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

Konstandi, Maria, Lang, Matti A., Kostakis, Dimitris, Johnson, Elizabeth O. and Marselos, Marios (2008) Predominant role of peripheral catecholamines in the stress-induced modulation of CYP1A2 inducibility by benzo(alpha)pyrene. Basic and Clinical Pharmacology and Toxicology, 102 1: 35-44. doi:10.1111/j.1742-7843.2007.00154.x

Author Konstandi, Maria
Lang, Matti A.
Kostakis, Dimitris
Johnson, Elizabeth O.
Marselos, Marios
Title Predominant role of peripheral catecholamines in the stress-induced modulation of CYP1A2 inducibility by benzo(alpha)pyrene
Formatted title
Predominant Role of Peripheral Catecholamines in the Stress-Induced Modulation of CYP1A2 Inducibility by Benzo(α)pyrene
Journal name Basic and Clinical Pharmacology and Toxicology   Check publisher's open access policy
ISSN 1742-7835
Publication date 2008-01-01
Sub-type Article (original research)
DOI 10.1111/j.1742-7843.2007.00154.x
Open Access Status Not Open Access
Volume 102
Issue 1
Start page 35
End page 44
Total pages 10
Place of publication United Kingdom, Denmark
Publisher Wiley-Blackwell Publishing
Language eng
Subject 0304 Medicinal and Biomolecular Chemistry
03 Chemical Sciences
Abstract The potential involvement of catecholamines and in particular of α2-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 α2-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 α2-adrenoceptors appear to interfere with the effect of stress on the regulation of CYP1A2 inducibility. Either blockade or stimulation of α2-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 α2-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.
Keyword Drug metabolizing enzymes
Rat liver
Cytochrome P450 Isozymes
Hydrocarbon receptor
Hormonal regulation
Oxidative stress
Gene expression
Q-Index Code C1
Q-Index Status Provisional Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
National Research Centre for Environmental Toxicology Publications
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Citation counts: TR Web of Science Citation Count  Cited 6 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 01 Dec 2009, 01:04:54 EST