Zhang Jiayi, Cao Yingying, Jin Ziqi, A Runa, Wang Xiaoxue, Zhang Lingyu, Hu Yingqi, Xue Yongzhi
Department of Pharmacology, Baotou Medical College, Institute of Pharmacokinetics and Liver Molecular Pharmacology, Baotou, China.
PLoS One. 2025 Jun 18;20(6):e0325135. doi: 10.1371/journal.pone.0325135. eCollection 2025.
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.
我们团队之前进行的研究表明，在卡介苗（BCG）诱导的免疫性肝损伤（肝炎）过程中，CYP2E1表达下调。然而，在肝炎的急性、慢性和恢复阶段，CYP2E1代谢活性的动态变化仍不清楚。本研究开发了一种使用呼气酒精分析仪的非侵入性方法，通过酒精代谢来评估CYP2E1代谢活性，并研究了大鼠酒精代谢的性别差异。使用BCG诱导的雄性大鼠肝炎模型，我们研究了肝炎不同阶段CYP2E1代谢活性的动态变化，并探讨了潜在机制。结果表明，呼气酒精分析方法在评估CYP2E1代谢活性方面具有高精度、线性和可重复性。CYP2E1代谢活性和蛋白表达随酒精摄入量增加呈诱导趋势（P < 0.05）。雌性大鼠的CYP2E1代谢活性显著高于雄性（P < 0.05），表明存在明显的性别差异。在BCG刺激后第6天，CYP2E1代谢活性受损最严重（P < 0.05）。值得注意的是，代谢活性的变化比蛋白表达的变化更早被检测到，且更明显。在肝脏NF-κB炎症通路和MAPK氧化应激通路中也观察到了类似的动态变化。总之，呼气酒精分析方法是评估大鼠CYP2E1代谢活性的有效工具。单次高剂量酒精后，CYP2E1可被显著诱导，雌性大鼠的代谢活性高于雄性。CYP2E1代谢活性在BCG刺激后第6天受损最明显，在第10天和第14天逐渐恢复，炎症和MAPK通路也有平行变化。CYP2E1蛋白表达在14天后恢复，晚于代谢活性的恢复。
