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Metabonomic identification of novel biomarkers in doxorubicin cardiotoxicity and protective effect of the natural antioxidant oleuropein
Author(s) -
Andreadou Ioanna,
Papaefthimiou Maria,
Zira Athina,
Constantinou Maria,
Sigala Fragiska,
Skaltsounis AlexiosLeandros,
TsantiliKakoulidou Anna,
Iliodromitis Efstathios K.,
Kremastinos Dimitrios T.,
Mikros Emmanuel
Publication year - 2009
Publication title -
nmr in biomedicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.278
H-Index - 114
eISSN - 1099-1492
pISSN - 0952-3480
DOI - 10.1002/nbm.1370
Subject(s) - cardiotoxicity , chemistry , antioxidant , pharmacology , oleuropein , oxidative stress , toxicity , doxorubicin , biochemistry , medicine , chemotherapy , organic chemistry
Doxorubicin (DXR) is a commonly used antineoplastic agent; however, its use is limited due to cardiotoxicity. Oxidative stress and consequent alterations of cardiac energetics are involved in the development of DXR toxicity. Oleuropein (Oleu) is a phenolic antioxidant, present in olive tree, reported to confer protection against DXR cardiotoxicity. In this study, NMR based‐metabonomics was applied to characterize the metabolic profile of the acute DXR cardiotoxicity in rats and to evaluate the metabolic alterations conferred by co‐treatment with Oleu. Wistar rats were divided into six groups and treated as follows: control group with a single injection of 2 mL normal saline intraperitoneally (i.p.), DXR group with a single dose of 20 mg/kg, i.p and DXR plus Oleu groups with 20mg/kg DXR i.p., and 100 or 200 mg/kg/BW of Oleu i.p. for 5 or 3 consecutive days starting either 2 days before or on the day of DXR administration. Hearts were excised 72 h after DXR treatment and 1 H‐NMR spectra of aqueous myocardium extracts were recorded. Principal Component Analysis (PCA) and Partial Least Square Discriminant Analysis (PLS‐DA) revealed differences in the metabolic profile between control and DXR attributed to several metabolites. A number of them were quantified by integration of the NMR spectra. Myocardial levels of acetate and succinate were increased in DXR compared to controls, while branched amino acids were decreased. These results correlate with nonenzymatic conversion of pyruvate to acetate and of α ‐ketoglutarate to succinate by DXR free radicals. Oleu completely restored the changes of metabolites to the normal levels. Acetate and succinate constitute novel biomarkers related to DXR, and Oleu treatment aids the compensation of distressed energy metabolic pathways. Copyright © 2009 John Wiley & Sons, Ltd.