Herbal Research Section, Indian Institute of Toxicology Research (CSIR) (Formerly-Industrial Toxicology Research Centre), P.O. Box-80, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India.
Toxicology. 2010 Sep 10;275(1-3):1-9. doi: 10.1016/j.tox.2010.05.001. Epub 2010 May 8.
Nimesulide (selective cyclooxygenase-2 inhibitor) is a nonsteroidal anti-inflammatory drug for the symptomatic treatment of painful conditions like osteoarthritis, spondilitis and primary dysmenorrhoea. Nimesulide induced liver damage is a serious side effect of this otherwise popular drug. The mechanism involved in nimesulide induced hepatotoxicity is still not fully elucidated. However, both mitochondrial dysfunction and oxidative stress have been implicated in contributing to liver injury in susceptible patients. Mitochondria besides being the primary source of energy, act as a hub of signals responsible for initiating cell death, irrespective of the pathway, i.e. apoptosis or necrosis. The present study was aimed to explore the role of compounding stress, i.e. Ca(2+) overload and GSH depletion in nimesulide induced mitochondrial toxicity and dysfunction. Our study showed that, nimesulide (100 microM) treatment resulted into rapid depletion of GSH (60%) in isolated rat liver mitochondria and significant Ca(2+) dependent MPT changed. Enhanced ROS generation (DCF fluorescence) was also observed in mitochondria treated with nimesulide. An important finding was that the concentration at which nimesulide oxidized reduced pyridine nucleotides (autofluorescence of NAD(P)H), it affected mitochondrial electron flow (MTT activity decreased by 75%) and enhanced mitochondrial depolarization significantly as assessed by Rhodamine 123 fluorescent probe. Therefore, nimesulide was found to aggravate redox imbalance and affect Ca(2+) dependent mitochondrial membrane permeability transition leading to dysfunction and ultimately cell death.
尼美舒利（选择性环氧化酶-2 抑制剂）是一种非甾体抗炎药，用于治疗骨关节炎、脊椎炎和原发性痛经等疼痛病症。尼美舒利引起的肝损伤是这种广受欢迎的药物的一种严重副作用。尼美舒利诱导肝毒性的确切机制尚未完全阐明。然而，线粒体功能障碍和氧化应激都与易感患者的肝损伤有关。线粒体不仅是能量的主要来源，还作为信号中心，负责启动细胞死亡，无论途径是凋亡还是坏死。本研究旨在探讨复合应激（即 Ca2+超载和 GSH 耗竭）在尼美舒利诱导的线粒体毒性和功能障碍中的作用。我们的研究表明，尼美舒利（100 μM）处理导致分离的大鼠肝线粒体中 GSH（60%）迅速耗竭，并发生显著的 Ca2+依赖性 MPT 改变。用尼美舒利处理的线粒体中也观察到 ROS 生成增强（DCF 荧光）。一个重要的发现是，尼美舒利氧化还原型吡啶核苷酸（NAD(P)H 自发荧光）的浓度，它影响线粒体电子流（MTT 活性降低 75%），并显著增强线粒体去极化，如用罗丹明 123 荧光探针评估。因此，尼美舒利加重了氧化还原失衡，影响了 Ca2+依赖性线粒体膜通透性转换，导致功能障碍，最终导致细胞死亡。
