関根秀一, 伊藤晃成, 堀江利治
    • Organizer
      第29回生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      仙台
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Phosphorylation status of ezrin correlates with membrane localization of Mrp2 in intestine2007

    • Author(s)
      Nakano T, Sekine S, Ito K, Horie T.
    • Organizer
      126th meeting of pharmaceutical society of japan
    • Place of Presentation
      Toyama
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Mrp2 localization is reversibly regulated by protein kinases2007

    • Author(s)
      Sekine S, Ito K, Horie T
    • Organizer
      8th International ISSX
    • Place of Presentation
      Sendai
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Tha phosphorylation status of ezrin regulates Mrp2 localization in rat intestine2007

    • Author(s)
      Nakano T, Sekine S, Ito K, Horie T
    • Organizer
      8th International ISSX
    • Place of Presentation
      Sendai
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] The balance of PKA/PKC activation reversibly regulates vesicular trafficking of Mrp22007

    • Author(s)
      Sekine S, Ito K, Horie T
    • Organizer
      29th Symposium on biomembrane-drug interaction
    • Place of Presentation
      Sendai
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Mrp2 localization is reversibly regulated by protein kinases2007

    • Author(s)
      Shuichi Sekine, Kousei Ito, Toshiharu Horie
    • Organizer
      8th International ISSX
    • Place of Presentation
      仙台
    • Related Report
      2007 Annual Research Report
  • [Presentation] Tha phosphorylation status of ezrin regulates MrP2 localization in rat intestine2007

    • Author(s)
      Takahumi Nakano, Shuichi Sekine.Kousei Ito, Toshiharu Horie
    • Organizer
      8th Intemational ISSX
    • Place of Presentation
      仙台
    • Related Report
      2007 Annual Research Report
  • [Book] Drug-drug interactions in pharmaceutical development2007

    • Author(s)
      Shitara Y, Horie T, Sugiyama Y
    • Total Pages
      244
    • Publisher
      John Wiley and Sons
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Remarks] 「研究成果報告書概要(和文)」より

    • URL

      http://www.p.chiba-u.ac.jp/lab/yakuzai/index.html

    • Related Report
      2007 Final Research Report Summary
  • [Remarks]

    • URL

      http://www.p.chiba-u.ac.jp/lab/yakuzai/index.html

    • Related Report
      2007 Annual Research Report

URL: 

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

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