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Ferroptosis is Involved in Acetaminophen Induced Cell Death

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Pathology & Oncology Research

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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Acknowledgments

This work was financially supported by National Scientific Research Fund grant (OTKA 105416), MedinProt National Excellence foundation and by the New Széchenyi Development Plan (TÁMOP-4.2.1/B-09/1/KMR-2010-0002). Tamás Lőrincz is a Gedeon Richter Plc Talentum fellowship recipient.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Applied Biotechnology and Food Science, Laboratory of Biochemistry and Molecular Biology, Budapest University of Technology and Economics, 1111 , Szent Gellért tér 4., Budapest, Hungary

    Tamás Lőrincz & András Szarka

  2. Department of Functional Pharmacology, Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary

    Katalin Jemnitz

  3. Department of Medical Chemistry, Molecular Biology and Pathobiochemistry Pathobiochemistry, Research Group of Hungarian Academy of Sciences and Semmelweis University, 1444, Budapest, , POB 260, Hungary

    Tamás Kardon & József Mandl

  4. Pathobiochemistry Research Group of Hungarian Academy of Sciences and Semmelweis University, 1444, P.O. Box 260, Budapest, Hungary

    András Szarka

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  1. Tamás Lőrincz
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  2. Katalin Jemnitz
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  3. Tamás Kardon
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  4. József Mandl
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Correspondence to András Szarka.

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Lőrincz, T., Jemnitz, K., Kardon, T. et al. Ferroptosis is Involved in Acetaminophen Induced Cell Death. Pathol. Oncol. Res. 21, 1115–1121 (2015). https://doi.org/10.1007/s12253-015-9946-3

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  • DOI: https://doi.org/10.1007/s12253-015-9946-3

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