Regulation of Drug-Metabolizing Enzymes and Drug Metabolism by Inflammatory Responses

Inflammation caused by activation of innate immune responses can have a significant impact on drug metabolism via regulation of drug-metabolizing enzymes, particularly the cytochrome P450s. Clinical evidence exists for significant impact of viral, bacterial, and parasitic as well as sterile inflammatory diseases in humans. Proinflammatory cytokines known to regulate hepatic acute phase proteins are also the major players in regulating drug-metabolizing enzymes, although their relative roles may vary according to the specific disease state. Downregulation can result in increased incidence of adverse effects, or reduced bioactivation of drugs or toxicants, and is the basis for disease-dependent interactions of antiinflammatory therapeutic proteins with small-molecule drugs. Mechanisms behind these effects include direct and indirect transcriptional suppression as well as posttranscriptional mechanisms, including microRNA and nitric oxide‒mediated effects.