title: Stress-mediated modulation of B(alpha)P-induced hepatic CYP1A1: role of catecholamines.
abstract: The present study investigated the involvement of catecholamines in stress-mediated alterations in CYP1A1 induction by benzo(alpha)pyrene (B(alpha)P) in Wistar rats. This was achieved by measuring EROD activity and CYP1A1 mRNA levels in liver tissue from rats exposed to restraint stress and B(alpha)P coupled with pharmacological modulation of peripheral and central catecholamine levels and different adrenoceptors. In a state of reserpine-induced central and peripheral catecholamine depletion, stress strongly suppressed EROD induction. Peripheral catecholamines do not appear to play a critical role in the stress-mediated modulation of EROD inducibility by B(alpha)P. Stress did not alter EROD inducibility by B(alpha)P when peripheral catecholamines were either depleted by guanethidine or supplemented by peripheral adrenaline administration. On the other hand, central noradrenergic systems appear to have a role in the stress-mediated changes in B(alpha)P-induced EROD activity and Cyp1A1 gene expression. Stimulation or blockade of noradrenaline release with atipamezole and dexmedetomidine, respectively, significantly modified the up-regulating effect of stress. Alpha1 adrenoceptors also appear to participate in the effect of stress on EROD inducibility. Alpha1-blockade with prazosin potentiated the up-regulating effect of stress, possibly preventing the down-regulating effect of noradrenaline. Beta adrenoceptors also seem to be involved directly or indirectly in the stress-mediated modulation of Cyp1A1, as propranolol (beta-antagonist) blocked the down-regulating effect of stress on B(alpha)P-induced Cyp1A1 gene expression. Plasma corticosterone alterations after stress were not related to alterations in the B(alpha)P-induced EROD activity and Cyp1A1 gene expression. In conclusion, stress appears to interfere in the regulation of B(alpha)P-induced hepatic CYP1A1 in an unpredictable manner and via signalling pathways not always directly related to catecholamines. In particular, whenever drug treatment disrupts noradrenergic neurotransmission, other stress-stimulated factors appear to modify the induction of CYP1A1. In summary, regulation of induction of hepatic CYP1A1 during stress appears to involve various components of the stress system, including central and peripheral catecholamines, which interact in a complex manner, yet to be elucidated.
authors.affiliation: Department of Pharmacology, Medical School, University of Ioannina, GR-451 10 Ioannina, Greece. mkonstan@cc.uoi.gr
authors.forename: Maria
authors.initials: M
authors.lastname: Konstandi
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Johnson
authors.forename: Marios
authors.initials: M
authors.lastname: Marselos
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kostakis
authors.forename: Andreas
authors.initials: A
authors.lastname: Fotopoulos
authors.forename: Matti A
authors.initials: MA
authors.lastname: Lang
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D002395:Catecholamines / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000378:metabolism*; D020927:Dexmedetomidine / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012110:Reserpine / Q000494:pharmacology; D012149:Restraint, Physical; D013312:Stress, Physiological / Q000201:enzymology*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D007093:Imidazoles; D012333:RNA, Messenger; C050701:atipamezole; D001564:Benzo(a)pyrene; D020927:Dexmedetomidine; D012110:Reserpine; D011433:Propranolol; D019363:Cytochrome P-450 CYP1A1; D003345:Corticosterone; D011224:Prazosin