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

  • Author / Creator
    Alsaad,Abdulaziz M
  • 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.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Specialization
    • Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • Dr. Ayman El-Kadi
  • Examining committee members and their departments
    • Clanachan, Alexander (Pharmacology)
    • Suebert, John (Pharmacy and Pharmaceutical Sciences)