Platelet-activating factor (PAF) involvement in acetaminophen-induced liver toxicity and regeneration.
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.
Grypioti
A D
AD
Department of Experimental Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, GR 11527 Athens, Greece.
Theocharis
S E
SE
Papadimas
G K
GK
Demopoulos
C A
CA
Papadopoulou-Daifoti
Z
Z
Basayiannis
A C
AC
Mykoniatis
M G
MG
D000082:Acetaminophen / Q000633:toxicity*; D000123:Acetyltransferases / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D008940:Mitotic Index; D010972:Platelet Activating Factor / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013937:Thymidine Kinase / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D018712:Analgesics, Non-Narcotic; D010972:Platelet Activating Factor; D000082:Acetaminophen; D004247:DNA; D000123:Acetyltransferases; C046035:1-alkylglycerophosphocholine acetyltransferase; D013937:Thymidine Kinase