Shin Sang Mi, Kim Sang Geon
Innovative Drug Research Center for Metabolic and Inflammatory Diseases, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Mol Pharmacol. 2009 Jan;75(1):242-53. doi: 10.1124/mol.108.051128. Epub 2008 Oct 22.
4-Methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz), a prototype drug candidate containing a 1,2-dithiole-3-thione moiety, has been widely studied as a cancer chemopreventive agent. Oltipraz and other novel 1,2-dithiole-3-thione congeners have the capability to prevent insulin resistance via AMP-activated protein kinase (AMPK) activation. Arachidonic acid (AA, a proinflammatory fatty acid) exerts a deleterious effect on mitochondria and promotes reactive oxygen species (ROS) production. This study investigated whether AA alone or in combination with iron (catalyst of autooxidation) causes ROS-mediated mitochondrial impairment, and if so, whether oltipraz and synthetic 1,2-dithiole-3-thiones protect mitochondria and cells against excess ROS produced by AA + iron. Oltipraz treatment effectively inhibited mitochondrial permeability transition promoted by AA + iron in HepG2 cells, thereby protecting cells from ROS-induced apoptosis. Oltipraz was found to attenuate apoptosis induced by rotenone (complex I inhibitor), but not that by antimycin A (complex III inhibitor), suggesting that the inhibition of AA-induced apoptosis by oltipraz might be associated with the electron transport system. AMPK activation by oltipraz contributed to cell survival, which was supported by the reversal of oltipraz's restoration of mitochondrial membrane potential by concomitant treatment of compound C. By the same token, an AMPK activator inhibited AA + iron-induced mitochondrial permeability transition with an increase in cell viability. Moreover, new 1,2-dithiole-3-thiones with the capability of AMPK activation protected cells from mitochondrial permeability transition and ROS overproduction induced by AA + iron. Our results demonstrate that oltipraz and new 1,2-dithiole-3-thiones are capable of protecting cells from AA + iron-induced ROS production and mitochondrial dysfunction, which may be associated with AMPK activation.
4-甲基-5-(2-吡嗪基)-1,2-二硫杂环戊烯-3-硫酮（奥替普拉）是一种含有1,2-二硫杂环戊烯-3-硫酮部分的原型候选药物，作为一种癌症化学预防剂已被广泛研究。奥替普拉和其他新型1,2-二硫杂环戊烯-3-硫酮同系物具有通过激活AMP活化蛋白激酶（AMPK）来预防胰岛素抵抗的能力。花生四烯酸（AA，一种促炎脂肪酸）对线粒体产生有害影响并促进活性氧（ROS）的产生。本研究调查了单独的AA或与铁（自氧化催化剂）联合使用是否会导致ROS介导的线粒体损伤，如果是，奥替普拉和合成的1,2-二硫杂环戊烯-3-硫酮是否能保护线粒体和细胞免受AA+铁产生的过量ROS的影响。奥替普拉处理有效地抑制了HepG2细胞中由AA+铁促进的线粒体通透性转换，从而保护细胞免受ROS诱导的凋亡。发现奥替普拉可减轻鱼藤酮（复合体I抑制剂）诱导的凋亡，但不能减轻抗霉素A（复合体III抑制剂）诱导的凋亡，这表明奥替普拉对AA诱导的凋亡的抑制作用可能与电子传递系统有关。奥替普拉激活AMPK有助于细胞存活，同时用化合物C处理可逆转奥替普拉对线粒体膜电位的恢复，这支持了这一点。同样，一种AMPK激活剂抑制了AA+铁诱导的线粒体通透性转换，并提高了细胞活力。此外，具有激活AMPK能力的新型1,2-二硫杂环戊烯-3-硫酮可保护细胞免受AA+铁诱导的线粒体通透性转换和ROS过量产生的影响。我们的结果表明，奥替普拉和新型1,2-二硫杂环戊烯-3-硫酮能够保护细胞免受AA+铁诱导的ROS产生和线粒体功能障碍，这可能与AMPK激活有关。
