Postnatal Mice Have Low Susceptibility to Paracetamol Toxicity

Abstract

ABSTRACT. 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. Therefore, despite having greater capacity to generate N-acetyl-p-benzoquinone imine, 2-wk-old mice had no hepatotoxic effects from a dose that killed at least 50% of adult mice. Factors that relate to the detoxification of N-acetyl-p-benzoquinone imine in the liver are implicated in the lesser susceptibility of postnatal mice to paracetamol toxicity. (Pediatr Res 29: 496-499,1991) to detoxify this metabolite by conjugation to GSH (2-4), and a number of incompletely understood processes initiated by NAPQI that lead to cell death (5).It is generally accepted that children are less susceptible to paracetamol toxicity than are adults (6). This impression has developed from clinical observations that the incidence of overdose toxicity is less in the young (7). However, the scientific basis for this has yet to be confirmed.Our present study is aimed at examining developmental aspects of the susceptibility of mice to paracetamol toxicity. Previous work in this field has been conflicting, with some research indicating that young mice (8) and rats (9) are more susceptible to high doses of paracetamol. However, the majority of findings indicate that during the postnatal period young rats and mice are less susceptible to toxicity (10, II). These latter observations have been attributed to the immaturity of the cytochrome P-450-linked mixed function oxidase enzymes in the postnatal period and the consequent decrease in the rate of activation of paracetamol to NAPQI (10) or to a lack of susceptibility to hepatotoxins in general (12). We have recently observed that hepatocytes from postnatal mice are less su...

Acetaminophen-Induced Liver Injury Alters Expression and Activities of Cytochrome P450 Enzymes in an Age-Dependent Manner in Mouse Liver

“…The results of ALT and AST levels in plasma as well as H&E staining confirmed an injury of liver in adult mice as expected. Mice at younger ages were reported to be more resistant to AILI (Adamson et al, 1991). In the present study, the resistance to AILI in the mice at the infant age was further confirmed.…”

Long-term Exposure to Acetaminophen is a Crucial for Activity of Selected Antioxidative Enzymes and Level of Lipid Peroxidation Process in Rat Liver

“…Previous reports [15,[22][23][24][25] have shown that the large dose of PC administration in the chronic manner resulted in the liver injury. Accordingly, PC had a negative influence upon liver metabolism by means of PC-protein adducts formation [26][27][28][29]. In our study we found clear-cut free radical-dependent mechanism of paracetamol toxic action influencing the rat liver after 8 and 12 weeks, when administered in a dose of 2.4 g/kg of body weigth/24 hrs, in a form of a potable solution.…”

Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life

“… 17 Furthermore, paracetamol metabolites detected in the urine from babies from breastfeeding mothers, differ significantly from those detected in the urine of healthy adults who have ingested paracetamol. Neonates have significantly higher levels of paracetamol in their urine compared with adults, and adults have greater levels of urinary paracetamol sulfate, 17 confirming that the pharmacokinetics and pharmacodynamics of paracetamol differ substantially in murine 28 and human neonates and infants compared with children and adults. 29 As it is technically very difficult to perform oral gavage in newborn mice, the importance of oral paracetamol ingestion in early life on subsequent AAD was indirectly determined in our study by administering paracetamol to mothers only during lactation and assessing AAD just prior to weaning at 3 weeks.…”