Boulares A Hamid, Contreras Francisco J, Espinoza Luis A, Smulson Mark E
Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, DC 20007, USA.
Toxicol Appl Pharmacol. 2002 Apr 15;180(2):92-9. doi: 10.1006/taap.2002.9350.
The toxic jet fuel JP-8 induces morphological and biochemical changes characteristic of apoptosis in rat lung epithelial (RLE-6TN) cells. The mechanism of JP-8 toxicity in these cells was further investigated in an attempt to identify potential therapeutic interventions. Given that oxidative stress and changes in the concentrations of endogenous antioxidants, such as glutathione (GSH), have been associated with the cellular damage elicited by numerous toxicants, the possibility that JP-8 induces cellular oxidative stress was investigated. Experimentally induced depletion of intracellular GSH or exposure of cells to a low concentration of H(2)O(2) markedly enhanced JP-8-induced cell death. A significant reduction in intracellular concentrations of GSH was noted in RLE-6TN cells shortly after exposure to JP-8. Furthermore, JP-8 induced the generation of reactive oxygen species (ROS) in RLE-6TN cells. Consistent with the notion that JP-8 toxicity is mediated by generation of ROS and depletion of intracellular GSH, JP-8-induced cell death was inhibited by exogenous GSH or the thiol-containing antioxidant N-acetyl-cysteine. This protective effect was associated with marked inhibition of both the activation of caspase-3 and the loss of the mitochondrial membrane potential induced by JP-8. Inhibition of the JP-8-induced activation of poly(ADP-ribose) polymerase by 3-aminobenzamide did not protect cells against JP-8 toxicity. Together, these results indicate that thiol antioxidants are highly effective in rescuing cells from JP-8-induced cell death and that they may provide a basis for new therapeutic approaches to counteract JP-8 toxicity.
有毒喷气燃料JP - 8可诱导大鼠肺上皮（RLE - 6TN）细胞发生凋亡特有的形态学和生化变化。为了确定潜在的治疗干预措施，对JP - 8在这些细胞中的毒性机制进行了进一步研究。鉴于氧化应激以及内源性抗氧化剂（如谷胱甘肽（GSH））浓度的变化与多种毒物引起的细胞损伤有关，因此研究了JP - 8是否会诱导细胞氧化应激。实验性诱导细胞内GSH耗竭或使细胞暴露于低浓度的H₂O₂中，可显著增强JP - 8诱导的细胞死亡。在暴露于JP - 8后不久，RLE - 6TN细胞内的GSH浓度显著降低。此外，JP - 8可诱导RLE - 6TN细胞产生活性氧（ROS）。与JP - 8毒性是由ROS生成和细胞内GSH耗竭介导的观点一致，外源性GSH或含硫醇的抗氧化剂N - 乙酰半胱氨酸可抑制JP - 8诱导的细胞死亡。这种保护作用与显著抑制JP - 8诱导的caspase - 3激活和线粒体膜电位丧失有关。3 - 氨基苯甲酰胺抑制JP - 8诱导的聚（ADP - 核糖）聚合酶激活并不能保护细胞免受JP - 8毒性的影响。总之，这些结果表明硫醇抗氧化剂在挽救细胞免受JP - 8诱导的细胞死亡方面非常有效，并且它们可能为对抗JP - 8毒性的新治疗方法提供基础。
