PT - JOURNAL ARTICLE AU - Jacinthe Aubert AU - Karima Begriche AU - Matthieu Delannoy AU - Isabelle Morel AU - Julie Pajaud AU - Catherine Ribault AU - Sylvie Lepage AU - Mitchell R. McGill AU - Catherine Lucas-Clerc AU - Bruno Turlin AU - Marie-Anne Robin AU - Hartmut Jaeschke AU - Bernard Fromenty TI - Differences in Early Acetaminophen Hepatotoxicity between Obese <em>ob/ob</em> and <em>db/db</em> Mice AID - 10.1124/jpet.112.193813 DP - 2012 Sep 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 676--687 VI - 342 IP - 3 4099 - http://jpet.aspetjournals.org/content/342/3/676.short 4100 - http://jpet.aspetjournals.org/content/342/3/676.full SO - J Pharmacol Exp Ther2012 Sep 01; 342 AB - Clinical investigations suggest that hepatotoxicity after acetaminophen (APAP) overdose could be more severe in the context of obesity and nonalcoholic fatty liver disease. The pre-existence of fat accumulation and CYP2E1 induction could be major mechanisms accounting for such hepatic susceptibility. To explore this issue, experiments were performed in obese diabetic ob/ob and db/db mice. Preliminary investigations performed in male and female wild-type, ob/ob, and db/db mice showed a selective increase in hepatic CYP2E1 activity in female db/db mice. However, liver triglycerides in these animals were significantly lower compared with ob/ob mice. Next, APAP (500 mg/kg) was administered in female wild-type, ob/ob, and db/db mice, and investigations were carried out 0.5, 2, 4, and 8 h after APAP intoxication. Liver injury 8 h after APAP intoxication was higher in db/db mice, as assessed by plasma transaminases, liver histology, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. In db/db mice, however, the extent of hepatic glutathione depletion, levels of APAP-protein adducts, c-Jun N-terminal kinase activation, changes in gene expression, and mitochondrial DNA levels were not greater compared with the other genotypes. Furthermore, in the db/db genotype plasma lactate and β-hydroxybutyrate were not specifically altered, whereas the plasma levels of APAP-glucuronide were intermediary between wild-type and ob/ob mice. Thus, early APAP-induced hepatotoxicity was greater in db/db than ob/ob mice, despite less severe fatty liver and similar basal levels of transaminases. Hepatic CYP2E1 induction could have an important pathogenic role when APAP-induced liver injury occurs in the context of obesity and related metabolic disorders.