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First published on August 25, 2008; DOI: 10.1124/dmd.108.023077

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Received for publication June 24, 2008.
Revised August 19, 2008.
Accepted for publication August 21, 2008.

Modulation of cytochrome P450 gene expression and arachidonic acid metabolism during isoproterenol-induced cardiac hypertrophy in rats

Beshay N.M. Zordoky 1, Mona E. Aboutabl 1, Ayman O.S. El-Kadi 1*

1 University of Alberta

* Address correspondence to: E-mail: aelkadi{at}pharmacy.ualberta.ca

Abstract

Several CYP enzymes have been identified in the heart and their levels have been reported to be altered during cardiac hypertrophy. Moreover, there is a strong correlation between CYP-mediated arachidonic acid metabolites and the pathogenesis of cardiac hypertrophy. Therefore, we investigated the effect of isoproterenol-induced cardiac hypertrophy on the expression of several CYP genes and their associated CYP-dervided metabolites of arachidonic acid. Cardiac hypertrophy was induced by seven daily intraperitoneal injections of 5 mg/kg isoproterenol. Thereafter, the heart, lung, liver, and kidney were harvested and the expression of different genes was determined by real time-PCR. Heart microsomal protein from control or isoproterenol treated rats was incubated with 50 µM arachidonic acid, and arachidonic acid metabolites were determined by liquid chromatography-electron spray ionization-mass spectrometry. Our results show that isoproterenol treatment significantly increased the heart to body weight ratio as well as the hypertrophic markers. In addition, there was a significant induction of CYP1A1, CYP1B1, CYP4A3, and soluble epoxide hydrolase and a significant inhibition of CYP2C11 and CYP2E1 in the hypertrophied hearts as compared to the control. CYP1A1, CYP2E1, and CYP4A3 gene expression was induced in the kidney and CYP4A3 was induced in the liver of isoproterenol-treated rats. Isoproterenol treatment significantly reduced 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid formation and significantly increased their corresponding 8,9-, and 14,15-dihydroxyeicosatrienoic acid as well as the 20-hydroxyeicosatetraenoic acid metabolite. In conclusion, isoproterenol-induced cardiac hypertrophy alters arachidonic acid metabolism and its associated CYP enzymes, suggesting their role in the development and/or progression of cardiac hypertrophy.


Key words: arachidonic acid metabolism, cardiac toxicity, CYP expression, cytochrome P450, extrahepatic cytochrome P450




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