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Androgenic, Antiandrogenic, and Synandrogenic Actions of Progestins: Role of Steric and Allosteric Interactions with Androgen Receptors^*

LESLIE P. BULLOCK, C. WAYNE BARDIN and MERRY R. SHERMAN

Departments of Comparative Medicine and Medicine (L.P.B., C. W.B.),The Milton S. Hershey Medical Center, The Pennsylvania State University Hershey, Pennsylvania 17033
Memorial Sloan-Kettering Cancer Center (M.R.S.) New York, New York 10021

Address reprint requests to: Dr. Leslie P. Bullock, Department of Medicine, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, PA 17033.

Abstract

Progestins are known to mimic, potentiate, and/or antagonize the actions of androgens in various mammalian target tissues. Such androgenic, synandrogenic, and antiandrogenic responses to progestins were not detected in mice with defective androgen receptors (Tm/Y mice). The inference that the androgen receptor, rather than a progestin receptor, mediates these responses in normal animals was tested by in vivo and in vitro experiments in castrate mice and rats. 17a- Acetoxy-6a-methylprogesterone (MPA), a progestin with both androgenic and synandrogenic activities, stimulated the growth of mouse prostate-seminal vesicle, kidney, and submaxillary gland. The specific nuclear uptake of [nH]MPA or nH-labeled androgens by these organs in vivo was reduced more effectively by 5adihydrotestosterone than by MPA. Similar results were obtained in rats. In contrast, there was no evidence of nuclear uptake in Tm/Y mice. These data imply the involvement of the androgen receptor in the nuclear retetion of [³H]MPA.

The hypothesis of shared receptors was supported by ultracentrifugal analyses of progestin and androgen binding to mouse kidney cytosol. [³H]MPA and [³H]- testosterone ([³H]T) were both bound to high affinity, low capacity macromolecules with sedimentation coefficients of about 8S. This binding was displaced by nonradioactive MPA or T in a dose-dependent fashion, and by 100-fold excesses of 6-chloro-6-dehydro-17-acetoxy- l,2-methylene progesterone and other progestins, T and estradiol, but not by dexamethasone, a glucocorticoid. There was no detectable binding of [³H]MPA or[³H]T to 8S components in kidney cytosol from TfniY mice. High concentrations of 3–4S components that bound [³H]MPA but not [¹H]T were found in kidney cytosols from both TfmY and normal mice, but not in mouse plasma.

The competition by various progestins for [³H]T binding to mouse kidney cytosol was studied by adsorption of stroid-receptor complexes to DEAE-cellulose filters. The apparent affinities of several progestins for theandrogen receptor were not directly correlated with the magnitude or direction (agonist or antagonist) of their effects on renal)8-glucuronidase activity. The monotonic decrease in 3H-labeled androgen binding with increasing concentrations of synandrogenic progestins was inconsistent with the proposal that the synergistic response involves a cooperative increase in androgen binding to a multisite receptor.

The data were analyzed in terms of a mathematical model for combined steric and allosteric interactions. Unlike the classical allosteric model for interactions between identical or dissimilar ligands (Monod, J., J. Wyman, and J.-P. Changeux, J Mol Biol 12: 88, 1965), this model includes the competitive binding of similar ligands to the same sites, as well as their effects on the putative equilibrium between active and inactive states of the receptor. The observation that androgen binding to mouse kidney cytosol was similarly inhibited by progestins with disparate physiological effects (androgenic, antiandrogenic, synandrogenic,or undetectable) was consistent with the predictions of the steric-allosteric model

Footnotes

^* This research was supported by NIH Contract N01-2-2730 and NIH Grants CA-16814 and CA-08748.

Recipient of a Research Career Development Award No. K04-HD00137 from the NIH. Present address: The Population Council, Rockefeller University, New York, NY 10021.

Recipient of a Faculty Scholar Award from the Josiah Macy Jr. Foundation

Received March 1, 1978.

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