Hepatic responses of mice and rats to equivalent acetaminophen (APAP) insult [mouse]

The well-known difference in sensitivity of mice and rats to acetaminophen (APAP) liver injury has been related to differences in the fraction that is bioactivated to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). Physiologically-based pharmacokinetic modelling was used to identify doses of APAP (300 and 1000 mg/kg in mice and rats, respectively) yielding similar hepatic burdens of NAPQI, to enable the comparison of temporal liver tissue responses under conditions of equivalent chemical insult. Male C57Bl/6J mice (8 weeks old; 15-22 g body weight) or Sprague-Dawley rats (5 weeks old; 119-144 g body weigh) were fasted for 16 h prior to dosing. Acetaminophen (APAP) was solubilised in 1% (w/v) hydroxyethylcellulose (both, Sigma-Aldrich). Mice (n=5 per time point) and rats (n=5 per time point) were administered 300 mg/kg and 1000 mg/kg APAP, respectively, or vehicle (1% hydroxyethylcellulose) by oral gavage. The animals were sacrificed by exsanguination under isoflurane anaesthesia at baseline (0 h) and at 3, 6, 9 and 24 h after administration of APAP or vehicle. Liver tissue was collected for RNA extraction and hybridization on Affymetrix microarrays.