New insights into the downregulation of cytochrome P450 2E1 via nuclear factor κB-dependent pathways in immune-mediated liver injury

Abstract

The extent of immune-mediated hepatic damage (such as in viral hepatitis) is characterised by the downregulation of cytochrome P450s (CYPs), a class of drug-metabolising enzymes. However, whether this downregulation aids liver cells in maintaining their homeostasis or whether the damage is aggravated remains largely unexplored. Herein, we evaluated the effects of phosphorylation mediated by the protein kinase C (PKC)/cAMP-response element binding protein (CREB) and nitration mediated by inducible nitric oxide synthase (iNOS) on the downregulation of CYP2E1 during immune-mediated liver injury. Additionally, we investigated the regulatory mechanism mediated by the nuclear factor κB (NF-κB). The rat model of immune-mediated liver injury was replicated by administering a single i.v. injection of Bacillus Calmette–Guerin (BCG, 125 mg/kg) vaccine and three i.p. injections of ammonium pyrrolidine dithiocarbamate (25, 50, 100 mg/kg/d, days 11, 12, and 13); blood was then collected on day 14. Subsequently, the livers were extracted to identify the different pharmacokinetic and biochemical indicators involved in the process. Our study reports new findings on the dependence between PKC-mediated CREB phosphorylation in the anti-inflammatory pathway and nitration emergency induced by iNOS in pro-inflammatory pathways in the NF-κB pathway. The interaction of these two pathways leads to the downregulation and recovery of CYP2E1, thus alleviating inflammation and nitration stress. Our results confirm that BCG-mediated downregulation of CYP2E1 is linked to iNOS-induced nitration and PKC/NF-κB-mediated CREB phosphorylation, and that NF-κB is an important molecular target in this process. These findings suggest that the downregulation of CYP2E1 may be an autonomous process characteristic of liver cells, helping them adapt to environmental changes, alleviate further hypoxia in inflamed tissues, and minimise exposure to toxic and harmful metabolites.