Involvement of Mitochondrial Peroxynitrite in Nitric Oxide-Induced Glutathione Synthesis(Biochemistry/Molecular Biology)
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概要
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Cells respond to oxidative stress including nitric oxide (NO) by increasing cellular glutathione concentration, as a part of adaptive response against oxidative injury. To elucidate the mechanism by which NO induces glutathione we investigated the reactive oxygen species (ROS) generated in the cell. Treatment of RAW264.7 cells with NO donor, sodium nitroprusside (SNP), resulted in a temporary increase in glutathione in a dose-dependent manner, which peaked between 6h and 12h after treatment, whereas expression of γ-glutamylcysteine synthetase (γ-GCS) mRNA peaked around 3h after treatment. The increase was inhibited by NO scavengers, oxyhemoglobin and carboxyl-2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO). N-Acetyl-Lcysteine (NAC) also reduced the increase in glutathione to some extent, whereas both peroxynitrite scavenger ebselen and hydroxyl radical scavenger DMSO inhibited the increase in glutathione in a dose-dependent manner and complete inhibition was observed. Hydrogen peroxide exogenously added to the cell did not increase either glutathione or γ-GCS expression at any concentration, indicating that involvement of hydrogen peroxide is not likely. Flow cytometric analysis showed that SNP induced a marked dose-dependent increase in Rhodamine123 fluorescence, which was completely inhibited by ebselen in a dose-dependent manner, whereas, little increase in 2′, 7′-dichlorofluorescin (DCF) fluorescence was observed. Generation of peroxynitrite in mitochondria by SNP was confirmed by elevated level of nitrotyrosine in a mitochondria fraction isolated from SNP-treated cells, and the elevation was completely inhibited by ebselen as well. These results suggest that induction of glutathione (GSH) synthesis by SNP treatment is mediated by peroxynitrite generated in mitochondria.
- 公益社団法人日本薬学会の論文
- 2005-05-01
著者
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Kojima Shuji
Faculty Of Pharmaceutical Sciences Science University Of Tokyo
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Kurozumi Risa
Faculty of Pharmaceutical Sciences, Tokyo University of Science
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Takahashi Mareyuki
Faculty Of Pharmaceutical Sciences Tokyo University Of Science
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Kurozumi Risa
Faculty Of Pharmaceutical Sciences Tokyo University Of Science
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