Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone. Issue 174 (November 2017)

• Record Type: Journal Article
• Authors: Barnard, Lise; Gent, Rachelle; van Rooyen, Desmaré; Swart, Amanda C.
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 174(2017)
• Page Start: 86
• Page End: 95
• Publication Date: 2017-11
• Subjects: 11, 16-diOHP4 4-pregnen-11β, 16α-diol-3, 20-dione -- 11KA4 11-ketoandrostenedione -- 11KAdiol 11-keto-androstanediol -- 11KAST 11‐ketoandrosterone -- 11KDHT 11‐ketodihydrotestosterone -- 11KP4 11‐ketoprogesterone -- 11KPdiol 5α-pregnan-3α, 17α-diol-11, 20-dione -- 11KPdione 5α-pregnan-17α-ol-3, 11, 20-trione -- 11KT 11‐ketotestosterone -- 11OHA4 11β‐hydroxyandrostenedione -- 11OHAdiol 11β-hydroxyandrostanediol -- 11OHAdione 11β‐hydroxy-5α-androstanedione -- 11OHAST 11β‐hydroxyandrosterone -- 11OHDHT 11β‐hydroxydihydrotestosterone -- 11OHP4 11β‐hydroxyprogesterone -- 11OHPdiol 5α‐pregnan-3α, 11β, 17α-triol-20-one -- 11OHPdione 5α‐pregnan-11β, 17α-diol-3, 20-dione -- 11OHT 11β‐hydroxytestosterone -- 16OHP4 16α-hydroxyprogesterone -- 17OHP4 17α‐hydroxyprogesterone -- 17OHP5 17α‐hydroxypregnenolone -- A4 androstenedione -- Adiol androstanediol -- Adione androstanedione -- ALDO aldosterone -- AST androsterone -- DHEA dehydroepiandrosterone -- DHP dihydroprogesterone -- DHT dihydrotestosterone -- DHT-G dihydrotestosterone-glucuronide -- DOC 11-deoxycorticosterone -- 21dE 21‐deoxycortisone -- 21dF 21‐deoxycortisol -- P4 progesterone -- Pdiol 5α-pregnan-3α, 17α-diol-20-one -- Pdione 5α-pregnan-17α-ol-3, 20-dione -- T testosterone; 21-Hydroxylase deficiency (21OHD) -- Congenital adrenal hyperplasia (CAH) -- 11β-Hydroxysteriod dehydrogenase type 2 (11βHSD2) -- 17α-Hydroxyprogesterone -- Cytochrome P450 21-hydroxylase (CYP21A2) -- Steroid 5α-reductase (SRD5A); Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2017.07.034
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: Adrenal CYP11B isozymes catalyze the 11β-hydroxylation of 17α-hydroxyprogesterone. 11βHSD1 and 11βHSD2 convert 21-deoxycortisone (21dE) and 21-deoxycortisol (21dF). SRD5A catalyzes the conversion of 21dF and 21dE to 11OHPdione and 11KPdione. AKR1C2 reduces the C3-hydroxyl moiety in the biosynthesis of 11OHPdiol and 11KPdiol. 11OHPdiol and 11KPdiol are lysed by CYP17A1, yielding 11OHAST and 11KAST. Abstract: 21-Hydroxylase deficiency presents with increased levels of cytochrome P450 21‐hydroxylase substrates, progesterone and 17α-hydroxyprogesterone, which have been implicated in the production of androgens via the backdoor pathway. This study shows the biosynthesis of C11-oxy C21 steroids, 21-deoxycortisol and 21-deoxycortisone, and their metabolism by steroidogenic enzymes in the backdoor pathway yielding novel steroid metabolites: 5α‐pregnan-11β, 17α-diol-3, 20-dione; 5α-pregnan-17α-ol-3, 11, 20-trione; 5α‐pregnan-3α, 11β, 17α-triol-20-one and 5α-pregnan-3α, 17α-diol-11, 20-dione. The metabolism of 21-deoxycortisol was validated in LNCaP cells expressing the relevant steroidogenic enzymes showing for the first time that the steroid, produced at high levels in 21OHD, is metabolised via the C11-oxy derivatives of 5α‐pregnan-17α-ol-3, 20-dione and 5α‐pregnan-3α, 17α-diol-20-one to substrates for the lyase activity of CYP17A1, leading to the production of C11-oxy C19 steroids. 21-Deoxycortisol thus contributes to the pool of potent androgens in 21OHD, with novel steroid metabolites also presenting possible biomarkers in disease identification.