Intracellular Signaling Mechanisms of Acetaminophen-Induced Liver Cell Death

摘要: Acetaminophen hepatotoxicity is the leading cause of drug-induced liver failure. Despite substantial efforts in past, mechanisms acetaminophen-induced cell injury are still incompletely understood. Recent advances suggest that reactive metabolite formation, glutathione depletion, and alkylation proteins, especially mitochondrial critical initiating events for toxicity. Bcl-2 family members Bax Bid then form pores outer membrane release intermembrane e.g., apoptosis-inducing factor (AIF) endonuclease G, which translocate to nucleus initiate chromatin condensation DNA fragmentation, respectively. Mitochondrial dysfunction, due covalent binding, leads formation oxygen peroxynitrite, trigger permeability transition collapse potential. In addition diminishing capacity synthesize ATP, G AIF further released. Endonuclease together with an activated nuclear Ca2+,Mg2+-dependent endonuclease, degradation, thereby preventing recovery regeneration. Disruption Ca2+ homeostasis also activation intracellular proteases, calpains, can proteolytically cleave structural proteins. Thus, multiple including massive dysfunction ATP extensive modification proteins contribute development oncotic necrotic death after acetaminophen overdose. Based on recognition temporal sequence interdependency these mechanisms, it appears most promising therapeutically target either event (metabolic activation) or central propagating (mitochondrial peroxynitrite formation) prevent death.