title: Sertraline induces endoplasmic reticulum stress in hepatic cells.
abstract: 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, IRE1α, 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.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. FDA, Jefferson, AR 72079, USA.
authors.forename: Si
authors.initials: S
authors.lastname: Chen
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. FDA, Jefferson, AR 72079, USA.
authors.forename: Jiekun
authors.initials: J
authors.lastname: Xuan
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. FDA, Jefferson, AR 72079, USA.
authors.forename: Letha
authors.initials: L
authors.lastname: Couch
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. FDA, Jefferson, AR 72079, USA; Biological Sciences, University of Maryland, Baltimore, MD 21250, USA.
authors.forename: Advait
authors.initials: A
authors.lastname: Iyer
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. FDA, Jefferson, AR 72079, USA.
authors.forename: Yuanfeng
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Immunology and Internal Medicine, Microarray Core Facility, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. FDA, Jefferson, AR 72079, USA. Electronic address: Lei.Guo@fda.hhs.gov.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D046228:Microarray Analysis; D016133:Polymerase Chain Reaction; D012326:RNA Splicing / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000494:pharmacology*
chemical_list: D000469:Alkaline Phosphatase; D015415:Biomarkers; D053148:Caspase 3; D053179:Caspase 7; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline
keywords: Apoptosis; Drug-induced liver toxicity; Endoplasmic reticulum stress; MAPK pathway; Reporter gene assay; Sertraline