The metabolic fate and receptor interaction of 16 alpha-hydroxyprogesterone and its 5 alpha-reduced metabolite, 16 alpha-hydroxydihydroprogesterone

摘要

16 alpha-hydroxyprogesterone (16OHP4) is not well characterised in terms of metabolism and receptor interaction. We therefore investigated its metabolism by adrenal CYP11B and peripheral steroidogenic enzymes, SRD5A and AKR1C2. UHPLC-MS/MS analyses identified novel steroids: the biosynthesis of 4-pregnen-11 beta,16 alpha-dio1-3,20-dione catalysed by CYP11B2; the 5 alpha-reduction of the latter and 16OHP4 catalysed by SRD5A yielding 5 alpha-pregnan-11 beta,16 alpha-diol-3,20-diovne and 5 alpha-pregnan-16 alpha-ol-3,20-dione (16OH-DHP4); and 16OH-DHP4 converted by AKR1C2 to 5 alpha-pregnan-3 alpha,16 alpha-diol-20-one. Receptor studies showed 16OHP4, 16OH-DHP4, progesterone and dihydroprogesterone (DHP4) were weak partial AR agonists; 16OHP4, 16OH-DHP4 and DHP4 exhibited weak partial agonist activity towards PR-B with DHP4 also exhibiting partial agonist activity towards PR-A. Data showed that while the 5 alpha-reduction of P4 decreased PR activation significantly, 16OHP4 and 16OH-DHP4 exhibited comparable receptor activation. Although the clinical relevance of 16OHP4 remains unclear the elevated 16OHP4 levels characteristic of 21OHD, CAH, PCOS, prostate cancer, testicular feminization syndrome and cryptorchidism likely contribute towards these clinical conditions, inducing receptor-activated target genes. (C) 2016 Elsevier Ireland Ltd. All rights reserved.