Inflammatory Regulation of P450 Enzymes Implications for Drug Metabolism in the Time of COVID-19 | Dr. Edward T. Morgan

In the 1970s-80s, studies in rats and mice showed that various inflammatory stimuli or live bacterial or viral infections could reduce the capacity of microsomes from affected animals to metabolize prototypic cytochrome P450 drug substrates. With the advent of techniques able to measure specific P450 gene products, we learned that many of these effects are associated with selective down-regulation (suppression) of cytochrome P450 gene transcription. Studies in cultured hepatocytes identified pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-a as principal effectors of these changes. Cytokines were found to regulate P450 expression in an enzyme-selective and species-specific manner, suggesting that in vivo responses would be different in different inflammatory diseases. We also learned that drug transporters and Phase 2 drug metabolizing enzymes are subject to the same modes of regulation. In this webinar, we will review the data supporting these conclusions and the evidence that both acute and chronic inflammation significantly impact upon human drug metabolism in a variety of inflammatory disease scenarios including infections, cancer, rheumatoid arthritis and surgeries. We will also discuss the roles of nitric oxide in both inhibiting and down-regulating P450 enzymes under such conditions. Finally, we will explore the possible implications of this inflammatory regulation for the metabolism of cytochrome P450 drug substrates administered to patients with SARS-CoV-2 infections, particularly in the context of the “cytokine storm” reactions that some serious cases experience.