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- W3016452185 abstract "Cytochrome P450 (CYP11B1) and cytochrome 17α-hydroxylase (CYP17A1) play pivotal roles in the biosynthesis of adrenal glucocorticoids and androgens. It is generally accepted that CYP11B1 catalyses only the production of cortisol and corticosterone while CYP17A1 catalyses the hydroxylation of pregnenolone and progesterone at C17 and, in humans, the 17,20-lyase of 17-hydroxypregnenolone to produce DHEA. CYP11B1, however, also catalyses the biosynthesis of C11-oxy C21 steroids, 11β-hydroxyandrostenedione, 11β-hydroxyprogesterone (11OHPROG) and 21-deoxycortisol (21dF) in the adrenal [1, 2]. We investigated the potential role of CYP17A1 in the metabolism of these C11-oxy C21steroids leading to the production of 11keto-dihydrotestosterone since 17-hydroxyprogesterone has been shown to lead to the production of dihydrotestosterone in the backdoor pathway. The 17α-hydroxylase/17,20-lyase activity of CYP17A1 towards 11OHPROG and 21dF was assayed as well as the catalytic activity of the enzyme towards the downstream C11-oxy C21steroid products. In vitro conversions were carried out with 1 μM steroid substrate in HEK293 and in LNCaP cells transiently expressing CYP17A1 and metabolites analysed using UPC2-MS/MS. Both 11OHPROG and 11keto-progesterone (11KPROG) were hydroxylated at C17 producing 21dF, 0.27 μM and 21-deoxycortisone, 0.65 μM, respectively while no lyase activity was detected. It was only once reduced by 5α-reductase and 3α-hydroxysteroid dehydrogenase that the aforementioned steroids were also lyased to produce the C11-oxy C19steroids, 11-hydroxyandrosterone, 0.6 μM and 11-ketoandrosterone, 0.43 μM. In LnCaP cells 11OHPROG and 11KPROG were metabolised to C11-oxy C19steroids indicative of the C11-oxy backdoor pathway. In addition, in HEK293 cells transiently transfected with 11β-hydroxysteroid dehydrogenase (11βHSD) type 1 and 11βHSD2 the isozymes readily catalysed the interconversion of all the C11-keto C21steroid intermediates produced in the pathway with the production of the keto intermediates being favoured. Although the C11-oxy C21steroids produced in the adrenal may serve as ligands for the progesterone receptor they also potentially add to the pool of potent androgens via the C11-oxy backdoor pathway. These C11-oxy steroids would thus further contribute to the androgen pool in adrenal disorders and diseases characterised by androgen excess in which these steroids have been identified. We recently reported 11OHPROG, 11keto-dihydroprogesterone and pregnanetriol in circulation in BPH patients [3]. The C11-oxy C21steroids and C11-oxy C19steroids, however, remain to be fully explored –not only in pathophysiology but also in sexual differentiation and development. Support or Funding Information The South African National Research Foundation (IFR170125217588, CSUR160414162143)" @default.
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- W3016452185 date "2020-04-01" @default.
- W3016452185 modified "2023-10-07" @default.
- W3016452185 title "CYP11B and CYP17A1 in the Biosynthesis and Metabolism of C11‐oxy Steroids" @default.
- W3016452185 cites W2777914629 @default.
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- W3016452185 doi "https://doi.org/10.1096/fasebj.2020.34.s1.05214" @default.
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