Bio: Hartmut Jaeschke is University Distinguished Professor in the Dept of Pharmacology, Toxicology, and Therapeutics at the University of Kansas Medical Center, Kansas City, USA. He received his PhD degree in toxicology from the University of Tübingen, Germany, in 1983, and held faculty positions at Baylor College of Medicine, Houston, TX, the University of Arkansas for Medical Sciences, Little Rock, AR, and at the University of Arizona, Tucson, AZ, before joining KUMC in 2006. He has published more than 520 peer-reviewed manuscripts, invited reviews, and book chapters in the areas of liver toxicology and liver pathophysiology (“h-factor 128”; >68,000 citations; Google Scholar). He served on >25 Editorial Boards of most major liver and toxicology journals and he is currently Assoc. Editor of Toxicological Sciences and Editor-in-Chief of Livers. He is the recipient of the Translational Impact Award (2019) from SOT. His major research interests include basic mechanisms and translational aspects of drug-induced hepatotoxicity. 

Abstract: An overdose of acetaminophen (APAP) can cause hepatotoxicity and acute liver failure. The toxicity is initiated by the formation of a reactive metabolite (NAPQI) which binds to mitochondrial proteins and generates a mild oxidant stress in the cytosol thereby activating a MAP kinase cascade resulting in the activation (phosphorylation of c-jun N-terminal kinase (JNK). P-JNK translocates to the mitochondria and binds to the anchor protein Sab, which then triggers a further impairment of the electron transport chain with amplification of the oxidant stress, in the mitochondrial matrix and formation of peroxynitrite. Whereas the oxidant stress maintains the JNK activation cycle, peroxynitrite nitrates proteins and causes oxidative damage to mtDNA ultimately leading to the mitochondrial permeability transition pore opening and cessation of ATP synthesis. In addition, intermembrane proteins (e.g. endonuclease G) are released from mitochondria, translocate to the nucleus and induce DNA fragmentation as the point of no-return to necrotic cell death. The clinically approved antidote N-acetylcysteine (NAC) promotes the cytosolic synthesis of GSH, which can scavenge NAPQI during APAP metabolism and limit protein binding. In addition, after uptake into mitochondria, NAC can scavenge peroxynitrite. Thus, NAC is highly effective early after APAP ingestion, however, it shows limited efficacy at later time points. Recently, fomepizole, an antidote against toxic alcohols was recognized as potential novel therapeutic against APAP toxicity. Fomepizole inhibits Cyp2E1 and prevents NAPQI formation; in addition, it is an inhibitor of JNK and prevents the mitochondrial oxidant stress. Fomepizole is more effective than NAC, has a wider therapeutic window, less side effects and does not inhibit regeneration. Fomepizole is currently undergoing clinical evaluation in a phase III trial.

Reference: Jaeschke H, Ramachandran A. Acetaminophen hepatotoxicity: Paradigm for under-standing mechanisms of drug-induced liver injury. Annu Rev Pathol. 19: 453-478, 2024.