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.

Publication date: Available online 31 July 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Lise Barnard, Rachelle Gent, Desmaré van Rooyen, Amanda C. Swart
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.

Graphical abstract

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