Platelet-activating factor (PAF) involvement in acetaminophen-induced liver toxicity and regeneration

Abstract

Acetaminophen-induced toxicity has been attributed to cytochrome P-450-generated metabolites, which covalently modify target proteins. However, the mechanism of liver injury pathogenesis needs to be further elucidated. Platelet-activating factor (PAF) is one of the mediators involved in inflammatory tissue alterations associated with acute liver failure. In this study, alterations in blood PAF levels and the serum activity of PAF-acetylhydrolase (PAF-AH) were investigated over the time course of liver injury and regeneration induced by acetaminophen treatment in rats. The administration of a toxic dose of acetaminophen (3.5 g/kg) in rats caused acute hepatic injury, as evident by alterations of biochemical (serum enzymes: ALT, AST and ALP) and liver histopathological (degree of inflammation and apoptosis) indices between 20 and 40 h post-treatment. The hepatic damage was followed by liver regeneration, made evident by three independent indices ([3H]thymidine incorporation into hepatic DNA, liver thymidine kinase activity and hepatocyte mitotic index), presenting a peak at 72 h. The PAF levels were elevated at 24 and 28 h, presenting a remarkable peak at 32 h post-treatment. PAF-AH activity presented different kinetics to that of PAF. The enzyme activity was relatively low at all time points examined before the rise in PAF activity, peaking later, at 72, 84 and 96 h. Our data demonstrate that PAF is involved in the pathogenesis of acute liver failure and in augmented compensatory liver tissue repair post-acetaminophen treatment. However, the putative role of PAF during liver toxicity and regeneration remains to be established.

The effect of different doses of flumazenil on acetaminophen toxicity in rats

“…This hepatotoxin produces a dose-related centrilobular necrosis in the liver (3,17). Grypioti et al (18) reported that the elevated serum levels of hepatic AST, ALT (indicative of necrosis) and ALP (indicative of cholestasis) activities are in good agreement with the fi rst wave of liver injury observed between 20 and 40 h, and are due to the direct action of APAP on hepatocytes.…”

“…Grypioti et al (18) reported that ALT, AST and ALP values increased and that the liver changed histopathologically (grade of infl ammation and apoptosis). They observed in their rat model that hepatic injury was generated with a toxic dose (3.5 g/ kg) of acetaminophen.…”

Recombinant Platelet-Activating Factor–Acetylhydrolase Attenuates Paracetamol-Induced Liver Oxidative Stress, Injury, and Regeneration

“…However, the effect of rPAF-AH on liver injury caused by APAP has not been determined. We have previously reported that PAF was increased at almost the same time for all biochemical parameters (AST, ALT, and ALP) indicative of liver injury in APAP-treated rats (21). This correlation could be explained by the fact that PAF is considered to be one of the main mediators that cause organ injuries followed by necrosis [44][45][46].…”

“…In a previous study, we demonstrated that PAF is involved in the pathogenesis of acute liver injury and in augmented compensatory liver tissue repair post-APAP treatment [21]. In the present study we evaluated whether enhanced degradation of PAF by increasing PAF-AH levels has any influence on tissue recovery after APAP poisoning.…”

Therapy for acute pancreatitis with platelet-activating factor receptor antagonists

“…PAF has neurological toxicity [8] . It is also involved in etiopathogenesis of type-1 diabetes [9] and liver tissue repair post-acetaminophen treatment [10] .…”