Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues

Abstract In rat adenohypophysial cells in primary culture, the specific uptake of [ 3 ]Hitestosterone (T) is completely blocked by increasing concentrations of the pure antiandrogen flutamide-OH, the active metabolite of flutamide at an IC 50 value of 50 nM while unlabeled T causes a similar inhibition at an IC 50 value of 0.5 nM. After 210 min of incubation of 3 nM [ 3 H]T with the anterior pituitary cells, 80% of radioactivity is still present as unchanged T. Direct binding studies show that flutamide-OH and flutamide interact with the rat anterior pituitary androgen receptor at K i values of 55 and 1275 nM, respectively. In rat ventral prostate (cytosolic and nuclear fractions) and cytosol from human prostatic carcinoma, rat uterus and mouse Shionogi mammary carcinoma, the K i values ranged from 0.1 to 0.47 0.6 to 2.7, 62 to 205 and 1450 to 7550 nM for dihydrotestosterone, T, flutamide-OH and flutamide, respectively. Since the ability of flutamide-OH to inhibit the uptake of [ 3 H]T in intact adenohypophysial cells and to compete for binding to the adenohypophysial androgen receptor shows almost identical values at approximately 1% of the potency of T itself, it is most likely that the antiandrogen activity of flutamide-OH can be completely explained by the ability of the pure antiandrogen to displace androgen from their specific receptor in target tissues. In addition, the finding of similar binding characteristics in a series of other tissues suggests that a similar potency of the antiandrogen can be expected in the other androgen-target tissues.