Abstract
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.
Footnotes
This work was supported by the Institut Nationale de la Santé et de la Recherche Médicale. J.A. and K.B. were recipients of grants from the President of Université de Rennes 1 and the Région Bretagne, respectively.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- APAP
- acetaminophen
- ACO
- acyl-coenzyme A oxidase
- ALT
- alanine aminotransferase
- ANOVA
- analysis of variance
- AST
- aspartate aminotransferase
- γGCS
- γ-glutamylcysteine synthetase
- GSH
- glutathione
- GST
- glutathione transferase
- GSTK
- GST κ
- GSTP1
- GST π-1
- HES
- hematoxylin, eosin, and safran
- HO-1
- heme oxygenase-1
- HSC70
- heat shock cognate protein 70
- HSD
- Honestly Significant Difference
- Hsp70
- heat shock protein 70
- IGFBP-1
- insulin-like growth factor binding protein-1
- JNK
- c-Jun N-terminal kinase
- P-JNK
- phosphorylated JNK
- l-CPT1
- l-carnitine palmitoyltransferase 1
- mtDNA
- mitochondrial DNA
- NAFLD
- nonalcoholic fatty liver disease
- NAPQI
- N-acetyl-p-benzoquinone imine
- NASH
- nonalcoholic steatohepatitis
- Nrf2
- NF-E2-related factor-2
- PCR
- polymerase chain reaction
- RT-qPCR
- real-time quantitative PCR
- PDK4
- pyruvate dehydrogenase kinase 4
- PPARα
- peroxisome proliferator-activated receptor-α
- Trib3
- Tribbles homolog 3
- TUNEL
- terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling
- wt
- wild-type.
- Received February 28, 2012.
- Accepted May 29, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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