caa a22 4500 445853905 CHVBK 20180317145422.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s00204-010-0615-8 doi (NATIONALLICENCE)springer-10.1007/s00204-010-0615-8 In vivo and in vitro assessment of the role of glutathione antioxidant system in anthracycline-induced cardiotoxicity [Elektronische Daten] [Anna Vávrová, Olga Popelová, Martin Štěrba, Eduard Jirkovský, Pavlína Hašková, Helena Mertlíková-Kaiserová, Vladimír Geršl, Tomáš Šimůnek] 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, 3mg/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 (0.1-10μM) 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. Springer-Verlag, 2010 Anthracycline cardiotoxicity nationallicence Daunorubicin nationallicence Glutathione nationallicence Glutathione peroxidase nationallicence Glutathione reductase nationallicence Vávrová Anna Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic aut Popelová Olga Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, 500 38, Hradec Králové, Czech Republic aut Štěrba Martin Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, 500 38, Hradec Králové, Czech Republic aut Jirkovský Eduard Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic aut Hašková Pavlína Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic aut Mertlíková-Kaiserová Helena Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic aut Geršl Vladimír Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, 500 38, Hradec Králové, Czech Republic aut Šimůnek Tomáš Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic aut Archives of Toxicology Springer-Verlag 85/5(2011-05-01), 525-535 0340-5761 85:5<525 2011 85 204 https://doi.org/10.1007/s00204-010-0615-8 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00204-010-0615-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Vávrová Anna Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic aut NATIONALLICENCE 700 1- Popelová Olga Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, 500 38, Hradec Králové, Czech Republic aut NATIONALLICENCE 700 1- Štěrba Martin Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, 500 38, Hradec Králové, Czech Republic aut NATIONALLICENCE 700 1- Jirkovský Eduard Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic aut NATIONALLICENCE 700 1- Hašková Pavlína Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic aut NATIONALLICENCE 700 1- Mertlíková-Kaiserová Helena Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic aut NATIONALLICENCE 700 1- Geršl Vladimír Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, 500 38, Hradec Králové, Czech Republic aut NATIONALLICENCE 700 1- Šimůnek Tomáš Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic aut NATIONALLICENCE 773 0- Archives of Toxicology Springer-Verlag 85/5(2011-05-01), 525-535 0340-5761 85:5<525 2011 85 204 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer