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Role of CYP-mediated Arachidonic Acid Metabolites in Development of Cardiac Hypertrophy and Chronic Doxorubicin-induced Cardiotoxicity Open Access


Other title
Arachidonic acid
cardiac hypertrophy
Type of item
Degree grantor
University of Alberta
Author or creator
Alsaad,Abdulaziz M
Supervisor and department
Dr. Ayman El-Kadi
Examining committee member and department
Suebert, John (Pharmacy and Pharmaceutical Sciences)
Clanachan, Alexander (Pharmacology)
Faculty of Pharmacy and Pharmaceutical Sciences
Pharmaceutical Sciences
Date accepted
Graduation date
Master of Science
Degree level
Drug-induced cardiotoxicity is classified as a predisposing factor leading to cardiac hypertrophy and heart failure. Of importance, doxorubicin (DOX, adriamycin) is considered as an effective anticancer agent whose major limiting side effect is cardiotoxicity. Of importance, several studies showed that acute DOX cardiotoxicity alters cytochrome P450 (CYP)-mediated arachidonic acid (AA) metabolism. However, the clinical situation involves chronic drug administration. Therefore, we investigated the effect of chronic DOX treatment on expression of cardiac CYP enzymes and CYP-mediated AA metabolism in male Sprague–Dawley (SD) rats. Our results showed that chronic DOX treatment significantly induced gene expression and activity of CYP ω-hyroxylase and soluble epoxide hydrolase (sEH) enzymes. Inhibition of these enzymes significantly prevented DOX-mediated induction of hypertrophic markers in H9c2 cells confirming the role of these enzymes in DOX cardiotoxicity. In conclusion, CYP ω-hyroxylase and sEH enzymes might be considered as novel targets to treat and/or to protect against DOX cardiotoxicity.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Alsaad, A. M., Zordoky, B. N., El-Sherbeni, A. A., & El-Kadi, A. O. (2012). Chronic Doxorubicin cardiotoxicity modulates cardiac cytochrome p450-mediated arachidonic Acid metabolism in rats. Drug metabolism and disposition: the biological fate of chemicals, 40, 2126-2135.

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