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Inhibition of androgen metabolism and binding by a liposterolic extract of "Serenoa repens B" in human foreskin fibroblasts.

Author

Sultan C, Terraza A, Devillier C

Date

1/1984

Journal

J Steroid Biochem

Abstract

We previously suggested [Steroids 33, (1979) 3; Steroids 37, (1981) 6] that cultured genital skin fibroblasts should prove useful for screening of potential antiandrogens in human and living target cells. "Serenoa repens" lipidic extract (S.R.E.) was recently reported (Br. J. Pharmacol., in press) to inhibit androgen action in animals. The present investigation was designed to study the antiandrogenicity of this compound in human cells: we therefore analyzed the effects of S.R.E. on the intracellular conversion of testosterone (T) to 5 alpha-reduced derivatives, and we investigated interaction of S.R.E. with the intracellular androgen-receptor complex. Since the chemical structure of the active component of S.R.E. is still unknown, results are expressed in U/ml (one unit is defined as the amount of S.R.E. required to inhibit 50% of the specific binding (IC50) of [3H]1881 to rat prostate cytosol). S.R.E. at different dilutions (5.7 to 28.6 U/ml) is added to culture media containing [3H]T or [3H]dihydrotestosterone (DHT) and incubated at 37 degrees C with cultured fibroblasts. 28.6 U/ml S.R.E. significantly alters the formation of DHT and strongly inhibits 3 ketosteroid reductase mediated conversion of DHT to 5 alpha-androstane-3 alpha, 17 beta-diol, characterized radiochemically by thin-layer chromatography. S.R.E. is a good competitor for the whole cell androgen receptor: 7.1 U/ml S.R.E. gives 50% inhibition of the binding of 2 X 10(-9) M [3H]DHT to its receptor. Competitive binding assays after cell fractionation indicate that S.R.E. is less potent in nuclear than in cytosol receptors. Sucrose gradient centrifugation of the radioactive cell lysate of fibroblasts demonstrates that 28.6 U/ml S.R.E. abolishes 70% of the 3.6 S receptor-complex radioactive peak. The present studies show that S.R.E. inhibits 5 alpha- reductase, 3-ketosteroid reductase and receptor binding of androgens in cultured human foreskin fibroblasts. As the search for the ideal antiandrogen continues, S.R.E. appears to be a new type of antiandrogenic compound as therapeutics for the treatment of benign prostatic hypertrophy, hirsutism and so forth.

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