Sertraline, an Antidepressant, Induces Apoptosis in Hepatic Cells Through the Mitogen-Activated Protein Kinase Pathway

Abstract

Sertraline is generally used for the treatment of depression and is also approved for the treatment of panic, obsessive-compulsive, and posttraumatic stress disorders. Previously, using rat primary hepatocytes and isolated mitochondria, we demonstrated that sertraline caused hepatic cytotoxicity and mitochondrial impairment. In the current study, we investigated and characterized molecular mechanisms of sertraline toxicity in human hepatoma HepG2 cells. Sertraline decreased cell viability and induced apoptosis in a dose- and time-dependent manner. Sertraline activated the intrinsic checkpoint protein caspase-9 and caused the release of cytochrome c from mitochondria to cytosol; this process was Bcl-2 family dependent because antiapoptotic Bcl-2 family proteins were decreased. Pretreatment of the HepG2 cells with caspase-3, caspase-8, and caspase-9 inhibitors partially but significantly reduced the release of lactate dehydrogenase, indicating that sertraline-induced apoptosis is mediated by both intrinsic and extrinsic apoptotic pathways. Moreover, sertraline markedly increased the expression of tumor necrosis factor (TNF) and the phosphorylation of JNK, extracellular signal-regulated kinase (ERK1/2), and p38. In sertraline-treated cells, the induction of apoptosis and cell death was shown to be the result of activation of JNK, but not ERK1/2 or p38 in the mitogen-activated protein kinase (MAPK) pathway. Furthermore, silencing MAP4K4, the upstream kinase of JNK, attenuated both apoptosis and cell death caused by sertraline. Taken together, our findings suggest that sertraline induced apoptosis in HepG2 cells at least partially via activation of the TNF-MAP4K4-JNK cascade signaling pathway.

Comparison of the Anti-tumor Effects of Selective Serotonin Reuptake Inhibitors as Well as Serotonin and Norepinephrine Reuptake Inhibitors in Human Hepatocellular Carcinoma Cells

“…33) A recent report suggested that sertraline induces apoptosis in HepG2 cells through the MAPK pathway. 15) Based on these reports, it is suggested that apoptosis through activation of the caspase pathway is involved in sertraline-induced toxicity in HepG2 cells.…”

“…Recent reports have suggested that sertraline induces apoptosis in the human HCC cell line HepG2 through the MAPK pathway. 15) Mun et al showed the apoptotic effect of fluoxetine against the HCC cell line Hep3B. 16) However, comparison of anti-tumor effects of SSRIs and SNRIs on HepG2 cells has not been studied.…”

Endoplasmic Reticulum Stress in Drug- and Environmental Toxicant-Induced Liver Toxicity

“…Although it is generally considered safe, acute liver failure due to sertraline use has been documented [91][92][93][94][95][96][97][98][99]. Sertraline was demonstrated to be toxic in primary rat hepatocytes and human HepG2 cells; mitochondrial dysfunction and apoptosis are the underlying mechanisms [100,101]. Besides mitochondrial dysfunction and apoptosis, ER stress was found to contribute to sertraline's liver toxicity (SC and LG, unpublished data).…”

“…Both cell lines showed significantly decreased activity of SEAP or Gluc when treated with the well-known ER stress inducers brefeldin A or thapsigargin. The usefulness of these in vitro systems was demonstrated in a study on ER stress induced by sertraline, an antidepressant drug [101]. It is anticipated that such assays can be used in high-throughput settings to screen drugs for liver toxicity mediated by ER stress.…”

Endoplasmic Reticulum Stress Induction and ERK1/2 Activation Contribute to Nefazodone-Induced Toxicity in Hepatic Cells

“…Recently published studies suggest that by interacting with various signaling pathways, the MAPK signaling cascades play pivotal roles in drug-induced liver toxicity (Beggs et al ., 2015; Chen et al ., 2014d, 2015; Hu et al ., 2016; Poulsen et al ., 2014; Wu et al ., 2015). The MAPK cascade has 3 well-defined arms: extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 (Pearson et al ., 2001).…”