Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure

Acetaminophen (APAP) overdose is a common cause of drug-induced acute liver failure. Although hepatocyte cell death is considered to be the critical event in APAP-induced hepatotoxicity, the underlying mechanism remains unclear. Ferroptosis is a newly discovered type of cell death that is caused by...

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Bibliographic Details
Published in:Cell death & disease Vol. 11; no. 2; pp. 144 - 16
Main Authors: Yamada, Naoya, Karasawa, Tadayoshi, Kimura, Hiroaki, Watanabe, Sachiko, Komada, Takanori, Kamata, Ryo, Sampilvanjil, Ariunaa, Ito, Junya, Nakagawa, Kiyotaka, Kuwata, Hiroshi, Hara, Shuntaro, Mizuta, Koichi, Sakuma, Yasunaru, Sata, Naohiro, Takahashi, Masafumi
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 24.02.2020
Springer Nature B.V
Nature Publishing Group
Subjects:
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Acetaminophen
alpha-Tocopherol - pharmacology
Analgesics
Animal models
Animals
Antibodies
Antioxidants - pharmacology
Apoptosis
Arachidonic acid
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell death
Coenzyme A Ligases - genetics
Coenzyme A Ligases - metabolism
Cyclohexylamines - pharmacology
Cyclooxygenase 2 - genetics
Cyclooxygenase 2 - metabolism
Deferoxamine
Deferoxamine - pharmacology
Disease Models, Animal
Drug overdose
Fatty acids
Fatty Acids, Omega-6 - metabolism
Ferroptosis
Ferroptosis - drug effects
Glutathione
Hepatocytes
Hepatocytes - drug effects
Hepatocytes - metabolism
Hepatocytes - pathology
Hepatotoxicity
Homeostasis
Humans
Immunology
Iron Chelating Agents - pharmacology
Life Sciences
Lipid peroxidation
Lipid Peroxidation - drug effects
Lipids
Liver
Liver - drug effects
Liver - metabolism
Liver - pathology
Liver failure
Liver Failure, Acute - chemically induced
Liver Failure, Acute - metabolism
Liver Failure, Acute - pathology
Liver Failure, Acute - prevention & control
Mass spectroscopy
Mice, Inbred C57BL
Mice, Knockout
mRNA
Overdose
Oxidation
Oxidation-Reduction
Phenylenediamines - pharmacology
Polyunsaturated fatty acids
Supplements
Therapeutic applications
Vitamin E
ISSN:2041-4889, 2041-4889
Online Access:Get full text
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Summary:Acetaminophen (APAP) overdose is a common cause of drug-induced acute liver failure. Although hepatocyte cell death is considered to be the critical event in APAP-induced hepatotoxicity, the underlying mechanism remains unclear. Ferroptosis is a newly discovered type of cell death that is caused by a loss of cellular redox homeostasis. As glutathione (GSH) depletion triggers APAP-induced hepatotoxicity, we investigated the role of ferroptosis in a murine model of APAP-induced acute liver failure. APAP-induced hepatotoxicity (evaluated in terms of ALT, AST, and the histopathological score), lipid peroxidation (4-HNE and MDA), and upregulation of the ferroptosis maker PTGS2 mRNA were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1). Fer-1 treatment also completely prevented mortality induced by high-dose APAP. Similarly, APAP-induced hepatotoxicity and lipid peroxidation were prevented by the iron chelator deferoxamine. Using mass spectrometry, we found that lipid peroxides derived from n-6 fatty acids, mainly arachidonic acid, were elevated by APAP, and that auto-oxidation is the predominant mechanism of APAP-derived lipid oxidation. APAP-induced hepatotoxicity was also prevented by genetic inhibition of acyl-CoA synthetase long-chain family member 4 or α-tocopherol supplementation. We found that ferroptosis is responsible for APAP-induced hepatocyte cell death. Our findings provide new insights into the mechanism of APAP-induced hepatotoxicity and suggest that ferroptosis is a potential therapeutic target for APAP-induced acute liver failure.
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ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-020-2334-2