title: Stress is a critical player in CYP3A, CYP2C, and CYP2D regulation: role of adrenergic receptor signaling pathways.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Ioannina, Ioannina, Greece.
authors.forename: Evangelos P
authors.initials: EP
authors.lastname: Daskalopoulos
authors.forename: Foteini
authors.initials: F
authors.lastname: Malliou
authors.forename: Georgia
authors.initials: G
authors.lastname: Rentesi
authors.forename: Marios
authors.initials: M
authors.lastname: Marselos
authors.forename: Matti A
authors.initials: MA
authors.lastname: Lang
authors.forename: Maria
authors.initials: M
authors.lastname: Konstandi
mesh_terms: D000322:Adrenergic Agonists / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003345:Corticosterone / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004790:Enzyme Induction / Q000187:drug effects; D004837:Epinephrine / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008426:Maternal Deprivation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000737:chemistry / Q000378:metabolism*; D012149:Restraint, Physical / Q000009:adverse effects; D015398:Signal Transduction / Q000187:drug effects; D039181:Steroid 16-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D013315:Stress, Psychological / Q000378:metabolism* / Q000473:pathology
chemical_list: D000322:Adrenergic Agonists; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D011941:Receptors, Adrenergic; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D003345:Corticosterone; D004837:Epinephrine