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Cited by 75Drug-Induced Hepatotoxicity and ProtectionCell death mechanisms and regulationImmunotoxicology and immune responses

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

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Chen, Si, Xuan, Jiekun, Wan, Liqing, Lin, Haixia, Couch, Letha, Mei, Nan, Dobrovolsky, Vasily N., Guo, Lei·2014·Toxicological Sciences
DOI 10.1093/toxsci/kft254PMC PMC12376138
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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.

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  • Antidepressants damage normal cells, including osteoblasts, osteoclasts, hepatocytes, etc.

    “(c) antidepressants damage normal cells, including osteoblasts, osteoclasts, hepatocytes, etc [25, 28].”

    From Risk analysis of use of different classes of antidepressants on subsequent dementia: A nationwide cohort study in Taiwan (2017) · cites this paper as [28]

    The Abstract reports that sertraline caused cytotoxicity in rat primary hepatocytes, and the Results show cell damage in human HepG2 liver cells. This supports the hepatocyte example, but the paper does not establish damage to normal osteoblasts or osteoclasts, which are also included in the cited sentence. (LLM, conf=0.84)

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Metadata

Authors
Chen, S., Xuan, J., Wan, L., Lin, H., Couch, L., Mei, N., Dobrovolsky, V. N., & Guo, L.
Affiliations
National Center for Toxicological Research (US)
ORCID
Venue
Toxicological Sciences
Publisher
Oxford University Press (OUP)
Published
2013-11-05
Volume
137
Issue
2
Pages
404-415
ISSN
  • 1096-0929 (ISSN-L)
  • 1096-6080
DOI
10.1093/toxsci/kft254
PMC
PMC12376138
OpenAlex
W2157037483
Cited by
75
References
9
Citations by year
2026: 5 · 2025: 5 · 2024: 10 · 2023: 3 · 2022: 7 · 2021: 2 · 2020: 8 · 2019: 4 · 2018: 6 · 2017: 11 · 2016: 4 · 2015: 6 · 2014: 4
FWCI
3.04
Type
journal article
Language
en
Open access
Locations
  • Toxicological Sciences (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (FD999999)
  • U.S. Food and Drug Administration
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Keywords
sertraline, drug-induced liver injury, apoptosis, MAPK signaling, JNK, MAP4K4, TNF-α, caspase-9, cytochrome c release, Bcl-2 family proteins, intrinsic and extrinsic apoptotic pathways, HepG2 cells, antidepressant side effects
MeSH terms
Antidepressive Agents, Humans, Blotting, Western, Apoptosis, Protein Serine-Threonine Kinases, Cell Culture Techniques, Proto-Oncogene Proteins c-bcl-2, Sertraline, Gene Silencing, MAP Kinase Signaling System, Intracellular Signaling Peptides and Proteins, Membrane Potential, Mitochondrial, Caspase 3, Caspase 7, Caspase 9, Hep G2 Cells, Real-Time Polymerase Chain Reaction

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