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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
- Type of item
- Degree grantor
University of Alberta
- Author or creator
- 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
- 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.
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- 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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