Abstract
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.
Footnotes
This work was supported by the Canadian Institutes of Health Research [Grant 106665]. A.M.S.A. is a teaching assistant at King Saud University (KSU) and the recipient of the active scholarship from the ministry of higher education and KSU, Riyadh, Saudi Arabia.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- DOX
- doxorubicin
- P450
- cytochrome P450
- AA
- arachidonic acid
- EET
- epoxyeicosatrienoic acid
- HETE
- hydroxyeicosatetraenoic acid
- sEH
- soluble epoxide hydrolase
- DHET
- dihydroxyeicosatrienoic acid
- t-AUCB
- trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid
- RT
- reverse transcriptase
- HET0016
- N-hydroxy-N′-(4-butyl-2-methylphenyl)-formamidine
- PCR
- polymerase chain reaction
- LC-ESI-MS
- liquid chromatography-electrospray ionization-mass spectrometry
- HPLC
- high-performance liquid chromatography
- SD
- Sprague-Dawley
- IL
- interleukin
- ANP
- atrial natriuretic peptide
- MHC
- myosin heavy chain
- BNP
- brain natriuretic peptide
- TNFα
- tumor necrosis factor α
- Bax
- B-cell lymphoma 2-associated X protein.
- Received May 4, 2012.
- Accepted August 6, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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