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 cytochrome P450 2E1 (CYP2E1) induction could be major mechanisms accounting for such hepatic susceptibility. To explore this issue, experiments were performed in obese and 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 to 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 TUNEL assay. In db/db mice, however, the extent of hepatic glutathione depletion, levels of APAP-protein adducts, c-jun N-terminal kinase (JNK) activation, changes in gene expression and mitochondrial DNA levels were not greater compared to the other genotypes. Furthermore, in the db/db genotype, plasma lactate and β-hydroxybutyrate were not specifically altered, whereas 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 in 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.
- Received February 28, 2012.
- Revision received May 29, 2012.
- Accepted May 29, 2012.
- The American Society for Pharmacology and Experimental Therapeutics