油症原因物質2,3,4,7,8-Pentachlorodibenzofuranによる酸化的ストレス惹起の推定機構 : 肝臓での過酸化水素産生亢進と肝障害

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  • 山田 健一
    九州大学大学院薬学研究院分子衛生薬学分野
  • 武田 知起
    九州大学大学院薬学研究院分子衛生薬学分野
  • 黒木 廣明
    第一薬科大学
  • 三苫 千景
    九州大学病院油症ダイオキシン研究診療センター
  • 内 博史
    九州大学大学院医学研究院皮膚科学分野
  • 古江 増隆
    九州大学病院油症ダイオキシン研究診療センター | 九州大学大学院医学研究院皮膚科学分野
  • 山田 英之
    九州大学大学院薬学研究院分子衛生薬学分野
  • 石井 祐次
    九州大学大学院薬学研究院分子衛生薬学分野

書誌事項

タイトル別名
  • Possible Mechanism of 2,3,4,7,8-Pentachlorodibenzofuran-induced Oxidative Stress : Enhanced Production of Hydrogen Peroxide and the Liver Injury
  • ユショウ ゲンイン ブッシツ 2,3,4,7,8-Pentachlorodibenzofuran ニ ヨル サンカテキ ストレス ジャッキ ノ スイテイ キコウ : カンゾウ デ ノ カサンカスイソ サンセイ コウシン ト カン ショウガイ

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抄録

The mechanism of oxidative stress which is one of the major toxicities observed in 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) -treated mice was studied. Previously, we evaluated the dose-response relationship on the wasting syndrome and oxidative stress elicited with PenCDF (0.3, 1.0, 5.0 and 10 mg/kg, once, p.o.). Of PenCDF doses examined, the wasting syndrome and oxidative stress were most marked in 5 mg/kg. In disagreement with this, the hepatic ethoxyresorufin-O-deethylase (EROD) activity which is a marker of aryl hydrocarbon receptor-dependent induction of cytochrome P450 1a1 (Cyp1a1) was most significantly elevated at 0.3 mg/kg. To clarify this discripancy, in this study, we determined the contents of Cyp1a1 and 1a2 protein. The content of Cyp1a1 was well correlated with the EROD activity up to the PenCDF dose 1.0 mg/kg while the induction profile of Cyp1a2 was not correlated with it. Although, at the PenCDF 5.0 mg/kg, the contents of Cyp1a1 and 1a2 protein were induced consistently, the EROD activity declined to the level far smaller than the PenCDF dose 1.0 mg/kg. Further, the NADPH consumption was comparable among the PenCDF dose examined. Instead, the hydrogen peroxide production was elevated in S9 fraction most markedly by PenCDF dose 5.0 mg/kg. In agreement with this, the marker of hepatic injury, the serumAST and ALT activities were also most elevated at the same dose. Therefore, it is possible that PenCDF elicits oxidative stress and hepatic injury through the production of hydrogen peroxide via the mechanism involving uncoupling of the P450s.

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