Persistent Effects of a Synthetic Androstene Derivative on Activities of 3/-Hydroxysteroid Dehydrogenase and Glucose-6-phosphate Dehydrogenase in Rats

Abstract

The present study reports the effects of a synthetic steroidal inhibitor, 2[alpha]-cyano-4,4,17[alpha]-trimethyl-androst-5-en-17[beta]-ol-3-one, on the histochemical activities of the 3[alpha]-, 3[beta]- and 17[beta]-enzymes and on G-6-PD in rat tissues in vivo and in vitro and on the histochemical and biochemical activities of the steroid dehydrogenases extracted from Pseudomonas testosteroni, in vitro. This inhibitor in vivo markedly reduces the highly active 3B-enzyme in adrenal cortical, corpora luteal and ovarian follicular and stromal cells. These effects are evident as early as 3 hr after a single injection. Concomitantly, the activity of glucose-6-phosphate dehydrogenase (G-6-PD) is markedly increased in these same cells and in hepatic cells. Hyperplasia of the adrenal cortex and corpora lutea, reduction in activity of the 3[beta]-enzyme and an increase in activity of G-6-PD are apparent in the respective tissues at 24 hr after the last injection and persist for at least 4 weeks. The lower levels of activities of the 3[beta]-enzyme and the 17[beta]-enzyme in the intestinal mucosa are also slightly diminished by the inhibitor. The activities of either the 17[beta]-enzyme in the adrenal, ovary and liver or of the 3 [alpha]-enzyme in any tissue studied are not appreciably affected by the inhibitor. In vitro, the incorporation of the inhibitor in the incubation medium produces a similar pattern of inhibition of the hydroxysteroid dehydrogenases, with a variety of 3[beta]- and 17[beta]-substrates in tissue sections, including the trophoblast, which was studied only in the in vitro experiments. However, cyano-ketone has no in vitro effect on the activity of G-6-PD in any tissue studied. The inhibitor blocks the precipitation of diformazan histochemically and reduces the biochemical activity of extracts of Pseudomonas testosteroni equally well in medium containing any of the three 3[beta]-substrates or two 17[beta]-substrates. A predominant characteristic of this inhibitor, therefore, appears to be marked and persistent inhibition of activity of the 3[beta]-enzyme in steroidogenic endocrine tissues associated with an increased activity of G-6-PD in vivo.