ON THE MECHANISM OF TOXIC EFFECT OF DOXORUBICIN ON THE KIDNEYS

Abstract

THE AIM of the investigation was to specify effects of doxorubicin (DOX) on renal cells using eukaryotic model Saccharomyces cerevisiae since the mechanisms of toxic effects of DOX on the kidneys still remain obscure. MATREIALS AND METHODS. The investigation was performed with strain S.cerevisiae YPH499. Incubation of the cells with different concentrations of DOX lasted 24 hours. The degree of injury of DNA was evaluated by activity of the ribonucleotide reductase -3 (RNR3). The concentration of reduced glutathione (G[1]SH), oxidized glutation (G-SSG), contents of malonic dialdehyde (MDA) were determined. RESULTS. DOX caused a decrease of cell proliferation, resulted in growing concentration of G-SH and so a reliable growth of the concentration of G[1]SSG was noted, but in less degree. In control experiments the ratio G-SH/G-SSG was 7.33±0.28 while in experiments with 10, 20, 30, 40, 50 mkM DOX the ratio G-SH/G-SSG was 7.52± 1.08 (p>0.05); 5.51±0.46 (p<0.01); 6.38±2.39 (p>0.05); 5.19±0.63 (p<0.01) and 5.05±0.70 (p<0.01) respectively. DOX induced expression of gene RNR3. The content of malonic dialdehyde did not substantially change. CONCLUSION. During the incubation of S.cerevisiae in the medium containing DOX and glucose an increase of G-SH due to expression of gene RNR3 compensates the redundant formation of free radicals and does not lead to free-radical damage of biomolecules. In the kidneys of animals administration of DOX fails to provide a sufficient concentration of G-SH and under these conditions free radicals induce oxidative stress at the expense of redox of cyclic reactions of DOX.