Effects of antiandrogens (cyproterone acetate and flutamide) on the activity of nuclear protein phosphokinases and phosphatases of rat ventral prostate

M. J. Wilson, A. T. Davis, K. Ahmed

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The effect of in vivo administration of the antiandrogens flutamide and cyproterone acetate on the activities of prostatic chromatin-associated protein phosphokinases (toward endogenous and exogenous substrates) and nuclear phosphatase activities was studied. Intact male rats (315-335 g) were treated daily for up to 48 hr with either flutamide or cyproterone acetate producing both time- and dose-dependent declines in acidic-phosphoprotein kinase activity (dephosphosvitin as protein substrate). At a daily dose of 10 mg of antiandrogen for 48 hr, the decline in activity was 33% for cyproterone acetate and 36% for flutamide. The ability of the antiandrogens to compete with testosterone in relation to effects on prostatic chromatin-associated acidic-phosphoprotein kinase activity and phosphorylation of endogenous chromosomal proteins was examined by simultaneous treatment of castrated rats with antiandrogen and testosterone in vivo. A dose of 0.01 mg testosterone propionate/100 g body wt/day was found sufficient to maintain the chromatin-associated acidic-phosphoprotein kinase activity at the level of the intact animal. Both antiandrogens were effective in competiing with the androgen. At a dose 100-fold greater than testosterone propionate (on a molar basis), flutamide gave 55% and cyproterone acetate 27% reduction in acidic-phosphoprotein kinase activty compared with the control treated with testosterone and oil vehicle. Under the same treatment regimen, phosphorylation of endogenous proteins in chromatin was decreased 69% with flutamide and 65% with cyproterone acetate. Histone kinase activity of prostatic chromatin, compared with kinase activity toward dephosphophosvitin, was affected less by orchiectomy or by antiandrogen treatment of intact animals. Protein phosphatase activities measured with 32P-labeled phosvitin or lysine-rich histone as substrates, demonstrated a small decline in activity following treatment with antiandrogens (10-mg dose) for 48 hr, if these activities were expressed per unit of nuclear protein. A decline of about 50% in activity was evident when specific activity was expressed per unit nuclear DNA. This effect on nuclear protein phosphatase specific activities partially reflects the decline in the protein:DNA ratio observed following antiandrogen treatment. The alkaline phosphatase activity of the prostatic nucleus increased over twofold following 48 hr antiandrogen treatment (10-mg-dose), as was also found 48 hr after orchiectomy. The use of antiandrogens produces an effect comparable to orchiectomy on the protein phosphokinase reactions of prostatic chromatin, especially those involving acidic protein or endogenous protein substrates which suggests that these enzymes are under the control of events mediated via the 5α-dihydrotestosterone-receptor complex system.

Original languageEnglish (US)
Pages (from-to)212-217
Number of pages6
JournalMolecular Pharmacology
Issue number2
StatePublished - 1980


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