EFFECTS OF 4-MA, A POTENT INHIBITOR OF 5-ALPHA-REDUCTASE, ON 3-BETA-HYDROXYSTEROID DEHYDROGENASE DELTA(5)-DELTA(4)-ISOMERASE ACTIVITY IN GUINEA-PIG ADRENALS

Previous receptor have shown that 17 beta-N,N-Diethylcarbomoyl-4-methy l-4-aza-5 alpha-androstan-3-one (4-MA), a synthetic inhibitor of 5 alp ha-reductase, exerts on inhibitory effect on 3 beta-hydroxysteroid deh ydrogenase/Delta(5)-Delta(4)-isomerase (3 beta-HSD) activity. To chara cterize further the effects of 4-MA on steriodogenesis, guinea pig fas ciculata-glomerulosa cells in primary culture were treated for 24 h wi th 4-MA. Our data indicate the 4-MA reduced 3 beta-HSD activity in cul tured adrenal cells but had no effect on the activities of 11-hydroxyl ase, 21-hydroxylase, 17-hydroxylase, and 17,20-lyase. Be decreasing th e conversion of pregnenolone into progesterone or 17-hydroxypregenolon e into 17-hydroxyprogesterone, 4-MA caused the steroidogenic pathway t o shift toward the production of dehydroepiandrosterone. Despite the p resence of 4-MA, androstenedione and 11 beta-hydroxypregnenolone were produced at levels exceeding the control levels. In the presence of AC TH and 4-MA, cortisol production was inhibited by 90% whereas androste nedione and 11 beta-hydroxyandrostene-dione were reduced by only 40%. The effect of the compound was reversed by washing the adrenal cells w ith medium, Thus suggesting a direct action of 4-MA on the enzyme itse lf. In summary, our data indicate that 4-MA markedly reduces the produ ction of cortisol in the adrenals and partially alters the formation o f C-19 steroids. It is important to consider this finding in the use o f 4-azasteroids in the treatment of prostate cancer, which was previou sly found to be sensitive to secretion of adrenal C-19 steroids.