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Neurosci Biobehav Rev. 2014 Sep;45:149-67. doi: 10.1016/j.neubiorev.2014.05.011. Epub 2014 May 27.

Consequences of psychophysiological stress on cytochrome P450-catalyzed drug metabolism.

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Department of Pharmacology, School of Medicine, University of Ioannina, Ioannina GR-451 10, Greece. Electronic address:
Department of Anatomy, University of Athens, School of Medicine, Mikras Asias 75, 11527 Athens, Greece.
National Research Centre for Environmental Toxicology, University of Queensland, Coopers Plains, Australia.


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.


Adrenergic receptor; Cytochrome P450s; Drug metabolism; Glucocorticoids; Stress

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