Please use this identifier to cite or link to this item: http://hdl.handle.net/10553/49791
Title: Stanozolol and danazol, unlike natural androgens, interact with the low affinity glucocorticoid-binding sites from male rat liver microsomes
Authors: Fernàndez, Leandro 
Chirino, Ricardo 
Boada, Luis D. 
Navarro, Domingo
Cabrera, Noemí
Rio, Isidoro Del
Díazchico, Bonifacio N. 
Keywords: Dexamethasone-Binding
Radioligand Binding
Estrogen-Receptors
Anabolic Steroids
Nuclear Envelopes, et al
Issue Date: 1994
Publisher: 0013-7227
Journal: Endocrinology (Philadelphia) 
Abstract: Some 17 alpha-alkylated androgens used as anabolic agents, such as stanozolol (ST) and danazol (DA), have specific effects on the liver that are not exerted by testosterone. This gives rise to the possibility that a steroid-binding protein, other than the androgen receptor, could modulate the intracellular actions of these agents. Male rat liver microsomes contain a homogeneous population of [H-3]dexamethasone ([H-3]DEX)-binding sites which we have denominated low affinity glucocorticoid-binding sites (LAGS). Because glucocorticoids, progestagens, and the synthetic estrogen ethynyl estradiol compete with [H-3] DEX for binding to the LAGS, we aimed to study the possible interactions between androgens and the LAGS. To investigate whether several androgens had the capability of interacting with the LAGS, we performed competition experiments. The LAGS had no affinity for testosterone or methyltrienolone (R1881). However, some 17 alpha-alkylated androgens (DA (IC50, 116 nM) > ST much greater than fluoxymesterone > mestaline > methandriol much greater than methandrostenolone > methyltestosterone) were able to compete with [H-3]DEX binding to liver microsomes. ST and DA were potent inhibitors of [H-3]DEX binding to liver microsomes. They decreased both the affinity and the number of [H-3]DEX-binding sites, increased the dissociation rate of [H-3]DEX from the LAGS, and provoked a time- and dose-dependent inactivation of the [H-3]DEX-binding site. These results strongly suggest that ST and DA exert a negative allosteric modulation on [H-3]DEX binding to the LAGS. The in vivo administration of ST (but not other androgens) to male rats provoked a time- and dose-dependent decrease in the LAGS level. Full recovery of the LAGS concentration required at least 8 h and was blocked by protein synthesis inhibitors. Such results suggest that ST irreversibly inactivates the [H-3]DEX-binding site in vivo as it does in vitro.Taken together, these observations are indicative of an irreversible interaction between some 17 alpha-alkylated androgens and the LAGS both in vitro and in vivo and suggest that ST may be an important pharmacological tool that can be used in the elucidation of the molecular structure of the LAGS. These results also mean that the LAGS are a steroid-binding entity able to distinguish between natural androgens and 17 alpha-alkylated testosterone derivatives used as anabolic agents.
URI: http://hdl.handle.net/10553/49791
ISSN: 0013-7227
DOI: 10.1210/endo.134.3.8119180
Source: Endocrinology[ISSN 0013-7227],v. 134, p. 1401-1408
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