Ação toxica da estreptozotocina em culturas celulares de mamiferos

AUTOR(ES)
DATA DE PUBLICAÇÃO

1990

RESUMO

Streptozotocin is a naturally occurring nitrosoamide that has been extensively used as diabetes inducer in experimental animal models. Studies at the molecular level indicated the DNA as the major target of STZ, because of its alkylation properties. It?s known that alkylating agents induces an adaptive response in bacterias and in some mammalian ceIl lines. This led us to investigate the effects of STZ on DNA synthesis rate in V79 fibroblasts.STZ inhibited timidine-3H uptake in this cell line in a dose dependent manner. In a split-dose protocol (0,38 mM and 11,0 mM) we observed an increase in DNA synthesis rate when compared to that for the higher dose treatment only. Although this increase in DNA synthesis rate is small it was reproducibly found and statistically significant (Kruskall-Wallis test). These results show that STZ, similarly to other alkylating agents, induces an adaptive response in V79 cells. In comparison to V79 cells, HeIa human cell line showed a different DNA synthesis inhibition pattern: at the same concentration, STZ showed to be a much more potent toxin to V79 cells. Determinations of cellular survival capacity to STZ treatment showed, however, an absence of parallelism between both effects, the HeIa cells being more susceptible to the STZ lethal effect than V79 one. These results indicate that STZ toxicity isn t exclusively related with DNA and, therefore, aIkylation in targets other than DNA may be involved on the STZ toxicity mechanism. Besides. We observed that, in comparison to STZ, the non-diabetogenic analogue MNU, showed to be a more potent toxin to V79 cells. However, the DNA synthesis inhibition patterns of bath drugs were not much different to support the view that the DNA is the unique target for their toxic action. With the aim to determine wether the mitochondria could be another target for STZ or MNU inducing cell killing, we analysed the effects of both drugs in mitochondria "in situ" of digitoninpermeabiIized V79 ceIls. Determination of Ca++ fIux and oxygen consumption have indicated that these drugs increase the permeability of the inner membrane of mitochondria. The order of mitochondria susceptibility to MNU was markedly higher than to STZ in accordance to their killing effects. The results of the present studies provide an alternative for the toxic action of STZ and MNU, suggesting that besides DNA damage injuries to mitochondria could exert a critical role in the citoxicity of these nitroso coumpounds and in the diabetogenic action of STZ

ASSUNTO(S)

genetica

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