Sertraline induces endoplasmic reticulum stress in hepatic cells
Sertraline induces endoplasmic reticulum stress in hepatic cells
复制标题
DOI：
10.1016/j.tox.2014.05.007
复制
发表时间：
2014-08-01
期刊：
影响因子：
4.5
通讯作者：
Guo, Lei
中科院分区：
文献类型：
--
作者：
Chen, Si;Xuan, Jiekun;Guo, Lei
舍曲林用于治疗抑郁症，也用于治疗恐慌症、强迫症和创伤后应激障碍。以前，我们已经证明舍曲林引起肝细胞毒性，线粒体功能障碍和细胞凋亡的潜在机制。在这项研究中，我们使用芯片和其他生化和分子分析，以确定内质网（ER）应激作为一种新的分子机制。HepG 2细胞暴露于舍曲林，并进行全基因组基因表达微阵列分析。通路分析表明，ER应激是受显著影响的生物学变化之一。我们通过实时PCR和Western印迹证实了ER应激标记物的表达增加。典型的ER应激标志物如PERK、IRE 1 α和CHOP的表达显著增加。为了更好地研究ER应激介导的药物诱导的肝毒性，我们建立了体外系统，用于定量和有效地监测ER应激，使用高斯荧光素酶（Gluc）和分泌型碱性磷酸酶（SEAP）作为ER应激报告。这些体外系统使用众所周知的ER应激诱导剂进行了验证。在这两种报告基因检测中，舍曲林抑制Gluc和SEAP的分泌。此外，我们证明舍曲林诱导的细胞凋亡是偶联到ER应激和4-苯基丁酸，一种有效的ER应激抑制剂，细胞凋亡的影响被衰减。此外，我们发现MAP 4K 4-JNK信号通路参与了舍曲林诱导的内质网应激过程。综上所述，我们证明了内质网应激是舍曲林诱导肝毒性的机制。出版社：Elsevier爱尔兰Ltd.
Sertraline is used for the treatment of depression, and is also used for the treatment of panic, obsessive-compulsive, and post-traumatic stress disorders. Previously, we have demonstrated that sertraline caused hepatic cytotoxicity, with mitochondrial dysfunction and apoptosis being underlying mechanisms. In this study, we used microarray and other biochemical and molecular analyses to identify endoplasmic reticulum (ER) stress as a novel molecular mechanism. HepG2 cells were exposed to sertraline and subjected to whole genome gene expression microarray analysis. Pathway analysis revealed that ER stress is among the significantly affected biological changes. We confirmed the increased expression of ER stress makers by real-time PCR and Western blots. The expression of typical ER stress markers such as PERK, IRE1 alpha, and CHOP was significantly increased. To study better ER stress-mediated drug-induced liver toxicity; we established in vitro systems for monitoring ER stress quantitatively and efficiently, using Gaussia luciferase (Gluc) and secreted alkaline phosphatase (SEAP) as ER stress reporters. These in vitro systems were validated using well-known ER stress inducers. In these two reporter assays, sertraline inhibited the secretion of Gluc and SEAP. Moreover, we demonstrated that sertraline-induced apoptosis was coupled to ER stress and that the apoptotic effect was attenuated by 4-phenylbutyrate, a potent ER stress inhibitor. In addition, we showed that the MAP4K4-JNK signaling pathway contributed to the process of sertraline-induced ER stress. In summary, we demonstrated that ER stress is a mechanism of sertraline-induced liver toxicity. Published by Elsevier Ireland Ltd.