| Acute Doxorubicin Toxicity Differentially Alters Cytochrome P450 Expression and Arachidonic Acid Metabolism in Rat Kidney and Liver. | |
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MedLine Citation:
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PMID: 21571947 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The use of doxorubicin (DOX) is limited by significant cardiotoxicity, nephrotoxicity, and hepatotoxicity. We have previously shown that DOX cardiotoxicity induces several cardiac cytochrome P450 (P450) enzymes with subsequent alteration in P450-mediated arachidonic acid metabolism. Therefore, in the current study, we investigated the effect of acute DOX toxicity on P450 expression and arachidonic acid metabolism in the kidney and liver of male Sprague Dawley rats. Acute DOX toxicity was induced by a single intraperitoneal injection of 15 mg/kg of the drug. After 6 and 24 h, the kidneys and livers were harvested and the expression of several P450 gene and protein expressions were determined by real time-PCR and Western blot analyses, respectively. Kidney and liver microsomal protein from control or DOX treated rats was incubated with arachidonic acid, and its metabolites were determined by liquid chromatography-electron spray ionization-mass spectrometry. Our results showed that acute DOX toxicity caused an induction of CYP1B1 and CYP4A enzymes and an inhibition of CYP2B1 and CYP2C11 in both the kidney and liver. CYP2E1 was induced and soluble epoxide hydrolase (sEH) was inhibited in the kidney only. In addition, DOX toxicity caused a significant increase in the epoxyeicosatrienoic acids formation in the kidney and a significant increase in 20-hydroxyeicosatetraenoic acid formation in both the kidney and the liver. In conclusion, acute DOX toxicity alters the expression of several P450 and sEH enzymes in an organ-specific manner. These changes can be attributed to DOX-induced inflammation and resulted in altered P450-mediated arachidonic acid metabolism. |
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Authors:
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Beshay Nazmy Mounir Zordoky; Anwar Anwar-Mohamed; Mona Aboutabl; Ayman O S El-Kadi |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-13 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: - ISSN: 1521-009X ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1 Faculty of Pharmacy, University of Alberta; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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