TY  - THES
T1  - Assessment of in vitro cardiotoxicity using metabolomics and 13C metabolic flux analysis
A1  - Strigun,Alexander
Y1  - 2012/08/31
N2  - The potential of respiration measurements, metabolomics and 13C metabolic flux analysis (13CMFA) for the determination of drug-induced cardiotoxicity was analysed. Two cardiac in vitro models, namely murine HL-1 cells and human embryonic stem cell derived cardiomyocytes (hESC-CM) were applied for this purpose. Respiration measurement in HL-1 cells upon drug treatment revealed distinct EC50 profiles. The toxicity occurred either fast or with a delay. This effect was dependant on the mechanism of toxicity of the respective drugs. Metabolite profiling of HL-1 cells in response to sub-toxic drug concentrations was carried out by using HPLC. The considered metabolites included glucose, lactate, pyruvate and amino acids. The metabolic profiles were drug class dependant, as shown by multivariate statistics, thereby allowing classification of drugs according to their mechanisms of action. 13C-MFA was carried out to determine the effect of Ca2+ channel blocker verapamil and the cytostatic drug doxorubicin on the central metabolism at concentrations which were clinically relevant and non-toxic. Verapamil-treatment resulted in a highly efficient glucose metabolism in HL-1 cells. In both HL-1 cell and hESC-CM, doxorubicin-treatment resulted in an increased oxidative metabolism, most likely to avoid ATP-depletion. The obtained results potentially have pharmacological relevancy, but also provide novel strategies for preclinical toxicity determination of new drug compounds.
KW  - Kardiotoxizität
KW  - Metabolom
KW  - Metabolismus
KW  - Energiestoffwechsel
KW  - In vitro
KW  - Herzmuskelzelle
CY  - Saarbrücken
PB  - Universitäts- und Landesbibliothek
AD  - Postfach 151141, 66041 Saarbrücken
UR  - http://scidok.sulb.uni-saarland.de/volltexte/2012/4933
ER  -