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

已知苯巴比妥对雄性大鼠在低氧条件下会增加氟烷的还原代谢和自由基的形成，从而导致脂质过氧化，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)的显著诱导有关，表明肝脏中的血红素代谢发生了变化。在这个项目中，我们研究了用苯巴比妥预处理，然后暴露在氟烷和低氧环境下的大鼠的血红素代谢。苯巴比妥预处理的大鼠暴露在氟烷低氧环境中，细胞内游离血红素浓度迅速升高，非特异性β-氨基酮戊酸合成酶的mR NA水平显著降低，肝脏微粒体细胞色素P450含量显著降低。两种热休克蛋白的表达也显著增加，即短暂而剧烈的HO-I m RNA的诱导在6h达到最大值，以及对…的长时间诱导从2小时开始，热休克蛋白70的m RNA表达增加。HO-I蛋白水平也升高，主要分布在肝静脉周围带附近。血清丙氨酸氨基转移酶(ALT)活性作为肝功能损害的指标，随着时间的延长而持续升高，在实验的24小时末达到最大值。有趣的是，这些动物的氯化血红素预处理不仅诱导了肝脏HO-I，而且几乎完全取消了氟烷诱导的肝毒性，根据缺乏ALT活性的诱导和肝脏的正常组织学判断。因此，我们的研究结果表明，氟烷引起的肝毒性不仅是由于其还原代谢产物的形成，而且还由于作为一种强有力的促氧化剂的肝脏游离血红素浓度的增加，而HO-I诱导是对这种变化的重要保护性反应。这也是第一个证明氯化血红素在暴露于氟烷之前诱导HO-I的研究，有效地防止了氟烷引起的肝毒性。较少

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