Inhibition of androgen binding in human foreskin fibroblasts by antiandrogens

Abstract

Antiandrogen effects on androgen receptor binding and androgen metabolism were studied in cultured human newborn foreskin fibroblasts. Three different antiandrogens were tested in this system: (a) cyproterone acetate (CA); (b) RU23908; and (c) R2956. CA and R2956 were eqnipotent inhibitors of androgen binding to its intracellular receptor. The magnitude of this action was nearly twice as great against the endogenous androgen ligands, dihydrotestosterone (DHT) or testosterone (T), than with the synthetic ligand, methyltrienolone (R1881). Whereas the relative binding affinities of CA and R2956 were approximately 5–10 times less than T or DHT, RU23908 was another order of magnitude less effective as an inhibitor of androgen binding. The lower relative binding affinity determined for RU23908 could not be explained on the basis of a requirement for metabolic activation. Subcellular fractionation studies and sucrose density gradient analysis further confirmed the rank order of antiandrogenic potency. None of the antiandrogens influenced the rate or profile of metabolites from cellular metabolism of T or DHT. We propose that cultured human genital skin fibroblasts may serve as a valuable system for the future evaluation of antiandrogens in intact cells under physiologic conditions.