The role of heat shock proteins in inhaled anesthetics-induced organ toxicity

热休克蛋白在吸入麻醉药引起的器官毒性中的作用

• 批准号: 09671564
• 负责人: HIRAKAWA Masahisa
• 金额: $ 1.98万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671564/
• 关键词: halothane; stress protein; heme; heme oxygenase

Phenobarbital pretreatment of male rats is known to increase the reductive metabolism of halothane and free radical formation under hypoxia that leads to lipid peroxidation, and ultimately results in extensive hepatotoxicity. It is also associated with a marked induction of microsomal heme oxygenase-1 (HO-1), suggesting that there is an alteration in heme metabolism in the liver. In this project, we examined heme metabolism in rats pretreated with phenobarbital, followed by exposure to halothane and hypoxia. Exposure of phenobarbital-pretreated rats to halothane-hypoxia caused a rapid increase in cytosolic free heme concentration, a decrease in the level of mRNA for the non- specific delta-aminolevulinate synthase, all of which were precede by a significant decrease in microsomal cytochrome P450 content in the liver There were also marked increases in two heat-shock proteins, namely, a transient but dramatic induction of HO-i mRNA reaching at the maximum on 6h, and a prolonged inductio … More n of heat shock protein 70 mRNA starting 2h. The level of HO-i protein was also increased and principally detected around the perivenular zone in the liver. Serum alanine transaminase (ALT) activity, an indicator of hepatic dysfunction, increase continuously with time, reaching the maximum at the end of the experimental period of 24h. Interestingly, hemin pretreatment of these animals not only induced hepatic HO-I, but also almost completely abrogated the halothane-induced hepatotoxicity in this model, as judged by a lack of induction of ALT activity, and normal histology of the liver. Our findings thus indicate that halothane-induced hepatotoxicity is not only due to its reductive metabolite formation, but also due to an increase in hepatic free heme concentration that is a potent prooxidant, and HO-i induction is an important protective response against such changes. This is also the first study to demonstrate that hemin pretreatment, thereby inducing HO-i prior to exposure to halothane, effectively prevents the halothane-induced hepatotoxicity. Less

已知雄性大鼠的苯巴比妥预处理会增加氟烷的还原代谢和缺氧条件下的自由基形成，导致脂质过氧化，并最终导致广泛的肝毒性。它还与微粒体血红素加氧酶-1（HO-1）的显著诱导相关，表明肝脏中血红素代谢发生改变。在这个项目中，我们研究了血红素代谢的大鼠预先与苯巴比妥，然后暴露于氟烷和缺氧。苯巴比妥预处理的大鼠暴露于氟烷缺氧引起胞质游离血红素浓度迅速增加，非特异性δ-氨基乙酰丙酸合酶mRNA水平下降，所有这些都伴随着肝微粒体细胞色素P450含量的显著下降。两种热休克蛋白也显著增加，即，HO-i mRNA的诱导在6 h达到最大值，而HO-i mRNA的诱导在6 h达到最大值。 ...更多信息 热休克蛋白70 mRNA表达水平从2 h开始下降。HO-1蛋白的水平也增加，并且主要在肝中的小静脉周围区检测到。血清谷丙转氨酶（ALT）活性，肝功能障碍的指标，随着时间的推移不断增加，在实验期结束时的24小时达到最大值。有趣的是，这些动物的氯化血红素预处理不仅诱导肝脏HO-I，而且几乎完全消除了该模型中氟烷诱导的肝毒性，如通过缺乏ALT活性诱导和肝脏正常组织学所判断的。因此，我们的研究结果表明，氟烷诱导的肝毒性不仅是由于其还原性代谢产物的形成，而且还由于肝游离血红素浓度的增加，这是一种有效的促氧化剂，和HO-1诱导是一个重要的保护性反应，对这种变化。这也是首次证明氯化血红素预处理，从而在暴露于氟烷之前诱导HO-1，有效防止氟烷诱导的肝毒性的研究。少

项目成果

Yasuo Odaka, Toru Takahashi, Akira Yamasaki, Tsutomu Suzuki, Tadao Fujiwara, Teruo Yamada, Mashisa Hirakawa, Hiroyoshi, Fujita, Emiko Ohmori, Reiko Akagi: "Hemin pretreatment prevents Halothane-induced hepatotoxicity : The protective role of heme oxygenas

Yasuo Odaka、Toru Takahashi、Akira Yamasaki、Tsutomu Suzuki、Tadao Fujiwara、Teruo Yamada、Mashisa Hirakawa、Hiroyoshi、Fujita、Emiko Ohmori、Reiko Akagi：“血红素预处理可预防氟烷引起的肝毒性：血红素氧的保护作用

尾高 康夫 他6名: "ラットハロタン肝障害におけるHeme Oxygenase (HO) mRNAの誘導機序" Journal of Anesthesia. 12S. 1-L-05 (1997)

Yasuo Odaka 等 6 人：“大鼠氟烷肝损伤中血红素加氧酶 (HO) mRNA 的诱导机制”麻醉杂志 12S 1-L-05 (1997)。

Yasuo Odaka, Toru Takahashi, Tadao Fujiwwra, Hiroko Kanbara, Akira Yamasaki, Tsutomu Suzuki, Masahisa Hirakawa: "The mechanism Of Heme Oxygenase induction in rat hepatic disorder" Journal of Anesthesia. Vol.12, Supplement 1-L-05. (1997)

Yasuo Odaka、Toru Takahashi、Tadao Fujiwwra、Hiroko Kanbara、Akira Yamasaki、Tsutomu Suzuki、Masahisa Hirakawa：“大鼠肝病中血红素加氧酶诱导的机制”麻醉杂志。

Toru Takahashi, Yasuo Odaka, Tsutomu Suzuki, Akira Yamasaki, Takashi, Tsukiji, Masahisa Hirakawa, Reiko Akagi: "The role of heme in halothane-induced hepatic injury" Proceedings of The 9^<th> Biological Radical Research Meeting in Chugoku Shikoku District

Toru Takahashi、Yasuo Odaka、Tsutomu Suzuki、Akira Yamasaki、Takashi、Tsukiji、Masahisa Hirakawa、Reiko Akagi：“血红素在氟烷引起的肝损伤中的作用”中国四国地区第 9 届生物自由基研究会议论文集

高橋 徹 他6名: "吸入麻酔薬ハロタン肝障害において細胞内Hemeが果たす役割" 第9回 中国四国生体ラジカル研究会プログラム. 抄録集. (1998)

Toru Takahashi 等 6 人：“细胞内血红素在吸入麻醉氟烷肝损伤中的作用”第 9 次中国-四国生物激进研究组摘要（1998 年）。