RT Journal Article
SR Electronic
T1 Differences in Early Acetaminophen Hepatotoxicity between Obese <em>ob/ob</em> and <em>db/db</em> Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 676
OP 687
DO 10.1124/jpet.112.193813
VO 342
IS 3
A1 Aubert, Jacinthe
A1 Begriche, Karima
A1 Delannoy, Matthieu
A1 Morel, Isabelle
A1 Pajaud, Julie
A1 Ribault, Catherine
A1 Lepage, Sylvie
A1 McGill, Mitchell R.
A1 Lucas-Clerc, Catherine
A1 Turlin, Bruno
A1 Robin, Marie-Anne
A1 Jaeschke, Hartmut
A1 Fromenty, Bernard
YR 2012
UL http://jpet.aspetjournals.org/content/342/3/676.abstract
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.