Acetaminophen Hepatotoxicity

Abstract

Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as a clinical antidote. However, more recently, substantial progress was made in further elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown. The ensuing matrix swelling causes the release of intermembrane proteins such as endonuclease G, which translocate to the nucleus and induce DNA fragmentation. These pathophysiological signaling mechanisms can be additionally modulated by removing damaged mitochondria by autophagy and replacing them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory response. Although recruitment of inflammatory cells is necessary for removal of cell debris in preparation for regeneration, these cells have the potential to aggravate the injury. This review touches on the newest insight into the intracellular mechanisms of APAP-induced cells death and the resulting inflammatory response. Furthermore, it discusses the translation of these findings to humans and the emergence of new therapeutic interventions.

Functional modulation of liver mitochondria in lipopolysaccharide/drug co-treated rat liver injury model

“…Although the results obtained using this experimental animal model and in the human clinical setting have broadly been consistent with respect to the DILI risk associated with particular drugs, the model differs from humans in several respects. For example, the injury occurs within 24 hr of drug administration and liver histology is characterized by an infiltration of neutrophils in this animal model (Ramachandran and Jaeschke, 2019), whereas clinical DILI is generally characterized by delayed onset (Wang et al, 2018) and mononuclear leukocyte infiltration. However, even though the model does not perfectly mimic DILI in humans, it is considered useful for the screening of candidate drugs for potential liver toxicity and/or exploring the pathologic mechanism of any liver injury induced.…”

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

“…Acetaminophen (APAP, also known as paracetamol) is one of the most widely used analgesic or antipyretic drugs, and is safe when used at therapeutic doses. However, overdose of APAP causes liver damage in a dosedependent manner, and in severe cases, results in acute liver failure 1 . Once acute liver failure occurs, liver transplantation is the only established life-saving procedure 2 .…”

“…Thus, additional therapeutic approaches for APAP-induced hepatotoxicity are required and research is needed to understand the underlying mechanism. An enormous number of studies on the mechanism underlying APAP-induced hepatotoxicity have been reported so far, and they have clarified the mechanism to some extent 1 . For instance, APAP is metabolized to N-acetyl-p-benzoquinone imine (NAPQI) in hepatocytes by cytochrome P450 2E1 (CYP2E1) 4 .…”

Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH)

“…Acetaminophen overdose toxicity is the most common cause of acute liver failure and occurs because an acetaminophen metabolite (N-Acetyl-p-benzoquinone imine) causes glutathione depletion and mitochondrial protein adducts which in turn lead to elevated oxidant stress and GSK-3β, JNK, and Bax signaling. The ensuing mPT, ROS formation, and cell death can be substantially alleviated by CsA, NIM811, or Cyp D knockout although the degree of protection also depends on acetaminophen dose [158][159][160]. Chronic alcohol consumption in rodents was found to increase Cyp D, cause mitochondrial swelling, and sensitize mitochondria to mPT in the liver, although mitochondrial depolarization and hepatocyte apoptosis were not sensitive to CsA or Cyp D knockout [161][162][163].…”