Stress is a critical player in CYP3A, CYP2C, and CYP2D regulation: role of adrenergic receptor signaling pathways

Stress is a critical player in the regulation of the major cytochrome P-450s (CYPs) that metabolize the majority of the prescribed drugs. Early in life, maternal deprivation (MD) stress and repeated restraint stress (RS) modified CYP expression in a stress-specific manner. In particular, the express...

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Bibliographic Details
Published in:American journal of physiology: endocrinology and metabolism 2012-07, Vol.303 (1), p.E40-E54
Main Authors: Daskalopoulos, Evangelos P, Malliou, Foteini, Rentesi, Georgia, Marselos, Marios, Lang, Matti A, Konstandi, Maria
Format: Article
Language:English
Subjects:
Adrenergic Agonists - pharmacology
Animals
Aryl Hydrocarbon Hydroxylases - genetics
Aryl Hydrocarbon Hydroxylases - metabolism
Cells, Cultured
Corticosterone - metabolism
Cytochrome P-450 CYP2D6 - genetics
Cytochrome P-450 CYP2D6 - metabolism
Cytochrome P-450 CYP3A - genetics
Cytochrome P-450 CYP3A - metabolism
Cytochrome P450 Family 2
Enzyme Induction - drug effects
Epinephrine - metabolism
Hepatocytes - cytology
Hepatocytes - drug effects
Hepatocytes - metabolism
Isoenzymes - genetics
Isoenzymes - metabolism
Male
Maternal Deprivation
Protein Kinase Inhibitors - pharmacology
Rats
Rats, Wistar
Receptors, Adrenergic - chemistry
Receptors, Adrenergic - metabolism
Restraint, Physical - adverse effects
RNA, Messenger - metabolism
Signal Transduction - drug effects
Steroid 16-alpha-Hydroxylase - genetics
Steroid 16-alpha-Hydroxylase - metabolism
Stress, Physiological
Stress, Psychological - metabolism
Stress, Psychological - pathology
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Summary:Stress is a critical player in the regulation of the major cytochrome P-450s (CYPs) that metabolize the majority of the prescribed drugs. Early in life, maternal deprivation (MD) stress and repeated restraint stress (RS) modified CYP expression in a stress-specific manner. In particular, the expression of CYP3A1 and CYP2C11 was increased in the liver of MD rats, whereas RS had no significant effect. In contrast, hepatic CYP2D1/2 activity was increased by RS, whereas MD did not affect it. The primary effectors of the stress system, glucocorticoids and epinephrine, highly induced CYP3A1/2. Epinephrine also induced the expression of CYP2C11 and CYP2D1/2. Further investigation indicated that AR-agonists may modify CYP regulation. In vitro experiments using primary hepatocyte cultures treated with the AR-agonists phenylephrine, dexmedetomidine, and isoprenaline indicated an AR-induced upregulating effect on the above-mentioned CYPs mediated by the cAMP/protein kinase A and c-Jun NH₂-terminal kinase signaling pathways. Interestingly though, in vivo pharmacological manipulations of ARs using the same AR-agonists led to a suppressed hepatic CYP expression profile, indicating that the effect of the complex network of central and peripheral AR-linked pathways overrides that of the hepatic ARs. The AR-mediated alterations in CYP3A1/2, CYP2C11, and CYP2D1/2 expressions are potentially connected with those observed in the activation of signal transducer and activator of transcription 5b. In conclusion, stress and AR-agonists may modify the expression of the major CYP genes involved in the metabolism of drugs used in a wide range of diseases, thus affecting drug efficacy and toxicity.
ISSN:0193-1849
1522-1555
DOI:10.1152/ajpendo.00545.2011