Danazol inhibits human adrenal 21-and 11 beta-hydroxylation in vitro.
The effects of danazol on steroidogenesis in vitro in the 16-20 week old human fetal adrenal were examined by studying: 1) danazol binding to adrenal microsomal and mitochondrial cytochrome P-450, and 2) enzyme kinetics of danazol inhibition of the adrenal microsomal 21-hydroxylase and the mitochondrial 11 beta-hydroxylase. The addition of danazol to preparations of adrenal microsomes or mitochondria elicited a type I cytochrome P-450 binding spectrum. Danazol bound to microsomal cytochrome P-450 binding spectrum. Danazol bound to microsomal cytochrome P-450 with a high affinity apparent spectral dissociation constant (KS) of 1 microM and with a lower affinity K's of 10 microM. Danazol bound to mitochondrial cytochrome P-450 with a KS of 5 microM. In addition, danazol competitively inhibited the microsomal 21-hydroxylase (apparent enzymatic inhibition constant KI = 0.8 microM) and the mitochondrial 11 beta-hydroxylase (KI = 3 microM). These findings demonstrate that low concentrations of danazol directly inhibit steroidogenesis in the human fetal adrenal in vitro.
D000029:Abortion, Legal; D000311:Adrenal Glands / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003613:Danazol / Q000494:pharmacology*; D005260:Female; D005333:Fetus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D011245:Pregnadienes / Q000494:pharmacology*; D011247:Pregnancy; D013053:Spectrophotometry; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors*; D013255:Steroid 21-Hydroxylase / Q000037:antagonists & inhibitors*; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*
D011245:Pregnadienes; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D013255:Steroid 21-Hydroxylase; D013252:Steroid 11-beta-Hydroxylase; D003613:Danazol