11 beta-Hydroxy-11-ketosteroids equilibrium, a source of misinterpretation in steroid synthesis: evidence through the effects of trilostane on 11 beta-hydroxysteroid dehydrogenase in sheep and human adrenals in vitro.
Trilostane is known as an inhibitor of 3 beta-hydroxysteroid dehydrogenase. Conflicting data published on this drug led us to look for the effects of 0.02 to 0.5 mM of trilostane on the in vitro steroid synthesis in sheep adrenals and human adrenals (Cushing's or Conn's syndrome) in the presence of an NADPH-generating system. The synthesis of 4-androstenedione, 11 beta-hydroxyandrostenedione and 11-ketoandrostenedione were studied either from dehydroepiandrosterone or 4-androstenedione or 11 beta-hydroxyandrostenedione. The synthesis of 11-deoxycortisol, cortisol, cortisone, 4-androstenedione, 11 beta-hydroxyandrostenedione and 11-ketoandrostenedione were studied either from 17-hydroxyprogesterone or 11-deoxycortisol or cortisol. This study showed that trilostane inhibited 3 beta-hydroxysteroid dehydrogenase whereas it had no effect on 21-, 11- and 17-hydroxylase. Trilostane was responsible for an increased 11 beta-hydroxysteroid dehydrogenase activity in vitro, resulting in low yields of cortisol and 11 beta-hydroxyandrostenedione, and high yields of cortisone and 11-ketoandrostenedione. This unexpected effect of trilostane allowed us to show that erroneous conclusions (in this case: pseudo inhibition of 11 beta-hydroxylase) can be drawn if all the metabolic pathways from a determined precursor are not exhaustively documented when studying the effects of drugs on steroid synthesis in vitro. The decrease of cortisol synthesis by trilostane may thus be related to the effects of the drug on both 3 beta-hydroxysteroid-dehydrogenase (inhibitory effect) and 11 beta-hydroxysteroid-dehydrogenase (stimulatory effect). This latter effect was found to be species-dependent.
D042842:11-beta-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D000311:Adrenal Glands / Q000187:drug effects / Q000201:enzymology*; D000728:Androgens / Q000096:biosynthesis*; D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D003687:Dehydroepiandrosterone / Q000378:metabolism; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D006914:Hydroxysteroids / Q000096:biosynthesis*; D007664:Ketosteroids / Q000096:biosynthesis*; D012756:Sheep; D013045:Species Specificity
D000728:Androgens; D006914:Hydroxysteroids; D007664:Ketosteroids; D013196:Dihydrotestosterone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D015096:3-Hydroxysteroid Dehydrogenases; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; C009954:trilostane