Enzyme interactions of 2,10-ethanoandrostene-3,17-dione: aromatase and 17 beta-hydroxysteroid dehydrogenase.
An analogue of androstenedione containing an ethano bridge between carbons 2 and 10 of the A ring of the steroid, 1, has been evaluated as an inhibitor and a possible substrate of human placental aromatase. This compound was found to be a competitive inhibitor versus androstenedione (Kis = 25 +/- 2 nM) of the aromatase activity. Analyses of the incubation mixtures of 1 with human placental microsomes and NADPH by GC-MS indicated the formation of a new compound having an increase in molecular weight of 2 mass units (300 m.u.) from that of the parent steroid (298 m.u.). Subsequent analyses of incubations of 1 with an isolated 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) from Pseudomonas testosteronii in the presence of NADPH resulted in the formation of a new compound having the same retention time and molecular mass as that found for the product from the placental microsome incubation. Consequently, steroid 1 is both an inhibitor of human placental aromatase and a substrate for 17 beta-HSD.
Greway
A T
AT
Department of Medicinal Chemistry, Smith Kline & French Laboratories, King of Prussia, PA 19406-0939.
Mentzer
M
M
Levy
M A
MA
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000735:Androstenedione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D047072:Aromatase Inhibitors; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008861:Microsomes / Q000201:enzymology; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D013379:Substrate Specificity
D047072:Aromatase Inhibitors; C064257:2,10-ethanoandrost-4-ene-3,17-dione; D000735:Androstenedione; D015067:17-Hydroxysteroid Dehydrogenases; C032690:3-alpha-(17-beta)-hydroxysteroid dehydrogenase (NAD(+))