title: Inflammatory reactions and drug response: importance of cytochrome P450 and membrane transporters.
abstract: Inflammatory reactions (IRs), both infectious and aseptic, downregulate numerous enzymes of cytochrome P450 (CYP) and ATP-binding cassette transporters. The mechanism involves proinflammatory cytokines and activation of transcription factors, nuclear factor-κB, CCAAT-enhancer-binding protein-β and c-myc, which bind to negative regulatory elements and/or impede the binding of nuclear receptors to promoter elements. Downregulation of CYP enzymes and transporters modulates the kinetics of a drug, resulting in increased plasma and tissue concentrations of the drug and enhanced effect and/or toxicity. Clinical trials have shown that IRs increase the risk of myocardial infarction and stroke. In this article, we speculate that IRs downregulate cardiac and vascular CYP enzymes (CYP2C8/9 and CYP2J2) responsible for the formation of vasorelaxant products. Patients with IRs should be advised that the risk of drug adverse effects and of cardiovascular diseases is increased; therefore, the benefit-risk ratio and use of drugs with narrow therapeutic index should be revaluated, as well as the conditions precipitating cardiovascular events.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Montreal, PO Box 6128, Station Centre-ville, Montreal, Quebec, H3C 3J7, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dumais
authors.forename: Mirela
authors.initials: M
authors.lastname: Iovu
authors.forename: Patrick
authors.initials: P
authors.lastname: du Souich