Shining a Light on Inflammation as a Critical Modulator of Drug Metabolism.

Abstract

Since his graduate studies on alcohol induction of a novel cytochrome P450 (P450) enzyme, through his postdoctoral work on hormonal regulation of sexually differentiated cytochrome P450s (P450s), the author has maintained an interest in the regulation of drug metabolizing enzymes. This article is a recounting of his scientific career and focuses on his laboratory's work on inflammatory regulation of P450 enzymes that formed the basis for the Bernard B. Brodie Award. Key findings and publications are identified and discussed that contributed to the elucidation of some important principles: 1) inflammatory stimuli generally downregulate P450 enzymes, resulting in reduced metabolism of substrate drugs; 2) the main mechanism for this downregulation is transcriptional and involves both the activation of negatively acting transcription factors and the suppression of positive transcription factors; 3) inflammatory cytokines such as interleukin 1, interleukin 6, and tumor necrosis factor α act on hepatocytes to mediate this regulation; 4) these cytokines selectively regulate different P450 enzymes, and therefore different P450s are downregulated in different inflammatory diseases or disease models; 5) nitric oxide formed by inducible nitric oxide synthase 2 reacts with P450s in an enzyme-specific manner to stimulate their proteolytic degradation; and 6) both tyrosine nitration and heme nitrosylation are likely required for this NO-stimulated degradation. Finally, findings from clinical studies are discussed that shine a light on the importance of P450 regulation by inflammation for drug development, clinical practice, and personalized medicine. SIGNIFICANCE STATEMENT: This article discusses the key publications and findings in the author's laboratory that helped to identify inflammation as an important factor contributing to interindividual variation in drug metabolism.