Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

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 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.

A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen

“…Oxidative stress, including induced by APAP, can secondarily increase the expression of different genes such as heme oxygenase 1, γ-glutamylcysteine synthase, different glutathione S-transferases, heat shock protein 70 and tribbles pseudokinase 3 (Aubert et al, 2012; Chan et al, 2001). Importantly, nuclear factor, erythroid 2-like 2 (NRF2, or NFE2L2) is a transcription factor playing a major role in the regulation of most of these genes (Chan et al, 2001; Ma and He, 2012).…”

“…Indeed, several investigations in rodents and humans reported that NALFD is associated with more severe APAP-induced hepatotoxicity, especially after an overdose (Aubert et al, 2012; Kon et al, 2010; Michaut et al, 2014; Myers and Shaheen, 2008; NGuyen et al, 2008). Moreover, in vitro investigations showed that steatotic rat hepatocytes in primary culture were more susceptible to APAP-induced acute cytotoxicity (Kucera et al, 2012).…”

“…Indeed, some data in rodents and humans suggested that NALFD could be associated with more severe APAP-induced hepatotoxicity, especially after an overdose (Aubert et al, 2012; Kon et al, 2010; Michaut et al, 2014; Myers and Shaheen, 2008; NGuyen et al, 2008). One of these rodent studies proposed that higher APAP hepatotoxicity in NAFLD could be attributed to greater activity of CYP2E1 (Aubert et al, 2012), the primary enzyme responsible for the biotransformation of APAP to the highly toxic metabolite N-acetyl- p -benzoquinone imine (NAPQI) (Hinson et al, 2010; McGill and Jaeschke, 2013). Overall, our results indicate that HepaRG cells loaded with stearic acid can be used as a valuable model to study the mechanisms whereby APAP is more toxic in the context of NAFLD.…”

Metabolism and Disposition of Acetaminophen: Recent Advances in Relation to Hepatotoxicity and Diagnosis

“…It has also been suggested that concurrent mutations in other UGTs associated with 1A1 through linkage disequilibrium in some Gilbert’s syndrome patients could account for the differences (54). Interestingly, it was recently shown that obese mice with steatosis have higher expression of UGTs than wildtype controls, and samples from these animals had higher concentrations of APAP-glucuronide (55–56). The mechanism by which obesity leads to increased glucuronidation in mice is not yet known.…”

Functional validation of GWAS gene candidates for abnormal liver function during zebrafish liver development

“…This susceptibility, also found in trib1 morphants, might be APAP specific, but might also be correlated to plasma liver enzyme elevation. For example, liver enzymes increase not only during APAP-induced liver toxicity but also in other types of metabolic or toxic liver injury, and enzyme levels can be further increased by APAP exposure (Aubert et al, 2012; Kučera et al, 2012; Majhi et al, 2011). These functional data might inform further genomic studies to identify differentiating SNPs between pnpla3 and samm50 that could correlate with gene function.…”