Benzo(alpha)pyrene-induced up-regulation of CYP1A2 gene expression: Role of adrenoceptor-linked signaling pathways

Konstandi, Maria, Kostakis, Dimitris, Harkitis, Panagiotis, Johnson,Elizabeth O., Marselos, Marios, Adamidis, Konstadinos and Lang, Matti A. (2006) Benzo(alpha)pyrene-induced up-regulation of CYP1A2 gene expression: Role of adrenoceptor-linked signaling pathways. Life Sciences, 79 4: 331-341. doi:10.1016/j.lfs.2006.01.012

Author Konstandi, Maria
Kostakis, Dimitris
Harkitis, Panagiotis
Johnson,Elizabeth O.
Marselos, Marios
Adamidis, Konstadinos
Lang, Matti A.
Title Benzo(alpha)pyrene-induced up-regulation of CYP1A2 gene expression: Role of adrenoceptor-linked signaling pathways
Journal name Life Sciences   Check publisher's open access policy
ISSN 0024-3205
Publication date 2006-06-20
Sub-type Article (original research)
DOI 10.1016/j.lfs.2006.01.012
Open Access Status Not Open Access
Volume 79
Issue 4
Start page 331
End page 341
Total pages 11
Place of publication New York , USA
Publisher Elsevier
Language eng
Subject 11 Medical and Health Sciences
Abstract CYP1A2, a principal catalyst for metabolism of various therapeutic drugs and carcinogens, among others, is in part regulated by the stress response. This study was designed to assess whether catecholamines and in particular adrenergic receptor-dependent pathways, modulate benzo(α)pyrene (B(α)P)-induced hepatic CYP1A2. To distinguish between the role of central and peripheral catecholamines in the regulation of CYP1A2 induction, the effect of central and peripheral catecholamine depletion using reserpine was compared to that of peripheral catecholamine depletion using guanethidine. The effects of peripheral adrenaline and L-DOPA administration were also assessed. The results suggest that alterations in central catecholamines modulate 7-methoxyresorufin O-demethylase activity (MROD), CYP1A2 mRNA and protein levels in the B(α)P-induced state. In particular, central catecholamine depletion, dexmedetomidine-induced inhibition of noradrenaline release and blockade of α1-adrenoceptors with prazosin, up-regulated CYP1A2 expression. Phenylephrine and dexmedetomidine-induced up-regulation may be mediated, in part, via peripheral α1- and α2-adrenoceptors, respectively. On the other hand, the L-DOPA-induced increase in central dopaminergic activity was not followed by any change in the up-regulation of CYP1A2 expression by B(α)P. Central noradrenergic systems appeared to counteract up-regulating factors, most likely via α1- and α2-adrenoceptors. In contrast, peripheral alpha- and beta-adrenoceptor-related signaling pathways are linked to up-regulating processes. The findings suggest that drugs that bind to adrenoceptors or affect central noradrenergic neurotransmission, as well as factors that challenge the adrenoceptor-linked signaling pathways may deregulate CYP1A2 induction. This, in turn, may result in drug-therapy and drug-toxicity complications.
Keyword Benzo(alpha)pyrene
Hydrocarbon receptor
Cytochroomes P-450
Q-Index Code C1

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 11 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 01 Dec 2009, 01:04:24 EST