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Ferroptosis is Involved in Acetaminophen Induced Cell Death
Abstract
The recently described form of programmed cell death, ferroptosis can be induced by agents causing GSH depletion or the inhibition of GPX4. Ferroptosis clearly shows distinct morphologic, biochemical and genetic features from apoptosis, necrosis and autophagy. Since NAPQI the highly reactive metabolite of the widely applied analgesic and antipyretic, acetaminophen induces a cell death which can be characterized by GSH depletion, GPX inhibition and caspase independency the involvement of ferroptosis in acetaminophen induced cell death has been investigated. The specific ferroptosis inhibitor ferrostatin-1 failed to elevate the viability of acetaminophen treated HepG2 cells. It should be noticed that these cells do not form NAPQI due to the lack of phase I enzyme expression therefore GSH depletion cannot be observed. However in the case of acetaminophen treated primary mouse hepatocytes the significant elevation of cell viability could be observed upon ferrostatin-1 treatment. Similar to ferrostatin-1 treatment, the addition of the RIP1 kinase inhibitor necrostatin-1 could also elevate the viability of acetaminophen treated primary hepatocytes. Ferrostatin-1 has no influence on the expression of CYP2E1 or on the cellular GSH level which suggest that the protective effect of ferrostatin-1 in APAP induced cell death is not based on the reduced metabolism of APAP to NAPQI or on altered NAPQI conjugation by cellular GSH. Our results suggest that beyond necroptosis and apoptosis a third programmed cell death, ferroptosis is also involved in acetaminophen induced cell death in primary hepatocytes.
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“Acetaminophen has been reported to induce ferroptosis in primary hepatocytes via glutathione depletion [40], suggesting this may be a mechanism of drug-induced toxicity.”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [40]
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Metadata
- Authors
- Lőrincz, T., Jemnitz, K., Kardon, T., Mandl, J., & Szarka, A.
- Affiliations
- Budapest University of Technology and Economics (HU)
- Hungarian Academy of Sciences (HU)
- Semmelweis University (HU)
- Corresponding author
- Szarka, András
- Venue
- Pathology & Oncology Research
- Published
- 2015-05-12
- Volume
- 21
- Issue
- 4
- Pages
- 1115-1121
- ISSN
- 1219-4956 (ISSN-L)
- 1532-2807
- OpenAlex
- W657288929
- Cited by
- 219
- References
- 30
- Citations by year
- 2026: 8 · 2025: 32 · 2024: 29 · 2023: 26 · 2022: 29 · 2021: 24 · 2020: 25 · 2019: 19 · 2018: 9 · 2017: 10 · 2016: 6 · 2015: 1
- FWCI
- 6.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Pathology & Oncology Research (publishedVersion)
- PubMed (publishedVersion)
- Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
- Semmelweis University Repository (Semmelweis University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- ferroptosis, acetaminophen hepatotoxicity, N-acetyl-p-benzoquinone imine, glutathione depletion, GPX4, ferrostatin-1, necrostatin-1, RIP1 kinase, programmed cell death, primary hepatocytes, HepG2 cells, CYP2E1
- MeSH terms
- Acetaminophen, Animals, Cell Survival, Cyclohexylamines, Glutathione, Glutathione Peroxidase, Humans, Imidazoles, Imines, Indoles, Male, Phenylenediamines, Benzoquinones, Cell Death, Apoptosis, Cytochrome P-450 CYP2E1, GTPase-Activating Proteins, Hepatocytes, Cell Line, Tumor, Mice, Hep G2 Cells
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