Acute doxorubicin cardiotoxicity alters cardiac cytochrome P450 expression and arachidonic acid metabolism in rats

• Published in: Toxicology and applied pharmacology Vol. 242; no. 1; pp. 38 - 46
• Main Authors: Zordoky, Beshay N.M., Anwar-Mohamed, Anwar, Aboutabl, Mona E., El-Kadi, Ayman O.S.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 2010; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; ANIMALS; ANTI-INFECTIVE AGENTS; ANTIBIOTICS; Antibiotics, Antineoplastic - toxicity; ANTINEOPLASTIC DRUGS; ARACHIDONIC ACID; Arachidonic Acid - metabolism; Biological and medical sciences; BODY; CARBOXYLIC ACIDS; Cardiomegaly - enzymology; Cardiotoxicity; CARDIOVASCULAR DISEASES; CARDIOVASCULAR SYSTEM; CELL CONSTITUENTS; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - genetics; Cytochrome P450; DISEASES; DOSES; DOXORUBICIN; Doxorubicin - toxicity; DRUGS; ENZYMES; Epoxide Hydrolase; Epoxide Hydrolases - genetics; Epoxide Hydrolases - metabolism; Gene Expression Regulation, Enzymologic - drug effects; GENES; HEART; Heart Diseases - chemically induced; Heart Diseases - enzymology; Hydroxyeicosatetraenoic Acids - metabolism; HYDROXYLASES; INJECTION; INTAKE; INTRAPERITONEAL INJECTION; Isoenzymes - biosynthesis; Isoenzymes - genetics; L-Lactate Dehydrogenase - biosynthesis; L-Lactate Dehydrogenase - genetics; Male; MAMMALS; Medical sciences; METABOLISM; METABOLITES; MICROSOMES; Microsomes - drug effects; Microsomes - enzymology; MONOCARBOXYLIC ACIDS; Myocardium - enzymology; Myocardium - metabolism; NEOPLASMS; ORGANIC ACIDS; ORGANIC COMPOUNDS; ORGANS; OXIDOREDUCTASES; PATHOGENESIS; PROTEINS; RATS; Rats, Sprague-Dawley; RIBOSOMES; RODENTS; TOXICITY; Toxicology; VERTEBRATES; Cytochrome P450; Cardiotoxicity; DOX; Arachidonic acid; Doxorubicin; HETE; SD; LDH; DHET; EET; sEH; CYP; Epoxide Hydrolase; Antineoplastic agent; Heart; Rat; Toxicity; Lipids; Cardiovascular disease; Epoxide hydrolase; Isomerases; Heart disease; DNA topoisomerase (ATP-hydrolysing); Enzyme; Acute; Rodentia; Polyunsaturated fatty acid; Enzyme inhibitor; Topoisomerase II inhibitor; Metabolism; Vertebrata; Antibiotic; Mammalia; Animal; Ether hydrolases; Hydrolases; Anthracyclins; Circulatory system
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2009.09.012

Doxorubicin (DOX) is a potent anti-neoplastic antibiotic used to treat a variety of malignancies; however, its use is limited by dose-dependent cardiotoxicity. Moreover, there is a strong correlation between cytochrome P450 (CYP)-mediated arachidonic acid metabolites and the pathogenesis of many cardiovascular diseases. Therefore, in the current study, we have investigated the effect of acute DOX toxicity on the expression of several CYP enzymes and their associated arachidonic acid metabolites in the heart of male Sprague–Dawley rats. Acute DOX toxicity was induced by a single intraperitoneal injection of 15 mg/kg of the drug. Our results showed that DOX treatment for 24 h caused a significant induction of CYP1A1, CYP1B1, CYP2C11, CYP2J3, CYP4A1, CYP4A3, CYP4F1, CYP4F4, and EPHX2 gene expression in the heart of DOX-treated rats as compared to the control. Similarly, there was a significant induction of CYP1A1, CYP1B1, CYP2C11, CYP2J3, CYP4A, and sEH proteins after 24 h of DOX administration. In the heart microsomes, acute DOX toxicity significantly increased the formation of 20-HETE which is consistent with the induction of the major CYP ω-hydroxylases: CYP4A1, CYP4A3, CYP4F1, and CYP4F4. On the other hand, the formation of 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) was significantly reduced, whereas the formation of their corresponding dihydroxyeicosatrienoic acids was significantly increased. The decrease in the cardioprotective EETs can be attributed to the increase of sEH activity parallel to the induction of the EPHX2 gene expression in the heart of DOX-treated rats. In conclusion, acute DOX toxicity alters the expression of several CYP and sEH enzymes with a consequent alteration in arachidonic acid metabolism. These results may represent a novel mechanism by which this drug causes progressive cardiotoxicity.