Intracellular Signaling Mechanisms of Acetaminophen-Induced Liver Cell Death

Abstract

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

Chronic intermittent hypoxia predisposes to liver injury†

“…Acetaminophen is a hepatic prooxidant that depletes glutathione. 43 Therefore, synergy between acetaminophen and CIH could be a result of diminished antioxidant defense. Thus, CIH may predispose to fulminant hepatocellular injury in the presence of the second insult.…”

Role of free radicals in liver diseases

“…4). Oxidant stress of mitochondria triggers the mitochondrial membrane permeability transition pore, loss of the membrane potential of the mitochondria, depletion of ATP, and release of intermembrane proteins that are responsible for the typical nuclear DNA fragmentation of APAP-induced cell death [67]. We have found that antioxidants, such as silymarin [68], protect the liver of rats intoxicated with APAP [69].…”

“…In the past, researchers studying the toxic action mechanism of APAP focused on metabolic activation of the drug, depletion of glutathione, and covalent binding of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) to cellular proteins as the main cause of hepatic cell death [66]. More recently, it was discovered that covalent binding is not sufficient to kill liver cells but is a signal for the toxicity that requires amplification in the cell [67]. Intracellular steps critical for cell death include mitochondrial dysfunction and, importantly, the formation of ROS and peroxynitrite (Fig.…”

Inhibitory effects of Schisandra chinensis on acetaminophen-induced hepatotoxicity

“…Kon et al (15) found that mobilization of chelatable iron from lysosomes was key in acetaminophen hepatotoxicity. The formation of reactive oxygen species (ROS) increases following acetaminophen exposure, and agents that augment antioxidant defenses and scavenge ROS protect against acetaminophen toxicity in vitro and in vivo (16). In the present study, the mechanism and effect of Schisandra chinensis on acetaminophen-induced hepatotoxicity and liver failure in mice was evaluated by observing the extent of lysosomal disruption and ROS release.…”