Clinical investigations suggest that hepatotoxicity after acetaminophen (APAP) overdose could be more severe in the context of obesity and nonalcoholic fatty liver disease. The preexistence 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 -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.
The transfer of POPs in food of animal origin has been studied by a meta-analysis of 28 peer-reviewed articles using transfer rate (TR) for milk and eggs and bioconcentration factors (BCF) for eligible tissues after establishing an adapted methodology. TRs of the most toxic PCDD/Fs into milk were generally elevated and even higher into eggs. BCFs in excreting adult animals varied widely between studies complicating to hierarchize tissues or congeners, even if liver and fat seemed to bioconcentrate more than lean tissues. Short time studies have clearly shown low BCFs contrarily to field studies showing the highest BCFs. The BCFs of PCDD/Fs in growing animals were higher in liver than in fat or muscle. In contrast to easily bioconcentrating hexachlorinated congeners, octa-and heptachlorinated congeners barely bioconcentrate. PCB transfer into milk and eggs was systematically high for very lipophilic congeners. Highly ortho-chlorinated PCBs were transferred >50% into milk and eggs and even >70% for congeners 123 and 167 into eggs. BCFs of the most toxic PCBs 126 and 169 were significantly higher than for less toxic congeners. BCFs seem generally low in PBDEs except congeners 47, 153 and 154. DDT and its metabolites showed high bioconcentration. Differences between tissues appeared but were masked by a study effect. In addition to some methodologic recommendations, this analysis showed the high transfer of POPs into eggs, milk and liver when animals were exposed justifying a strong monitoring in areas with POP exposure.
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