Effect of flutamide-induced androgen-receptor blockade on adenylate cyclase activation through G-protein coupled receptors in rat prostate

The effect of the antiandrogen flutamide on the prostatic vasoactive intest inal peptide (VIP) receptor/effector system was studied in rats. Rats were s.c. injected with a daily dose of flutamide (15 mg/kg B.W.) or vehicle for 14 days. Drug treatment resulted in histological evidence of gland involut ion and increased plasma membrane fluidity as estimated by fluorescence spe ctroscopy. The number of VIP receptors and the stimulatory effect of VIP on adenylate cyclase activity in prostatic membranes decreased in flutamide-t reated rats. However, the pattern of forskolin stimulation of the enzyme ac tivity was not modified by this drug. Androgen-receptor blockade by flutami de also decreased the prostatic levels of alpha(s), alpha(i1/2), and alpha( i3/0), G-protein subunits, as estimated by an immunological procedure. Wher eas apoptotic DNA fragmentation was evidenced in prostate from 3-day castra ted animals, a heterogeneous electrophoretic pattern was observed after flu tamide treatment. Thus, androgen-receptor blockade by flutamide results in an important impairment of the components of the VIP receptor/effector syst em in rat prostate as well as in a modification of their coupling extent, w hich is presumably due to differences observed in plasma membrane fluidity. These results represent a crosstalk in the prostate between two mechanisms of signal transduction involved in cell proliferation. (C) 2000 Elsevier S cience Inc. All rights reserved.