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• W2078220586 abstract "Acetaminophen (APAP) or paracetamol hepatotoxicity is the most frequent cause of acute liver failure in the United States and many European countries. Animal studies have shown that the small fraction of the dose that is metabolized by cytochrome P-450 enzymes leads to formation of a reactive metabolite (NAPQI), which can be conjugated with glutathione but also binds to proteins. Although protein adduct formation, especially in mitochondria, correlates with cell toxicity, it is insufficient to trigger cell death. Instead, the initial mitochondrial dysfunction causes oxidant stress, which induces activation of MAP kinases ultimately causing c-jun-N-terminal kinase (JNK) phosphorylation and translocation to the mitochondria where P-JNK amplifies the oxidant stress and peroxynitrite formation. The enhanced mitochondrial oxidant stress together with translocation of lysosomal iron causes the membrane permeability transition pore (MPT) opening, resulting in the collapse of the membrane potential and cessation of ATP synthesis. The MPT also leads to mitochondrial matrix swelling, which causes the rupture of the outer membrane with release of endonuclease G and apoptosis-inducing factor and translocation to the nucleus, where these enzymes induce DNA fragmentation. The loss of mitochondrial function and the nuclear DNA fragmentation are key events in APAP-induced cell necrosis. The massive cell necrosis leads to the release of damage-associated molecular patterns, which, through activation of toll-like receptors on macrophages, trigger cytokine formation and leukocyte activation and recruitment. However, the preponderance of the experimental evidence suggests that this inflammatory response has limited effect on the injury but results in the preparation of the regenerative or repair phase. Although there has been enormous progress in understanding mechanisms of APAP-induced liver injury in animals, the insight into the human pathophysiology is more limited. However, in both human hepatocytes and in overdose patients, there is emerging evidence for the formation of protein adducts, the central role of mitochondrial damage and nuclear DNA fragmentation in necrotic cell death, and the repair function of inflammatory cells.1Jaeschke H. McGill M.R. Ramachandran A. Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity.Drug Metab Rev. 2012; 44: 88-106Crossref PubMed Scopus (658) Google Scholar, 2Jaeschke H. Williams C.D. Ramachandran A. Bajt M.L. Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity.Liver Int. 2012; 32: 8-20Crossref PubMed Scopus (345) Google Scholar, 3McGill M.R. Sharpe M.R. Williams C.D. et al.The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation.J Clin Invest. 2012; 122: 1574-1583Crossref PubMed Scopus (534) Google Scholar H. Jaeschke: grant/research support from McNeil Consumer Health; consultant for McNeil Consumer Health." @default.
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• W2078220586 date "2013-08-01" @default.
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• W2078220586 title "Acetaminophen-induced liver injury in experimental animals and humans" @default.
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• W2078220586 doi "https://doi.org/10.1016/j.clinthera.2013.07.367" @default.
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