Role of Pyroptosis in Acetaminophen-Induced Hepatotoxicity

Abstract

Acetaminophen (APAP) is a widely used pain reliever that can cause liver injury or liver failure in response to an overdose. Understanding the mechanisms of APAP-induced cell death is critical for identifying new therapeutic targets. In this respect it was hypothesized that hepatocytes die by oncotic necrosis, apoptosis, necroptosis, ferroptosis and more recently pyroptosis. The latter cell death is characterized by caspase-dependent gasdermin cleavage into a C-terminal and an N-terminal fragment, which forms pores in the plasma membrane. The gasdermin pores can release potassium, interleukin-1β (IL-1β), IL-18, and other small molecules in a sublytic phase, which can be the main function of the pores in certain cell types such as inflammatory cells. Alternatively, the process can progress to full lysis of the cell (pyroptosis) with extensive cell contents release. This review discusses the experimental evidence for the involvement of pyroptosis in APAP hepatotoxicity as well as the arguments against pyroptosis as a relevant mechanism of APAP-induced cell death in hepatocytes. Based on the critical evaluation of the currently available literature and understanding of the pathophysiology, it can be concluded that pyroptotic cell death is unlikely to be a relevant contributor to APAP-induced liver injury.

6-Hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline Demonstrates Anti-Inflammatory Properties and Reduces Oxidative Stress in Acetaminophen-Induced Liver Injury in Rats

“…Understanding the mechanisms of AAP-induced cell death is essential for identifying new therapeutic targets. It has been hypothesized that hepatocytes die through oncotic necrosis, apoptosis, necroptosis, ferroptosis, and pyroptosis [4]. Necrosis is widely believed to be the primary form of cell death in AAP-induced hepatotoxicity [3].…”

“…This metabolite is detoxified by conjugating it with glutathione (GSH). After hepatic GSH depletion, NAPQI binds to cellular proteins and causes toxicity [4,5]. The mitochondrial proteins, particularly complexes I and II of the mitochondrial electron transport chain, are the main targets of NAPQI in hepatocytes; this leads to electron leakage of oxygen and the formation of superoxide radicals.…”

Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury

“…Third, GSDMD and gasdermin E KO mice are not protected against cell death (111,112). Fourth, the expression of proteins needed to cause pyroptosis are predominantly located in liver macrophages not in hepatocytes, which are the main target of APAP toxicity (113).…”

The Protective Effect of <i>Moringa oleifera</i> Leaves Extract on Paracetamol Hepatotoxicity in Male Rats

“…Activation of the MAPK cascade, particularly c-Jun N-terminal kinase (JNK), intensifies oxidative stress triggered by PCM adducts linked to mitochondrial proteins. Cell death occurs as a result of matrix elongation, opening of the mitochondrial membrane permeability transition pore (MPTP), and an increase in reactive oxygen species and peroxynitrite produced by JNK translocation to the mitochondria [22,23].…”