Selective Protein Covalent Binding and Target Organ Toxicity

Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-? gene knockout mice

“…Thus, it is difficult to interpret the significance of the apparent decrease observed only at 8 hours. By contrast, binding to 58-kD ABP, which is better correlated with APAP toxicity, 4 was similar in the wild-type and the knockout mice, which is consistent with the similarity in the severity of APAP toxicity and provides further evidence that there was no apparent diminution in the net availability of APAP electrophiles.…”

“…Table 1 demonstrates that in TNF/LT-␣ Ϫ/Ϫ mice neither p-nitrophenol hydroxylase activity nor ethoxyresorufin-O-deethylase activity was different from those in wild-type animals, indicating that the basal levels of CYP2E1 and CYP1A2 remained unaffected in the knockout animals. 4,1998 indirect measure for the extent of formation of this electrophilic metabolite. Therefore, we monitored the time-dependent decline of hepatic GSH levels in both wild-type and TNF/LT-␣ Ϫ/Ϫ mice that were intraperitoneally injected with APAP (400 mg/kg) and killed at 0, 30, or 60 minutes posttreatment.…”

“…Despite considerable research, the mechanisms responsible for acetaminophen (APAP) hepatotoxicity in humans and experimental animals are not yet fully understood (for reviews see Nelson, 1 Vermeulen et al, 2 Hinson et al, 3 and Cohen et al 4 ). Metabolic activation 5 of APAP and subsequent binding of its electrophilic metabolite N-acetyl-p-benzoquinone imine (NAPQI) to glutathione (GSH) and, after GSH depletion, to nucleophilic protein targets 6 seems to be necessary but is not sufficient for toxicity.…”

“…Metabolic activation 5 of APAP and subsequent binding of its electrophilic metabolite N-acetyl-p-benzoquinone imine (NAPQI) to glutathione (GSH) and, after GSH depletion, to nucleophilic protein targets 6 seems to be necessary but is not sufficient for toxicity. 4,7 Several other mechanistic components of parenchymal cell injury have been proposed, including the generation of reactive oxygen species, [8][9][10][11] mitochondrial dysfunction [12][13][14] followed by disruption of calcium homeostasis and energy supply, or induction of apoptosis. 15 Apart from these events occurring intracellularly in parenchymal cells after APAP exposure, an important role has been attributed to nonparenchymal cells.…”

Highlight report: acetaminophen hepatotoxicity

“…Much effort has been invested to gain a better understanding of the molecular mechanisms of APAP hepatotoxicity (Saito et al 2010;Kon et al 2004;Hwang et al 2015;Sjogren et al 2014;Schyschka et al 2013;Singh et al 2013) and to identify biomarkers of APAP overdose (McGill et al 2014;Beger et al 2015). APAP is known to be metabolically activated to the reactive N-acetyl-p-benzoquinone imine (NAPQI), which forms protein adducts including mitochondrial proteins leading to mitochondrial oxidative stress (Ramachandran et al 2013;Cohen et al 1997). As a consequence c-jun N-terminal kinase is translocated to the mitochondria, which enhances generation of reactive oxygen species (Ramachandran et al 2013;Hanawa et al 2008;Saito et al 2010).…”