Role of NF-kappaB in the regulation of cytochrome P450 enzymes.
Nuclear factor kappa B (NF-kappaB) is an important transcription factor that regulates a wide spectrum of genes including cytochrome P450 (CYP), the most important family of drug metabolizing enzymes. Therefore, in this review, we addressed the potential role of NF-kappaB in CYP regulation. We proposed three mechanisms by which NF-kappaB can regulate CYP expression and activity. First, NF-kappaB can directly regulate the expression of CYP1A1, CYP2B1/2, CYP2C11, CYP2D5, CYP2E1, CYP3A7, and CYP27B1 through binding to the promoter region of these genes. Second, NF-kappaB indirectly regulates the transcription of CYP genes through mutual repression with some nuclear receptors that are involved in CYP regulation such as AhR, CAR, GR, PXR, RXR, PPAR, FXR, and LXR. Finally, NF-kappaB can regulate CYP activity at post-transcriptional level by inducing heme oxygenase or by affecting the CYP protein stability. In addition, increased inflammatory mediators, oxidative stress, and subsequent NF-kappaB activation have been demonstrated in many conditions such as inflammatory bowel diseases, rheumatoid arthritis, psychological stress, diabetes, aging, cancer, renal diseases, and congestive heart failure. Meanwhile, there is a significant alteration of CYP expression and activity in these diseases. Therefore, we propose that NF-kappaB could be one of the links between inflammation, oxidative stress, and CYP regulation in these diseases. In conclusion, NF-kappaB plays a crucial role in the regulation of CYP through several mechanisms and this role can explain the altered CYP regulation in many conditions.
Zordoky
Beshay N M
BN
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
El-Kadi
Ayman O S
AO
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014158:Transcription, Genetic
D016328:NF-kappa B; D003577:Cytochrome P-450 Enzyme System