Role of apoptosis in acetaminophen hepatotoxicity

Abstract

Acetaminophen overdose causes liver injury by mechanisms involving glutathione depletion, oxidative stress and mitochondrial dysfunction. The role of apoptosis in acetaminophen-induced cell killing is still controversial. Here, our aim was to evaluate the mitochondrial permeability transition (MPT) as a key factor in acetaminophen-induced necrotic and apoptotic killing of primary cultured mouse hepatocytes. Acetaminophen (10 micromol/L) induced necrotic killing in approximately 50% of hepatocytes after 6 h and cyclosporin A (CsA), MPT inhibitor, temporarily decreased necrotic killing after 6 h, but cytoprotection was lost after 16 h. Confocal microscopy revealed mitochondrial depolarization and inner membrane permeabilization at approximately 4.5 h after acetaminophen. CsA delayed these changes indicative of the MPT to about 11 h after acetaminophen. TUNEL labeling and caspase 3 activation also increased after acetaminophen. Fructose (20 mmol/L, an ATP-generating glycolytic substrate) plus glycine (5 mmol/L, a membrane stabilizing amino acid) prevented nearly all necrotic cell killing but paradoxically increased apoptosis. In conclusion, acetaminophen induces the MPT and ATP-depletion-dependent necrosis or caspase-dependent apoptosis as determined, in part, by ATP availability from glycolysis.

Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

“…The level of APAP covalent binding was not significantly different in fasted and fed mice. As seen in vitro, the basal level of hepatic ATP was increased by predosing APAP-treated fasted mice with glucose and glycine (45), and apoptosis was observed in these animals. Moreover, the levels of serum markers used to quantify necrosis also decreased after glucose/glycine coadministration.…”

Evaluation of Three-Dimensional Cultured HepG2 Cells in a Nano Culture Plate System: an In Vitro Human Model of Acetaminophen Hepatotoxicity

“…It has been reported that knockout mice of ASK-1, JNK1, JNK2, or AIF gene showed low hepatotoxicity against APAP injection (40). In addition, pharmacological inhibition of JNK or MPT using SP600125 or CyA, respectively, showed marked inhibition of hepatotoxicity induced by APAP in mice (40,41). Therefore, these molecules and events may play an important part in the development of cellular injury in APAP-induced hepatotoxicity.…”

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“…In agreement with our results some authors found that paracetamol induced necrotic and apoptotic changes in hepatocytes via initiation of the mitochondrial permeability transition. They proved that ATP synthesis by glycolysis led to switch between necrosis and apoptosis in liver cells by Kon et al 22 . Compounds C and D exhibited less degree of affection especially C. Some of the hepatic lobules appeared more or less similar to the control group while others showed signs of degeneration.…”