Ferroptosis is Involved in Acetaminophen Induced Cell Death

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1115-1121
Number of pages7
JournalPathology and Oncology Research
Volume21
Issue number4
DOIs
Publication statusPublished - May 12 2015

Fingerprint

Acetaminophen
Cell Death
Hepatocytes
Apoptosis
Cytochrome P-450 CYP2E1
Antipyretics
Autophagy
Hep G2 Cells
Caspases
Analgesics
Molecular Biology
Cell Survival
Necrosis
Phosphotransferases
ferrostatin-1
N-acetyl-4-benzoquinoneimine
Enzymes

Keywords

  • Acetaminophen
  • Ferroptosis
  • Glutathione
  • Hepatotoxicity
  • Necroptosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pathology and Forensic Medicine

Cite this

Ferroptosis is Involved in Acetaminophen Induced Cell Death. / Lőrincz, Tamás; Jemnitz, K.; Kardon, T.; Mandl, J.; Szarka, A.

In: Pathology and Oncology Research, Vol. 21, No. 4, 12.05.2015, p. 1115-1121.

Research output: Contribution to journalArticle

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