11 Alpha-Hydroxyprogesterone, A Potent 11 Beta-Hydroxysteroid Dehydrogenase Inhibitor, Is Metabolised By Steroid-5 Alpha-Reductase And Cytochrome P450 17 Alpha-Hydroxylase/17,20-Lyase To Produce C11 Alpha-Derivatives Of 21-Deoxycortisol And 11-Hydroxyandrostenedione In Vitro

11 alpha-Hydroxyprogesterone (11 alpha OHP4) and 11 beta-hydroxyprogesterone (11 beta OHP4) have been reported to be inhibitors of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) type 2, together with 11 beta-hydroxytestosterone and 11 beta-hydroxyandrostenedione, and their C11-keto derivatives being inhibitors of 11 beta HSD1. Our in vitro assays in transiently transfected HEK293 cells, however, show that 11 alpha OHP4 is a potent inhibitor of 11 beta HSD2 and while this steroid does not serve as a substrate for the enzyme, the aforementioned C11-oxy steroids are indeed substrates for both 11 beta HSD isozymes. 11 beta OHP4 is metabolised by 11 beta HSD2 yielding 11-ketoprogesterone with 11 beta HSD1 catalysing the reverse reaction, similar to the reduction of the other C11-oxy steroids. In the same model system, novel 11 alpha OHP4 metabolites were detected in its conversion by steroid-5 alpha-reductase (SRD5A) types 1 and 2 yielding 11 alpha-hydroxydihydroprogesterone and its conversion by cytochrome P450 17A1 (CYP17A1) yielding the hydroxylase product, 11 alpha,17 alpha-dihydroxyprogesterone, and the 17,20 lyase product, 11 alpha-hydroxyandrostenedione. We also detected both 11 alpha OHP4 and 11 beta OHP4 in prostate cancer tissue- similar to 23 and similar to 32 ng/g respectively with 11KP4 levels >300 ng/g. In vitro assays in PC3 and LNCaP prostate cancer cell models, showed that the metabolism of 11 alpha OHP4 and 11 beta OHP4 was comparable. In LNCaP cells expressing CYP17A1, 11 alpha OHP4 and 11 beta OHP4 were metabolised with negligible substrate, 4%, remaining after 48 h, while the steroid substrate 11 beta,17 alpha-dihydroxyprogesterone (21dF) was metabolised to C-11-keto C-19 steroids yielding 11-ketotestosterone.Despite the fact that 11 alpha OHP4 is not metabolised by 11 beta HSD2, it is a substrate for SRD5A and CYP17A1, yielding C11 alpha-hydroxy C-19 steroids as well as the C11 alpha-hydroxy derivative of 21dF-the latter associated with clinical conditions characterised by androgen excess. With our data showing that 11 alpha OHP4 is present at high levels in prostate cancer tissue, the steroid may serve as a precursor to unique C11 alpha-hydroxy C-19 steroids. The potential impact of 11 alpha OHP4 and its metabolites on human pathophysiology can however only be fully assessed once C11 alpha-hydroxyl metabolite levels are comprehensively analysed.