On the site of action of the anti-adrenal steroidogenic effect of cyproterone acetate.
Cyproterone acetate (CA) inhibited 1-24 ACTH (50 ng/l)-stimulated cortisol production by dispersed guinea-pig adrenal cells in a dose-related manner. Inhibition occurred over the range 10(-6) to 5 X 10(-5) moles/l. The concentration of drug which induced 50% inhibition was 4.6 X 10(-6) moles/l. The sites of action of this anti-steroidogenic effect have been established. Dispersed adrenal cells were challenged with the cortisol precursor steroids (all at 10(-5) moles/l) pregnenolone (Pe), 17 alpha hydroxypregnenolone (17-OH Pe), 17 alpha-hydroxyprogesterone (17-Po), and 11 deoxycortisol or 1-24 ACTH (100 ng/1) in the absence and presence of increasing concentrations of CA (10(-5) to 10(-4) moles/l). In the absence of drug, the steroid precursors or ACTH provoked cortisol secretion greater than 10-fold that secreted by cells incubated in their absence. ACTH-stimulated cortisol secretion was inhibited greater than 68% at concentrations of CA greater than 10(-5) moles/l. CA (10(-5) moles/l) had no significant effect on steroid-stimulated cortisol production when the delta 4, 3 ketosteroids 17-OH Po and 11-deoxycortisol were used, but depressed secretion by greater than 61% (P less than 0.001) when the delta 5 3 beta hydroxysteroids (Pe, 17-OH Pe) were employed. Increasing CA concentrations to 10(-4) moles/l had little effect on cortisol secretion provoked by 11-deoxycortisol, but significantly (P less than 0.05) depressed cortisol secretion stimulated by 17-OH Po. These results suggest that the major site of action of CA is delta 5, 3 beta hydroxysteroid dehydrogenase (3 beta-HSD) with a secondary effect on 21-hydroxylase activity. To confirm these findings cortisol secretion provoked by 17, 21, dihydroxypregnenolone (17, 21 diOH Pe) and 21 deoxycortisol (21-DOC) was measured in the absence and presence of increasing concentrations of CA. At the lowest concentration of CA (5 X 10(-6) moles/l), cortisol secretion provoked by 17, 21 diOH Pe was inhibited by 28% (P less than 0.01) whereas secretion provoked by 21-DOC was not significantly affected. At the highest concentration of CA (10(-4) moles/l), the relative inhibition was 80% for 17, 21 diOH Pe and 38% for 21-DOC. We conclude that cyproterone acetate inhibits adrenal steroidogenesis at both 3 beta-HSD and 21-hydroxylase, the degree of inhibition being more pronounced at 3 beta-HSD.
Lambert
A
A
Mitchell
R M
RM
Robertson
W R
WR
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D000305:Adrenal Cortex Hormones / Q000096:biosynthesis*; D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D003534:Cyproterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D017373:Cyproterone Acetate; D006168:Guinea Pigs; D006854:Hydrocortisone / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male
D000305:Adrenal Cortex Hormones; D017373:Cyproterone Acetate; D000324:Adrenocorticotropic Hormone; D003534:Cyproterone; D015096:3-Hydroxysteroid Dehydrogenases; D006854:Hydrocortisone