Predominant role of peripheral catecholamines in the stress-induced modulation of CYP1A2 inducibility by benzo(alpha)pyrene
Φόρτωση...
Ημερομηνία
Συγγραφείς
Konstandi, M.
Lang, M. A.
Kostakis, D.
Johnson, E. O.
Marselos, M.
Τίτλος Εφημερίδας
Περιοδικό ISSN
Τίτλος τόμου
Εκδότης
Περίληψη
Τύπος
Είδος δημοσίευσης σε συνέδριο
Είδος περιοδικού
peer-reviewed
Είδος εκπαιδευτικού υλικού
Όνομα συνεδρίου
Όνομα περιοδικού
Basic Clin Pharmacol Toxicol
Όνομα βιβλίου
Σειρά βιβλίου
Έκδοση βιβλίου
Συμπληρωματικός/δευτερεύων τίτλος
Περιγραφή
The 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.
Περιγραφή
Λέξεις-κλειδιά
Adrenergic alpha-2 Receptor Agonists, Adrenergic alpha-Agonists/pharmacology, Animals, Benzo(a)pyrene/*pharmacology, Catecholamines/*metabolism, Cytochrome P-450 CYP1A2/*biosynthesis/genetics, Dexmedetomidine/pharmacology, Drug Therapy, Combination, Environmental Pollutants/*pharmacology, Enzyme Induction/drug effects, Gene Expression Regulation, Enzymologic/drug effects, Guanethidine/pharmacology, Imidazoles/pharmacology, Injections, Intraperitoneal, Male, Microsomes, Liver/drug effects/enzymology, Rats, Rats, Wistar, Receptors, Adrenergic, alpha-2/metabolism, Reserpine/pharmacology, Restraint, Physical, Stress, Physiological/*enzymology
Θεματική κατηγορία
Παραπομπή
Σύνδεσμος
http://www.ncbi.nlm.nih.gov/pubmed/17973897
http://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
http://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
Γλώσσα
en
Εκδίδον τμήμα/τομέας
Όνομα επιβλέποντος
Εξεταστική επιτροπή
Γενική Περιγραφή / Σχόλια
Ίδρυμα και Σχολή/Τμήμα του υποβάλλοντος
Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής