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• W2149201275 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, <i>ob/ob</i>, and <i>db/db</i> mice showed a selective increase in hepatic CYP2E1 activity in female <i>db/db</i> mice. However, liver triglycerides in these animals were significantly lower compared with <i>ob/ob</i> mice. Next, APAP (500 mg/kg) was administered in female wild-type, <i>ob/ob</i>, and <i>db/db</i> 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 <i>db/db</i> mice, as assessed by plasma transaminases, liver histology, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. In <i>db/db</i> 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 <i>db/db</i> genotype plasma lactate and β-hydroxybutyrate were not specifically altered, whereas the plasma levels of APAP-glucuronide were intermediary between wild-type and <i>ob/ob</i> mice. Thus, early APAP-induced hepatotoxicity was greater in <i>db/db</i> than <i>ob/ob</i> 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." @default.
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• W2149201275 date "2012-05-30" @default.
• W2149201275 modified "2023-10-14" @default.
• W2149201275 title "Differences in Early Acetaminophen Hepatotoxicity between Obese<i>ob/ob</i>and<i>db/db</i>Mice" @default.
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• W2149201275 doi "https://doi.org/10.1124/jpet.112.193813" @default.
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