In vivo estrogen bioactivities and in vitro estrogen receptor binding and transcriptional activities of anticoagulant synthetic 17ß-aminoestrogens
Por:
Jaimez R., Cooney A., Jackson K., Lemus A.E., Lemini C., Cárdenas M., García R., Silva G., Larrea F.
Publicada:
1 ene 2000
Resumen:
Estrogenic activities of the two 17?-aminoestrogen (AE) derivatives, prolame and butolame, were studied upon coagulation, serum luteinizing hormone (LH) and uterine weight, including endometrial morphology in castrated female rats. We have also investigated the ability of these two compounds, as well as another AE pentolame, to activate transcription through the estrogen receptor ? (ER?) and the estrogen receptor ? (ER?). Administration of prolame and butolame to castrated animals increased significantly (P < 0.01) the mean clotting time when compared with that obtained in the group of control animals. Butolame was a more potent anticoagulant than prolame (P < 0.01), as judged by their corresponding IC50 (5.4 ± 0.65 and 66.6 ± 2.57 ?g/animal, respectively). In contrast, estradiol significantly shortened blood clotting times (P < 0.005). Both prolame and butolame caused a significant inhibition of serum LH levels (EC50 8.10 ± 0.79 and 17 ± 64 ?g/animal, respectively), and restored castration-induced reduction in uterine weight of ovariectomized rats (EC50 4.14 ± 1.57 and 17.0 ± 1.78 ?g/animal, respectively). In terms of the effects of prolame, butolame and pentolame in transient transfection assays, all the three AE activated ER dependent reporter gene expression, however, only at high concentrations. Prolame had the highest activity followed by butolame and pentolame. Induction of transcription by these compounds was preferentially mediated through the ER?, especially in the case of pentolame where little, if any, activation occurred through the ER?. None of the compounds showed antagonistic activities through either ER subtype. The overall data suggest that modifications in the structure and length of the amino-alcohol side-chain at C-17 might have an impact on the affinity and estrogenic intrinsic properties of AE at the level of diverse target tissues. Copyright (C) 2000 Elsevier Science Ltd.
Filiaciones:
Department of Cell Biology, Baylor College of Medicine, Houston, TX, United States
Department of Reproductive Biology, Inst. Nac. Nutr. Salvador Z., México, Mexico
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