RT Journal Article
SR Electronic
T1 Chronic Doxorubicin Cardiotoxicity Modulates Cardiac Cytochrome P450-Mediated Arachidonic Acid Metabolism in Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2126
OP 2135
DO 10.1124/dmd.112.046631
VO 40
IS 11
A1 Abdulaziz M. S. Alsaad
A1 Beshay N. M. Zordoky
A1 Ahmed A. El-Sherbeni
A1 Ayman O. S. El-Kadi
YR 2012
UL http://dmd.aspetjournals.org/content/40/11/2126.abstract
AB Doxorubicin [(DOX) Adriamycin] is an effective anticancer agent whose major limiting side effect is cardiotoxicity. This cardiotoxicity is predicted only by the cumulative dose of DOX where the clinical situation involves chronic drug administration. Therefore, we investigate the effect of chronic DOX cardiotoxicity on expression of the cardiac cytochrome P450 (P450) enzymes and arachidonic acid (AA) metabolism in male Sprague-Dawley (SD) rats. The chronic toxicity was induced by multiple intraperitoneal injections for a cumulative dose of 15 mg/kg divided into six injections within 2 weeks. After 14 days of the last injection, the heart, liver, and kidney were harvested, and the expression of different genes was determined by real-time polymerase chain reaction. In addition, microsomal protein from the heart was prepared and incubated with AA. Thereafter, different AA metabolites were analyzed by liquid chromatography-electrospray ionization-mass spectrometry. The chronic DOX cardiotoxicity significantly induced gene expression of hypertrophic markers, apoptotic markers, CYP2E1, CYP4A3, CYP4F1, CYP4F5, and soluble epoxide hydrolase (sEH) enzyme, which was accompanied by an increase in the activity of P450 ω-hydroxylases and sEH. In addition, both the sEH inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid, and the ω-hydroxylase inhibitor, N-hydroxy-N′-(4-butyl-2-methylphenyl)-formamidine (HET0016), significantly prevented the DOX-mediated induction of the hypertrophic markers in the cardiac-derived H9c2 cells, which further confirms the role of these enzymes in DOX cardiotoxicity. Furthermore, gene expression of P450 and sEH was altered in an organ-specific manner. As a result, the chronic DOX administration leads to an imbalance between P450-mediated cardiotoxic and cardioprotective pathways. Therefore, P450 ω-hydroxylases and sEH might be considered as novel targets to prevent and/or treat DOX cardiotoxicity.