Regulation of human placental 17β-hydroxysteroid oxidoreductase: Mechanism of stimulation of 17β-estradiol formation from estrone by 5α-dihydrotestosterone in homogenates and villi in vitro

Abstract

The mechanism of stimulation of 17β-estradiol (E2) formation from estrone (E1) by 5α-dihydrotestosterone (5α-DHT) in placental villi was investigated by examining; (1) if dehydroepiandrosterone (DHA) was stimulatory, (2) if NAD(P)H-generating, non-steroidal substrates stimulated E2 formation, (3) the subcellular localization of the effect, (4) if NAD(P) or NAD(P)H was required and (5) rates of 5α-DHT oxidation by villi and microsomes. Although 5α-DHT and DHA both inhibited the E2 to E1 reaction in villi and microsomes, only 5α-DHT stimulated the conversion of E1 and E2. Glucose and lactate were slightly stimulatory when compared with 5α-DHT. Stimulation of E2 formation was observed with microsomes but not with cytosol, and NAD or NADP was required. The results indicate that neither inhibition of the back reaction, E2 to E1, nor NADH or NADPH formation via the 3β-hydroxysteroid dehydrogenase/5-ene-3-ketosteroid isomerase reaction can account for the stimulation. It is proposed that the mechanism of stimulation involves one or more forms of membrane-bound 17β-hydroxysteroid oxidoreductase with NADH or NADPH formed as a product of 5α-DHT oxidation being used as the cofactor for E1 reduction. This may involve a direct transfer of reduced pyridine nucleotide between enzyme molecules without equilibration with intracellular coenzyme pools.