| Project/Area Number |
16390014
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Physical pharmacy
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| Research Institution | Chiba University |
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Principal Investigator |
HORIE Toshiharu Chiba University, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学研究院, 教授 (90120154)
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| 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)
桝渕 泰宏 千葉大学, 大学院・薬学研究院, 助教授 (10209455)
伊藤 晃成 千葉大学, 大学院・薬学研究院, 助手 (30323405)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥10,300,000 (Direct Cost: ¥10,300,000)
Fiscal Year 2005: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2004: ¥6,500,000 (Direct Cost: ¥6,500,000)
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| Keywords | oxidative stress / cholestasis / MRP2 / glutathione / biliary excretion / transporter / protein kinase C / nitric oxide / 酸化的ストレス / 肝障害 / 化学発光 / 脂質過酸化 |
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| 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.
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