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

Journal Article · Fri Jan 01 04:00:00 EST 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.09.012· OSTI ID:21344824

Zordoky, Beshay N.M.; Anwar-Mohamed, Anwar; Aboutabl, Mona E ^[1]

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1. Faculty of Pharmacy and Pharmaceutical Sciences, 3126 Dentistry/Pharmacy Centre, University of Alberta, Edmonton, Alberta, T6G 2N8 (Canada)

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 omega-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.

• OSTI ID: 21344824
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 242; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANIMALS
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
ANTINEOPLASTIC DRUGS
ARACHIDONIC ACID
BODY
CARBOXYLIC ACIDS
CARDIOVASCULAR DISEASES
CARDIOVASCULAR SYSTEM
CELL CONSTITUENTS
DISEASES
DOSES
DOXORUBICIN
DRUGS
ENZYMES
GENES
HEART
HYDROXYLASES
INJECTION
INTAKE
INTRAPERITONEAL INJECTION
MAMMALS
METABOLISM
METABOLITES
MICROSOMES
MONOCARBOXYLIC ACIDS
NEOPLASMS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
OXIDOREDUCTASES
PATHOGENESIS
PROTEINS
RATS
RIBOSOMES
RODENTS
TOXICITY
VERTEBRATES