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In vivo and in vitro assessment of the role of glutathione antioxidant system in anthracycline-induced cardiotoxicity
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SYSNO ASEP 0370022 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title In vivo and in vitro assessment of the role of glutathione antioxidant system in anthracycline-induced cardiotoxicity Author(s) Vávrová, A. (CZ)
Popelová, O. (CZ)
Štěrba, M. (CZ)
Jirkovský, E. (CZ)
Hašková, P. (CZ)
Mertlíková-Kaiserová, Helena (UOCHB-X) RID, ORCID
Geršl, V. (CZ)
Šimůnek, T. (CZ)Number of authors 8 Source Title Archives of Toxicology - ISSN 0340-5761
Roč. 85, č. 5 (2011), s. 525-535Number of pages 11 s. Language eng - English Country DE - Germany Keywords anthracycline cardiotoxicity ; daunorubicin ; glutathione ; glutathione peroxidase ; glutathione peroxidase Subject RIV CE - Biochemistry CEZ AV0Z40550506 - UOCHB-X (2005-2011) UT WOS 000290318800008 DOI 10.1007/s00204-010-0615-8 Annotation The clinical usefulness of anthracycline antineoplastic drugs is limited by their cardiotoxicity. Its mechanisms have not been fully understood, although the induction of oxidative stress is widely believed to play the principal role. Glutathione is the dominant cellular antioxidant, while glutathione peroxidase (GPx) together with glutathione reductase (GR) constitutes the major enzymatic system protecting the cardiac cells from oxidative damage. Therefore, this study aimed to assess their roles in anthracycline cardiotoxicity. Ten-week intravenous administration of daunorubicin (DAU, 3 mg/kg weekly) to rabbits induced heart failure, which was evident from decreased left ventricular ejection fraction and release of cardiac troponins to circulation. However, no significant changes in either total or oxidized glutathione contents or GR activity were detected in left ventricular tissue of DAU-treated rabbits when compared with control animals. GPx activity in the cardiac tissue significantly increased. In H9c2 rat cardiac cells, 24-h DAU exposure (0.1–10 lM) induced significant dose-dependent toxicity. Cellular content of reduced glutathione was insignificantly decreased, oxidized glutathione and GR activity were unaffected, and GPx activity was significantly increased. Neither buthionine sulfoximine (BSO, glutathione biosynthesis inhibitor) nor 2-oxo-4-thiazolidine-carboxylic acid (OTC, glutathione biosynthetic precursor) had significant effects on DAU cytotoxicity. This contrasted with model oxidative injury induced by hydrogen peroxide, which cytotoxicity was increased by BSO and decreased by OTC. In conclusion, our results suggest that the dysfunction of glutathione antioxidant system does not play a causative role in anthracycline cardiotoxicity. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2012
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