Abstract
The binding characteristics of RU 486 with the glucocorticoid receptor (GR) and the progestin receptor (PR) were studied in order to explain the potent antiglucocorticoid and antiprogestin activities of the compound. In vitro, (3H)RU 486 bound to the same cytosol receptors as (3H) dexamethasone (GR) and (3H)R 5020 (PR); the sedimentation coefficients, number of binding sites and specificity were similar. However, the affinity of (3H)RU 486 for these receptors was higher than that of the potent agonists, as indicated by the high affinity constant determined from Scatchard plots and by the slow dissociation rates from the GR and PR. With the cytosol receptor under heat activation, the agonists were able to give rise to more stable complexes, but (3H)RU 486 dissociated faster from the activated than from the non-activated GR. This impeded activation of the (3H)RU 486-GR complex was confirmed by observations of its lower affinity than that of (3H)dexamethasone-GR complex for DNA-cellulose and by a low retention in the nucleus that may be related to RU 486’s lack of glucocorticoid activity. Conversely, the uterine (3H)RU 486-PR complex did not undergo an acceleration of dissociation rate under heat activation, and its affinity for DNA-cellulose was similar to that of the activated (3H)R 5020-PR complex. This led to a high level of nuclear retention unrelated to the lack of progestin activity of RU 486. In contrast to in vitro interaction, high in vivo doses of RU 486 were needed to interact with the cytosol receptors in the rat; this cannot be explained by a binding to rat plasma protein.
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© 1985 Plenum Press, New York
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Moguilewsky, M., Philibert, D. (1985). Biochemical Profile of RU 486. In: Baulieu, EE., Segal, S.J. (eds) The Antiprogestin Steroid RU 486 and Human Fertility Control. Reproductive Biology. Springer, New York, NY. https://doi.org/10.1007/978-1-4684-1242-0_7
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DOI: https://doi.org/10.1007/978-1-4684-1242-0_7
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