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Abstract
Alterations in cellular GSH and its compartmentation were investigated as a possible mechanism of toxicity of the anthracycline derivative daunorubicin in neonatal heart cells. Cultured beating heart cells from neonatal rats were exposed to daunorubicin at therapeutically relevant concentrations and the resulting changes in cellular GSH as well as cytosolic and mitochondrial pools of GSH were determined. Toxicity was estimated as an increased permeability of the plasma membrane to cytosolic enzymes, e.g., lactate dehydrogenase.
Control heart cells were found to contain 12.2 ± 1.8 nmolesGSH/IO6 cells. Daunorubicin causedarapid initial decrease followed by a transient increase in cellular GSH. The extent of the latter increase was dependent on the concentration of daunorubicin. High concentrations of daunorubicin gave only a slight increase followed by a pronounced decrease in cellular GSH.
By applying a digitonin-based method the effect of daunorubicin on the cytosolic and mitochondrial pools of GSH were separated. The concentration of cytosolic and mitochondrial reduced GSH was estimated to be 89 ± 1.5nmoles, 10 cells and 3.3 ± 0.6 nmoles/106 cells. respectively. The results indicate that daunorubicin caused a decrease of cytosolic GSH and. after a short lag period. a release of lactate dehydrogenase. No decrease of mitochondrial GSH occurred under these conditions indicating that daunorubicin influences selectively cytosolic GSH.
No lipid peroxidation products were detected in DRB-treated cells under conditions when lactate dehydrogenase was released. Likewise, addition of the iron-chelator desferrioxamin did not influence the release of lactate dehydrogenase. whereas dithiothreitol offered partial protection.
The results provide support for an oxidative mechanism in which the decrease in the cytosolic pool of GSH may be the causative factor of daunorubicin-induced toxicity. This decrease in GSH may affect the cytosolic NADPH and various redox groups on proteins, thereby altering the permeability of the plasma membrane and finally causing cell damage.