Kinetic analysis of human placental, ovarian, and adrenal 3 beta-hydroxysteroid dehydrogenase inhibition by epostane in vitro.
The effect of epostane [(2 alpha,4 alpha,5 alpha,17 beta)-4,5-epoxy-17-hydroxy-4,17-dimethyl-3-oxo- androstane-2-carbonitrile] on the conversion of pregnenolone to progesterone and of dehydroepiandrosterone (DHA) to androstenedione was studied in human term placental microsomes and in comparison with human ovarian and adrenal microsomes. Using pregnenolone as substrate, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity in the three tissues had a similar Km (3-6 microM) but Vmax ranged from 1.3 nmol/mg protein per min in ovary to 10 nmol/mg protein per min in placenta. Epostane inhibited 3 beta-HSD activity in all three tissues with the characteristics of a pure competitive inhibitor: mean Ki values were 1.7 microM for placenta, 0.5 microM for adrenal and 0.1 microM for ovary. Moreover, in placental microsomes epostane inhibited the conversion of DHA to androstenedione with a Ki of 0.6 microM. The mechanism of action of epostane explains its effectiveness in blocking progesterone synthesis during the luteal phase and in pregnancy in women, and its strong anti-steroidogenic effect in other endocrine tissues in vitro.
Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, Oxford, U.K.
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López Bernal
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000293:Adolescent; D000311:Adrenal Glands / Q000201:enzymology*; D000328:Adult; D000368:Aged; D000737:Androstenols / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000201:enzymology; D008875:Middle Aged; D009928:Organ Specificity; D010053:Ovary / Q000201:enzymology*; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy
D000737:Androstenols; C046855:epostane; D015096:3-Hydroxysteroid Dehydrogenases