Differences in early acetaminophen hepatotoxicity between obese ob/ob and db/db mice.
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.
Institut National de la Santé et de la Recherche Médicale, U991, Université de Rennes 1, Rennes, France.
Jacinthe
J
Aubert
Karima
K
Begriche
Matthieu
M
Delannoy
Isabelle
I
Morel
Julie
J
Pajaud
Catherine
C
Ribault
Sylvie
S
Lepage
Mitchell R
MR
McGill
Catherine
C
Lucas-Clerc
Bruno
B
Turlin
Marie-Anne
MA
Robin
Hartmut
H
Jaeschke
Bernard
B
Fromenty
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000082:Acetaminophen / Q000097:blood / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D005234:Fatty Liver / Q000097:blood / Q000378:metabolism / Q000473:pathology; D005260:Female; D020719:Glucuronides / Q000097:blood; D005978:Glutathione / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019344:Lactic Acid / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009765:Obesity / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D013431:Sulfates / Q000097:blood; D014280:Triglycerides / Q000097:blood
D004272:DNA, Mitochondrial; D020719:Glucuronides; D013431:Sulfates; D014280:Triglycerides; D019344:Lactic Acid; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione; D020155:3-Hydroxybutyric Acid