Dynamic CYP2E1 expression and metabolic activity changes in male rats during immune liver injury and sex differences in alcohol metabolism

Abstract

Previous studies conducted by our team have demonstrated that CYP2E1 expression is downregulated during Bacillus Calmette-Guérin (BCG)-induced immune liver injury (hepatitis). However, the dynamic changes in CYP2E1 metabolic activity during the acute, chronic, and recovery phases of hepatitis remain unclear. This study developed a non-invasive approach using a breath alcohol analyzer to assess CYP2E1 metabolic activity through alcohol metabolism and examined sex-based differences in alcohol metabolism in rats. Using a BCG-induced male rat hepatitis model, we investigated the dynamic changes in CYP2E1 metabolic activity at different stages of hepatitis and explored the underlying mechanisms. The results indicated that the breath alcohol analysis method exhibited high precision, linearity, and reproducibility in assessing CYP2E1 metabolic activity. CYP2E1 metabolic activity and protein expression displayed an induction trend with increased alcohol intake (P < 0.05). Female rats exhibited significantly higher CYP2E1 metabolic activity compared to males (P < 0.05), indicating significant sexual dimorphism. On day 6 post-BCG stimulation, CYP2E1 metabolic activity was most severely impaired (P < 0.05). Notably, alterations in metabolic activity were detected earlier and were more pronounced than changes in protein expression. Similar dynamic changes were observed in the hepatic NF-κB inflammatory pathway and the MAPK oxidative stress pathway. In conclusion, the breath alcohol analysis method is an effective tool for assessing CYP2E1 metabolic activity in rats. CYP2E1 can be significantly induced following a single high dose of alcohol, with female rates exhibiting greater metabolic activity compared to males. CYP2E1 metabolic activity showed the most notable impairment on day 6 post-BCG, with gradual recovery observed at days 10 and 14, and parallel changes observed in inflammatory and MAPK pathways. The recovery of CYP2E1 protein expression occurred after 14 days, which was later than that of the metabolic activity.