beta-Diethylaminoethyl-2, 2-diphenylpentanoate (SKF 525-A)-mediated translocation of uterine estrogen receptor from the cytosolic to the nuclear compartment in isolated rat uteri

WH Bulger and D Kupfer

The current study examines whether beta-diethylaminoethyl-2, 2- diphenylpentanoate (SKF 525-A), a recognized inhibitor of microsomal monooxygenase activity, interacts with the uterine estrogen receptor in a manner similar to that of classical estrogens. Incubation of SKF 525- A with isolated uteri from immature rats diminished the levels of cytosolic estrogen receptor and increased the amount of nuclear estrogen receptor. Similar results were obtained with uteri from ovariectomized or ovariectomized and adrenalectomized rats, indicating that the action of SKF 525-A did not depend on the availability of ovarian or adrenal hormones. Additionally, experiments with uterine cytosol from immature rats, employing analysis by Scatchard and Lineweaver-Burk plots, demonstrated that SKF 525-A (0.05 mM) competitively inhibited [3H] estradiol binding to the estrogen receptor, suggesting that both compounds bind to the same site on the receptor. The Ki for SKF 525-A was determined to be 100 micrometers, indicating that SKF 525-A has a relatively low affinity for the receptor. Further confirmation of this finding was obtained by assessing the relative inhibition of [3H] estradiol binding to uterine cytosol estrogen receptor by SKF 525-A versus that of unlabeled estradiol. The affinity of SKF 525-A for the estrogen receptor appears to be about 0.001% that of estradiol. These studies demonstrate that, like estradiol, SKF 525-A interacts with the estrogen receptor. Additionally, it was concluded that the "estrogenic" (uterotropic) activity observed in vivo [Calhoun et al. Proc. Soc. Exp. Biol. Med. 136:47 to 50 (1971)] with SKF 525-A, is mediated through the uterine estrogen receptor.

Volume 21, Issue 3, pp. 533-537, 05/01/1982
Copyright © 1982 by American Society for Pharmacology and Experimental Therapeutics