title: Influence of 19-nortestosterone and androgens on progesterone biosynthetic enzymes in early human placental explants.
abstract: We recently showed that the production of progesterone (P4) in human placental explant culture from early gestation is enhanced by treatment with 19-nortestosterone (19-NT) or with certain androgens, namely androstenedione (A-dione), 5 alpha-androstane-3 alpha,17 beta diol (3 alpha-diol) and 5 alpha-androstane-3 beta,17 beta diol (3 beta-diol). This stimulation of P4 was explored further in this study. There was little metabolism of radioactive P4 when incubated for 24 h in the presence or absence of these steroids. The role of different steroids in the regulation of P450 cholesterol side-chain cleavage enzyme (P450scc) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) was evaluated by measuring the conversion of P4 derived from unlabelled 25-hydroxycholesterol and from labelled pregnenolone, respectively. The results showed that 19-NT, A-dione and 3 alpha-diol stimulated P450scc activity; however, 3 beta-diol was ineffective. While 19-NT and 3 beta-diol enhanced the bioconversion of pregnenolone to P4, A-dione and 3 alpha-diol were without effect. The initial rapid stimulation of P4 by 19-NT within 2 h of incubation was not blocked by concurrent treatment with cycloheximide (CH). However, after incubation for 24 h, 70% of the 19-NT-stimulated P4 was abolished by CH. During the same incubation period, P4 stimulation by A-dione, 3 alpha- and 3 beta-diol were completely blocked by treatment with CH. Thus our observations suggest that 19-NT-stimulated P4 accumulation is due to the combined effects on P450scc and 3 beta-HSD enzyme activities. A-dione and 3 alpha-diol increase biosynthesis of P4 by acting selectively on P450scc enzyme. However, the stimulatory action of 3 beta-diol on P4 is only at the level of 3 beta-HSD. Since CH blocks the stimulatory actions, the mechanism(s) by which androgens (A-dione, 3 alpha-diol and 3 beta-diol) and norandrogen (19-NT) augment the biosynthetic enzyme activities appears to be mediated by a process inhibited by CH. Since CH interference was absent during the initial rapid P4-stimulation by 19-NT, there may be a direct action of this steroid at the cellular level which is not dependent on new protein synthesis.
authors.affiliation: Montreal General Hospital, Department of Medicine, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Begum-Hasan
authors.forename: B E
authors.initials: BE
authors.lastname: Murphy
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D015113:Androstane-3,17-diol / Q000494:pharmacology*; D002478:Cells, Cultured; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism; D007536:Isomerism; D009277:Nandrolone / Q000494:pharmacology*; D010920:Placenta / Q000187:drug effects*; D011284:Pregnenolone / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*
chemical_list: D006888:Hydroxycholesterols; D015113:Androstane-3,17-diol; D011374:Progesterone; D009277:Nandrolone; D011284:Pregnenolone; C007997:25-hydroxycholesterol; D003513:Cycloheximide; D015096:3-Hydroxysteroid Dehydrogenases; D002786:Cholesterol Side-Chain Cleavage Enzyme