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 reports have shown that 17 beta-N,N-Diethylcarbamoyl-4-methyl-4-aza- 5 alpha-androstan-3-one (4-MA), a synthetic inhibitor of 5 alpha-reductase, exerts an inhibitory effect on 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) activity. To characterize further the effects of 4-MA on steroidogenesis, guinea pig fasciculata-glomerulosa cells in primary culture were treated for 24 h with 4-MA. Our data indicate that 4-MA reduced 3 beta-HSD activity in cultured adrenal cells but had no effect on the activities of 11-hydroxylase, 21-hydroxylase, 17-hydroxylase, and 17,20-lyase. Be decreasing the conversion of pregnenolone into progesterone or 17-hydroxypregnenolone into 17-hydroxyprogesterone, 4-MA caused the steroidogenic pathway to shift toward the production of dehydroepiandrosterone. Despite the presence of 4-MA, androstenedione and 11 beta-hydroxyandrostenedione were produced at levels exceeding the control levels. In the presence of ACTH and 4-MA, cortisol production was inhibited by 90% whereas androstenedione and 11 beta-hydroxyandrostenedione were reduced by only 40%. The effect of the compound was reversed by washing the adrenal cells with medium, thus suggesting a direct action of 4-MA on the enzyme itself. In summary, our data indicate that 4-MA markedly reduces the production of cortisol in the adrenals and partially alters the formation of C-19 steroids. It is important to consider this finding in the use of 4-azasteroids in the treatment of prostate cancer, which was previously found to be sensitive to secretion of adrenal C-19 steroids.
Perron
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CHUL Research Center, Sainte-Foy, Quebec, Canada.
Bélanger
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D000726:Androgen Antagonists / Q000494:pharmacology*; D000735:Androstenedione / Q000096:biosynthesis; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology*; D002478:Cells, Cultured; D042944:Cholestenone 5 alpha-Reductase; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D006854:Hydrocortisone / Q000096:biosynthesis; D008297:Male; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011375:Progesterone Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013251:Steroid Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013256:Steroids / Q000096:biosynthesis / Q000378:metabolism; D015383:Zona Fasciculata / Q000201:enzymology / Q000378:metabolism*; D015384:Zona Glomerulosa / Q000201:enzymology / Q000378:metabolism*
C021425:3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase; D000726:Androgen Antagonists; D001378:Azasteroids; D009097:Multienzyme Complexes; D013256:Steroids; D013196:Dihydrotestosterone; D000735:Androstenedione; C031563:17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one; D010088:Oxidoreductases; D011375:Progesterone Reductase; D042944:Cholestenone 5 alpha-Reductase; D013251:Steroid Isomerases; D006854:Hydrocortisone