Postnatal mice have low susceptibility to paracetamol toxicity.
The hepatotoxicity of paracetamol in mice of 2, 3, 8-10, 24-26, 32-34, and 52-54 wk of age was determined by lethality data, histopathologic examination of the liver, and appearance of glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase activities in the plasma over an 8-h exposure period. At a dose of 300 mg/kg, there was evidence of hepatocytic necrosis and transaminase leakage in the 32- to 34- and 52- to 54-wk-old mice, but lethality was only recorded in the oldest age group. At 500 mg/kg, paracetamol produced 30% lethality in 3-wk-old mice and between 50 and 90% lethality in the adult age groups. There was histologic evidence of hepatocytic necrosis at all of these ages and its extent increased with age. Similarly, there were increases in plasma transaminases in each of these age groups. However, in 2-wk-old mice there was no lethality, no hepatocytic necrosis, and no increase in plasma transaminases. The lack of susceptibility of 2-wk-old mice to paracetamol toxicity was not due to immaturity of the cytochrome P-450 enzymes responsible for metabolism of paracetamol to its reactive metabolite (N-acetyl-p-benzoquinone imine). In fact, the activity of this enzyme pathway in 2-wk-old mice was greater than that in adults. The partial clearance of the glutathione-derived metabolites of paracetamol after a nontoxic (50 mg/kg) dose was 80% greater in 2-wk-old mice than in 8- to 10-wk-old mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Adamson
G M
GM
Departments of Pharmacology, University of Western Australia, Nedlands.
Papadimitriou
J M
JM
Harman
A W
AW
D000082:Acetaminophen / Q000493:pharmacokinetics / Q000633:toxicity*; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D016227:Benzoquinones / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000503:physiopathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004198:Disease Susceptibility; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007097:Imines / Q000378:metabolism; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice / Q000254:growth & development*; D009336:Necrosis
D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; C028473:N-acetyl-4-benzoquinoneimine; D005978:Glutathione