Predominant role of peripheral catecholamines in the stress-induced modulation of CYP1A2 inducibility by benzo(alpha)pyrene

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dc.contributor.authorKonstandi, M.en
dc.contributor.authorLang, M. A.en
dc.contributor.authorKostakis, D.en
dc.contributor.authorJohnson, E. O.en
dc.contributor.authorMarselos, M.en
dc.date.accessioned2015-11-24T18:57:15Z
dc.date.available2015-11-24T18:57:15Z
dc.identifier.issn1742-7843-
dc.identifier.urihttps://olympias.lib.uoi.gr/jspui/handle/123456789/19145
dc.rightsDefault Licence-
dc.subjectAdrenergic alpha-2 Receptor Agonistsen
dc.subjectAdrenergic alpha-Agonists/pharmacologyen
dc.subjectAnimalsen
dc.subjectBenzo(a)pyrene/*pharmacologyen
dc.subjectCatecholamines/*metabolismen
dc.subjectCytochrome P-450 CYP1A2/*biosynthesis/geneticsen
dc.subjectDexmedetomidine/pharmacologyen
dc.subjectDrug Therapy, Combinationen
dc.subjectEnvironmental Pollutants/*pharmacologyen
dc.subjectEnzyme Induction/drug effectsen
dc.subjectGene Expression Regulation, Enzymologic/drug effectsen
dc.subjectGuanethidine/pharmacologyen
dc.subjectImidazoles/pharmacologyen
dc.subjectInjections, Intraperitonealen
dc.subjectMaleen
dc.subjectMicrosomes, Liver/drug effects/enzymologyen
dc.subjectRatsen
dc.subjectRats, Wistaren
dc.subjectReceptors, Adrenergic, alpha-2/metabolismen
dc.subjectReserpine/pharmacologyen
dc.subjectRestraint, Physicalen
dc.subjectStress, Physiological/*enzymologyen
dc.titlePredominant role of peripheral catecholamines in the stress-induced modulation of CYP1A2 inducibility by benzo(alpha)pyreneen
heal.abstractThe potential involvement of catecholamines and in particular of alpha(2)-adrenoceptor-related signalling pathways, in the regulation of drug-metabolizing enzymes by stress was investigated in Wistar rats after exposure to the environmental pollutant benzo(alpha)pyrene. For this purpose, total cytochrome P450 content, the CYP1A2 mRNA levels, 7-methoxyresorufin-O-dealkylase (MROD), 7-pentoxyresorufin-O-dealkylase (PROD) and p-nitrophenol hydroxylase activity levels were determined in the livers of rats exposed to repeated restraint stress after treatment with benzo(alpha)pyrene coupled with pharmacological manipulations of peripheral and/or central catecholamines and alpha(2)-adrenoceptors. The data show that stress is a significant factor in the regulation of CYP1A2 induction and that catecholamines play a central role in the stress-mediated modulation of hepatic CYP1A2 inducibility by benzo(alpha)pyrene. The up-regulating effect of stress on benzo(alpha)pyrene-induced CYP1A2 gene expression was eliminated after a generalized catecholamine depletion with reserpine. Similarly, in a state where only peripheral catecholamines were depleted and central catecholamines remained intact after guanethidine administration, the up-regulating effect of stress was eliminated. It is apparent that stress up-regulates the induction of CYP1A2 by benzo(alpha)pyrene mainly via peripheral catecholamines, while central catecholamines hold a minor role in the regulation. Pharmacological manipulations of alpha(2)-adrenoceptors appear to interfere with the effect of stress on the regulation of CYP1A2 inducibility. Either blockade or stimulation of alpha(2)-adrenoceptors with atipamezole and dexmedetomidine respectively, eliminated the up-regulating effect of stress on CYP1A2 benzo(alpha)pyrene-induced expression, while it enhanced MROD activity. In contrast, stress and pharmacological manipulations of catecholamines and alpha(2)-adrenoceptors did not affect total P450 content, the CYP2B1/2-dependent PROD and the CYP2E1-dependent p-nitrophenol hydroxylase activities. In conclusion, stress is a significant factor in the regulation of the CYP1A2 inducibility by benzo(alpha)pyrene, which in turn is involved in the metabolism of a large spectrum of toxicants, drugs and carcinogenic agents. Although the mechanism underlying the stress effect on CYP1A2 induction has not been clearly elucidated, it appears that peripheral catecholamines hold a predominant role, while central catecholamines and in particular, central noradrenergic pathways hold a minor role.en
heal.accesscampus-
heal.fullTextAvailabilityTRUE-
heal.identifier.primary10.1111/j.1742-7843.2007.00154.x-
heal.identifier.secondaryhttp://www.ncbi.nlm.nih.gov/pubmed/17973897-
heal.identifier.secondaryhttp://onlinelibrary.wiley.com/store/10.1111/j.1742-7843.2007.00154.x/asset/j.1742-7843.2007.00154.x.pdf?v=1&t=h0upgf2s&s=59c806157c44c023a13af6521d6d212e28e406c9-
heal.journalNameBasic Clin Pharmacol Toxicolen
heal.journalTypepeer-reviewed-
heal.languageen-
heal.publicationDate2008-
heal.recordProviderΠανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικήςel
heal.typejournalArticle-
heal.type.elΆρθρο Περιοδικούel
heal.type.enJournal articleen

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