Mitochondrial oxidative stress and dysfunction induced by isoniazid: study on isolated rat liver and brain mitochondria
Mitochondrial oxidative stress and dysfunction induced by isoniazid: study on isolated rat liver and brain mitochondria
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DOI：
10.3109/01480545.2015.1092039
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发表时间：
2016-04-02
影响因子：
2.6
通讯作者：
Hosseini, Mir-Jamal
中科院分区：
文献类型：
--
作者：
Ahadpour, Morteza;Eskandari, Mohammad Reza;Hosseini, Mir-Jamal
异烟肼（INH或异烟酰肼）用于治疗和预防结核病。肝和脑是异烟肼毒性的两个重要靶器官。然而，INH肝毒性或神经毒性背后的确切机制尚未完全了解。考虑到线粒体是INH毒性的可能分子靶点之一，本研究的目的是评估INH线粒体毒性的机制。通过微分超离心法从雄性Sprague-Dawley大鼠分离线粒体，并与不同浓度的INH（25-2000 μ M）孵育以研究线粒体参数。结果表明，INH可与线粒体呼吸链相互作用，抑制其活性。我们的研究结果表明，线粒体活性氧（ROS）的形成，脂质过氧化和线粒体膜电位崩溃后，暴露在INH的离体肝线粒体的升高。然而，在脑线粒体中获得了不同的结果。值得注意的是，与肝线粒体相比，在较高浓度的INH中观察到显著的谷胱甘肽氧化、三磷酸腺苷（ATP）耗竭和脂质过氧化。结论：INH可能通过与线粒体电子传递链的相互作用、脂质过氧化、线粒体膜电位下降和细胞色素c的排出等途径启动其对肝线粒体的毒性作用，最终导致细胞死亡。
Isoniazid (INH or isonicotinic hydrazide) is used for the treatment and prophylaxis of tuberculosis. Liver and brain are two important target organs in INH toxicity. However, the exact mechanisms behind the INH hepatotoxicity or neurotoxicity have not yet been completely understood. Considering the mitochondria as one of the possible molecular targets for INH toxicity, the aim of this study was to evaluate the mechanisms of INH mitochondrial toxicity on isolated mitochondria. Mitochondria were isolated by differential ultracentrifugation from male Sprague-Dawley rats and incubated with different concentrations of INH (25-2000 mu M) for the investigation of mitochondrial parameters. The results indicated that INH could interact with mitochondrial respiratory chain and inhibit its activity. Our results showed an elevation in mitochondrial reactive oxygen species (ROS) formation, lipid peroxidation and mitochondrial membrane potential collapse after exposure of isolated liver mitochondria in INH. However, different results were obtained in brain mitochondria. Noteworthy, significant glutathione oxidation, adenosine triphosphate (ATP) depletion and lipid peroxidation were observed in higher concentration of INH, as compared to liver mitochondria. In conclusion, our results suggest that INH may initiate its toxicity in liver mitochondria through interaction with electron transfer chain, lipid peroxidation, mitochondrial membrane potential decline and cytochrome c expulsion which ultimately lead to cell death signaling.