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2005 Fiscal Year Final Research Report Summary

MRP2 mediated defense against oxidative stress in liver

Research Project

Project/Area Number 16390014
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, 大学院・薬学研究院, 教授 (90120154)

Co-Investigator(Kenkyū-buntansha) SHITARA Yoshihisa  Chiba University, Graduate School of Pharmaceutical Sciences, Lecturer, 大学院・薬学研究院, 講師 (00306656)
SEKINE Shuichi  Chiba University, Graduate School of Pharmaceutical Sciences, Research Associate, 大学院・薬学研究院, 助手 (70401007)
Project Period (FY) 2004 – 2005
Keywordsoxidative stress / cholestasis / MRP2 / glutathione / biliary excretion / transporter / protein kinase C / nitric oxide
Research Abstract

Oxidative stress in the liver is sometimes accompanied by cholestasis. We have described the internalization of multidrug resistance-associated protein 2/ ATP-binding cassette transporter family 2 (Mrp2/Abcc2), a biliary transporter involved in bile-salt-independent bile flow, under ethacrynic acid (EA)-induced acute oxidative stress in rat liver. However, the signaling pathway and regulatory molecules have been remained to be investigated. In this research, we investigated the mechanism of EA-induced Mrp2 internalization using isolated rat hepatocyte couplets (IRCHs). The Mrp2-index, defined as the ratio of Mrp2 positive canalicular membrane staining in IRCHs per number of cell nuclei, was significantly reduced by treatment with EA. By using this system, we have found EA produced a reduction in GSH,Ca^<2+> elevation, NO production, nPKC activation in a sequential manner, finally leading to selective Mrp2 internalization. In addition to this, we demonstrated one of the non-steroidal anti-inflammatory drugs, Naproxen induced oxidative stress also leads to cholestasis caused by decrease excretion of GSH into bile. As GSH itself is known to be a good substrate of Mrp2, we thought Mrp2 internalization also caused Naproxen-induced cholestasis. Finally, these new findings might be able to solve the mechanism of cholestasis caused by drug-induced hepatitis and aging.

  • Research Products

    (8 results)

All 2006 2005

All Journal Article (8 results)

  • [Journal Article] Naproxen-induced oxidative stress in the isolated perfused rat liver2006

    • Author(s)
      Yokoyama H, Horie T, Awazu S
    • Journal Title

      Chem. Biol. Interact. 160 (2)

      Pages: 150-158

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Naproxen-induced oxidative stress in the isolated per fused rat liver2006

    • Author(s)
      Yokoyama H, Horie T, Awazu S
    • Journal Title

      Chem.Biol.Interact. 160-2

      Pages: 150-158

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Apical/basolateral surface expression of drug transporters and its role in vectorial drug transport2006

    • Author(s)
      Ito K, Suzuki H, Horie T, Sugiyama Y
    • Journal Title

      Pharm.Res. 22(10)

      Pages: 1559-1577

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Functional analysis of dog multidrug resistance associated 2(Mrp2) in Comparison with rat Mrp22005

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

      Drug Metab. Dispos. 33 (2)

      Pages: 225-232

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Apical/basolateral surface expression of drug transporters and its role in vectorial drug transport2005

    • Author(s)
      Ito K, Suzuki H, Horie T, Sugiyama Y
    • Journal Title

      Pharm. Res. 22 (10)

      Pages: 1559-1577

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Mrp2/Abcc2 transport activity is stimulated by Protein kinase C alpha in a bacula virus co-expression system2005

    • Author(s)
      Ito K, Wakabayashi T, Horie T
    • Journal Title

      Life Sci. 77 (5)

      Pages: 539-550

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Functional analysis of dog raultidrug resistance associated protein 2 (Mrp2) in comparison with rat Mrp22005

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

      Drug Metab.Dispos. 33(2)

      Pages: 225-232

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Mrp2/Abcc2 transport activity is stimulated by Protein kinase C alpha in a bacula virus co-expression system2005

    • Author(s)
      Ito K, Wakabayashi T, Horie T
    • Journal Title

      Life Sci. 77(5)

      Pages: 539-550

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2007-12-13  

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