Effect of indanyl analogues of diethylstilboestrol on morphological transformation of Syrian hamster embryo fibroblasts and micronuclei in vitro.
Two analogues of the carcinogenic oestrogen diethylstilboestrol (DES), indenoestrol A (IA) and indenoestrol B (IB), have been studied with respect to their genotoxic and cell transforming properties in mammalian cells. The conformation and oestrogenicity of IA and IB are very similar, but they differ with respect to their ease of peroxidation and the resulting reactive intermediates: only IA is readily converted to a p-quinone. Both DES derivatives caused morphological transformation of Syrian hamster embryo (SHE) fibroblasts with similar efficiency at concentrations (1 to 10 mum) that did not affect cloning efficiency. In addition, IA and IB (5 to 50 mum) induced micronuclei in the same cell system. These micronuclei were detectable as early as 1-3 hr after a 5-hr treatment with IA or IB. Such a time course is characteristic of compounds that cause mitotic disturbances. Indomethacin, an inhibitor of prostaglandin H synthase (the enzyme responsible for oxidation of DES in target cells), did not affect the frequency of micronuclei induced by IA or by IB. From these data we conclude that peroxidative metabolism resulting in quinone formation is not a prerequisite for the genotoxicity of these compounds. In addition to DES and several of its analogues the indanyl derivatives now also have been shown to be active in both of these short-term assays, suggesting that the in vitro micronucleus formation and morphological cell transformation are causally related events.
Schiffmann
D
D
Institute of Toxicology, University of Würzburg, Germany.
Degen
G H
GH