Possible role of oxygen radicals in cell transformation by diethylstilbestrol and related compounds

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Abstract
Diethylstilbestrol (DES) and four derivatives, viz. tetrafluoro-DES, 3''-hydroxy-DES, Z,Z-dienestrol and hexestrol, were examined for their abilities to form superoxide radicals and to induce DNA strand break in the presence of horseradish peroxidase/hydrogen peroxide metabolism in a cell-free system. Furthermore, the induction of strand breaks by these compounds was tested in Syrian hamster embryo (SHE) cells in vitro. Formation of superoxide radicals could be demonstrated by reduction of nitro blue tetrazolium for DES but not for its derivatives. With isolated superhelical DNA, induction of strand breaks in the presence of Fe3+ was observed for DES, tetrafluoro-DES and 3''-hydroxy-DES, while hexestrol and Z,Z-dienestrol were ineffective. In SHE cells, alkaline elution technique showed that DNA strands breaks were induced by DES and all derivatives tested, although only at cytotoxic concentrations. It is concluded that DES, under conditions of peroxidative metabolism, can give rise to superoxide generation and DNA strand breaks, and that these events may play a role in the process of DES-induced cell transformation.