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Predominant Role of Peripheral Catecholamines in the Stress‐Induced Modulation of CYP1A2 Inducibility by Benzo(α)pyrene
Author(s) -
Konstandi Maria,
Lang Matti A.,
Kostakis Dimitris,
Johnson Elizabeth O.,
Marselos Marios
Publication year - 2008
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2007.00154.x
Subject(s) - chemistry , cyp1a2 , endocrinology , medicine , benzo(a)pyrene , alpha (finance) , catecholamine , stimulation , pyrene , pharmacology , cytochrome p450 , biochemistry , biology , enzyme , construct validity , nursing , organic chemistry , patient satisfaction
The potential involvement of catecholamines and in particular of α 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(α)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(α)pyrene coupled with pharmacological manipulations of peripheral and/or central catecholamines and α 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(α)pyrene. The up‐regulating effect of stress on benzo(α)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(α)pyrene mainly via peripheral catecholamines, while central catecholamines hold a minor role in the regulation. Pharmacological manipulations of α 2 ‐adrenoceptors appear to interfere with the effect of stress on the regulation of CYP1A2 inducibility. Either blockade or stimulation of α 2 ‐adrenoceptors with atipamezole and dexmedetomidine respectively, eliminated the up‐regulating effect of stress on CYP1A2 benzo(α)pyrene‐induced expression, while it enhanced MROD activity. In contrast, stress and pharmacological manipulations of catecholamines and α 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(α)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.