title: Consequences of psychophysiological stress on cytochrome P450-catalyzed drug metabolism.
abstract: Most drugs are metabolized in the liver by cytochromes P450 (CYPs). Stress can modify CYP-catalyzed drug metabolism and subsequently, the pharmacokinetic profile of a drug. Current evidence demonstrates a gene-, stress- and species-specific interference in stress-mediated regulation of genes encoding the major drug-metabolizing CYP isozymes. Stress-induced up-regulation of CYPs that metabolize the majority of prescribed drugs can result in their increased metabolism and consequently, in failure of pharmacotherapy. In contrast, stress-induced down-regulation of CYP isozymes, including CYP2E1 and CYP2B1/2, potentially reduces metabolism of several toxicants and specific drugs-substrates resulting in increased levels and altered toxicity. The primary stress effectors, the adrenergic receptor-linked pathways and glucocorticoids, play primary and distinct roles in stress-mediated regulation of CYPs. Evidence demonstrates that stress regulates major drug metabolizing CYP isozymes, suggesting that stress should be considered to ensure pharmacotherapy efficacy and minimize drug toxicity. A detailed understanding of the molecular events underlying the stress-dependent regulation of drug metabolizing CYPs is crucial both for the design of new drugs and for physiology-based pharmacokinetic and pharmacodynamic modeling.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Ioannina, Ioannina GR-451 10, Greece. Electronic address: mkonstan@cc.uoi.gr.
authors.forename: Maria
authors.initials: M
authors.lastname: Konstandi
authors.affiliation: Department of Anatomy, University of Athens, School of Medicine, Mikras Asias 75, 11527 Athens, Greece.
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Johnson
authors.affiliation: National Research Centre for Environmental Toxicology, University of Queensland, Coopers Plains, Australia.
authors.forename: Matti A
authors.initials: MA
authors.lastname: Lang
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D010599:Pharmacokinetics; D013315:Stress, Psychological / Q000201:enzymology*
chemical_list: D003577:Cytochrome P-450 Enzyme System
keywords: Adrenergic receptor; Cytochrome P450s; Drug metabolism; Glucocorticoids; Stress