Nrf2 Antioxidative System is Involved in Cytochrome P450 Gene Expression and Activity: A Delay in Pentobarbital Metabolism in Nrf2-Deficient Mice

Abstract

NF-E2-related factor 2 (Nrf2) is a transcriptional regulator of biologic defense proteins, such as antioxidant proteins and phase II detoxification enzymes. Cytochrome P450 (P450) enzymes have been shown to regulate phase I metabolism of various drugs and are partially regulated by Nrf2; however, the influence of Nrf2 on drug pharmacokinetics is not known. Here, we showed that Nrf2 depletion prolonged the effect of pentobarbital, a sleep-promoting drug. Pretreatment with phenobarbital, a P450 inducer, shortens the sleeping time associated with pentobarbital-induced sedation in wild-type (WT) mice; however, this effect was not observed in Nrf2 2/2 mice. Furthermore, the blood pentobarbital concentration was higher in Nrf2 2/2 mice than in WT mice at 30-60 minutes, and the phenobarbital-induced enhancement of its clearance was attenuated in Nrf2 2/2 mice compared with WT mice. Total P450 content was decreased in Nrf2 2/2 mouse livers, and the phenobarbitalinduced increase in P450 content was lower in Nrf2 2/2 mice than WT mice. Cyp1a2, Cyp2a5, Cyp2c29, and Cyp2e1 gene expression levels under physiologic conditions and Cyp1a2, Cyp2a5, and Cyp2b10 gene expression levels under phenobarbital-treated conditions were lower in Nrf2 2/2 mice compared with WT mice. Additionally, pentobarbital metabolism in liver microsomes was attenuated by Nrf2 depletion. Taken together, these findings suggested that Nrf2 influenced pentobarbital pharmacokinetics through the regulation of drug metabolism and P450 gene expression. Thus, Nrf2-mediated regulation of P450 may contribute to the biologic defense against increased reactive oxygen species production. SIGNIFICANCE STATEMENTNF-E2-related factor 2 (Nrf2) plays a critical role in the cellular defense against oxidative stress. Nrf2 2/2 mice with reduced ability to eliminate reactive oxygen species (ROS) showed a significant delay in emergence from pentobarbital-induced sleep, which was associated with decreased P450 activities and gene expression. Our findings provide that Nrf2 dysfunction or ROS that exceed a threshold level of the eliminating ability of the Nrf2 system may reduce P450 activity.

Transcriptional Profiling of Exosomes Derived from Staphylococcus aureus‐Infected Bovine Mammary Epithelial Cell Line MAC‐T by RNA‐Seq Analysis

“…CYP1A2 was enriched in reactive oxygen species metabolic pathways. It has been reported that CYP1A2 could regulate various metabolic processes to participate in the production of reactive oxygen species during oxidative stress [ 29 , 30 ]. SKP2 helps to inhibit oxidative stress induced-DNA damage and cell apoptosis, which limits the misincorporation of ROS-damaged dNTPs into genomic DNA, making cells more resistant to such stress [ 31 ].…”

The Foraging Gene, a New Environmental Adaptation Player Involved in Xenobiotic Detoxification

“…Previous works with mouse primary hepatocyte cultures [ 47 , 48 ] suggested that PKG was involved in phenobarbital-induced upregulation of CYP2b9/10 or CYP3A expression. A recent publication demonstrated that PKG can regulate the function of Nrf2 [ 49 ], a gene known to control the expression of P450s [ 50 ] and more specifically Cyp6a2 [ 51 ]. As Cyp6a2 expression has previously been shown to be controlled by phenobarbital [ 52 , 53 ], all these published data are consistent with our current data highlighting a direct link between PKG and the expression of the P450 Cyp6a2 .…”

Transcription factor Nrf2 as a potential therapeutic target for COVID-19

“…In addition, Nrf2 can also contribute to biodefense against increased reactive oxygen species by mediating the regulation of cytochrome P450 (CYP), a class of heme-containing monooxygenases. Nrf2 depletion has been shown to reduce liver microsomal cytochrome P450 content in the experiments of Takashi Ashino et al This is mainly due to increased expression of the P450 genes Cyp2a5 and Cyp2b10 by Nrf2 (Ashino et al 2020 ). Recent studies have shown that CYP may be involved in the development of lung injury, kidney injury, and liver injury in patients with COVID-19.…”