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HERO ID
1007596
Reference Type
Journal Article
Title
3-methylcholanthrene and benzo(a)pyrene modulate cardiac cytochrome P450 gene expression and arachidonic acid metabolism in male Sprague Dawley rats
Author(s)
Aboutabl, ME; Zordoky, BN; El-Kadi, AO
Year
2009
Is Peer Reviewed?
Yes
Journal
British Journal of Pharmacology
ISSN:
0007-1188
EISSN:
1476-5381
Volume
158
Issue
7
Page Numbers
1808-1819
Language
English
PMID
19889059
DOI
10.1111/j.1476-5381.2009.00461.x
Web of Science Id
WOS:000272305300018
Abstract
BACKGROUND AND PURPOSE: There is a strong correlation between cytochrome P450 (P450)-dependent arachidonic acid metabolism and the pathogenesis of cardiac hypertrophy. Several aryl hydrocarbon receptor (AhR) ligands were found to alter P450-dependent arachidonic acid metabolism. Here, we have investigated the effect of 3-methylcholanthrene (3-MC) and benzo(a)pyrene (BaP), two AhR ligands, on the development of cardiac hypertrophy. EXPERIMENTAL APPROACH: Male Sprague Dawley rats were injected (i.p.) daily with either 3-MC (10 mg kg(-1)) or BaP (20 mg kg(-1)) for 7 days. Then hearts were removed, and the heart to body weight ratio and the gene expression of the hypertrophic markers and P450 genes were determined. Levels of arachidonic acid metabolites were determined by liquid chromatography-electron spray ionization-mass spectrometry. KEY RESULTS: Both 3-MC and BaP increased the heart to body weight ratio as well as the hypertrophic markers, atrial natriuretic peptide and brain natriuretic peptide. 3-MC and BaP treatment increased the gene expression of CYP1A1, CYP1B1, CYP2E1, CYP4F4, CYP4F5 and soluble epoxide hydrolase. Both 3-MC and BaP treatments increased the dihydroxyeicosatrienoic acids (DHETs) : epoxyeicosatrienoic acids (EETs) ratio and the 20-hydroxyeicosatetraenoic acid (20-HETE) : total EETs ratio. Treatment with benzo(e)pyrene, an isomer of BaP that is a poor ligand for the AhR, did not induce cardiac hypertrophy in rats, confirming the role of AhR in the development of cardiac hypertrophy. Treatment with the omega-hydroxylase inhibitor, HET0016, significantly reversed BaP-induced cardiac hypertrophy. CONCLUSIONS AND IMPLICATIONS: 3-MC and BaP induce cardiac hypertrophy by increasing the ratio of DHETs : EETs and/or the ratio of 20-HETE : total EETs, through increasing soluble epoxide hydrolase activity.
Keywords
Animals; Arachidonic Acid/metabolism; Benzo(a)pyrene/ toxicity; Cardiomegaly/chemically induced/ physiopathology; Chromatography, Liquid; Cytochrome P-450 Enzyme System/ drug effects/genetics/metabolism; Gene Expression Regulation, Enzymologic/drug effects; Heart/drug effects; Hydroxyeicosatetraenoic Acids/metabolism; Ligands; Male; Methylcholanthrene/ toxicity; Organ Size/drug effects; Rats; Rats, Sprague-Dawley; Receptors, Aryl Hydrocarbon/drug effects/metabolism; Spectrometry, Mass, Electrospray Ionization
Tags
IRIS
•
Benzo(a)pyrene (BaP)
Cardiotox - selected for full text review (private)
Considered
Identified During External Peer Review
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