11β-hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways. (15th June 2015)

• Record Type: Journal Article
• Authors: Swart, Amanda C.; Storbeck, Karl-Heinz
• Is Part Of: Molecular and cellular endocrinology. Volume 408(2015)
• Page Start: 114
• Page End: 123
• Publication Date: 2015-06-15
• Subjects: 3α-adiol 5α-androstane-3α, 17β-diol -- 3α-atriol 5α-androstane-3α, 11β, 17β-triol -- 3β-adiol 5α-androstane-3β, 17β-diol -- 3αHSD 3α-hydroxysteroid dehydrogenase -- 3βHSD 3β-hydroxysteroid dehydrogenase -- 5α-dione 5α-androstanedione -- 11βHSD 11β-hydroxysteroid dehydrogenase -- 11K-3α-adiol 11-keto-5α-androstane-3α, 17β-diol -- 11K-5α-dione 11-keto-5α-androstanedione -- 11KA4 adrenosterone / 11-ketoandrostenedione -- 11KAST 11-ketoandrosterone -- 11KDHT 11-ketodihydrotestosterone -- 11KT 11-ketotestosterone -- 11OH-5α-dione 11OH-5α-androstanedione -- 11OHA4 11β-hydroxyandrostenedione -- 11OHAST 11β-hydroxyandrosterone -- 11OHDHT 11β-hydroxydihydrotestosterone -- 11OHT 11β-hydroxytestosterone -- 17βHSD 17β-hydroxysteroid dehydrogenase -- A4 androstenedione -- AKR1C1 20α(3β)-hydroxysteroid dehydrogenase -- AKR1C2 3α-hydroxysteroid dehydrogenase type 3 -- AKR1C3 17β-hydroxysteroid dehydrogenase type 5 -- AR androgen receptor -- ALDO aldosterone -- AST 5α-androstan-3α-ol-17-one -- CORT corticosterone -- CRPC castration resistant prostate cancer -- CYP11A1 cytochrome P450 side-chain cleavage -- CYP11B1 cytochrome P450 11β-hydroxylase -- CYP11B2 cytochrome P450 aldosterone synthase -- CYP17A1 cytochrome P450 17α-hydroxylase/17, 20-lyase -- DHT dihydrotestosterone -- DOC deoxycorticosterone -- MR mineralocorticoid receptor -- RL-HSD RODH like 3α-HSD/17βHSD6 -- SRD5A steroid 5α-reductase -- T testosterone; Adrenal steroidogenesis -- Cytochrome P450 11β-hydroxylase -- Androgen deprivation therapy (ADT) -- Abiraterone acetate -- Castration resistant prostate cancer (CRPC) -- 11-Ketodihydrotestosterone (11KDHT); Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2014.12.009
• Languages: English
• ISSNs: 0303-7207

Abstract

Highlights: Human CYP11B enzymes catalyse the 11β-hydroxylation of A4 and T. 11OHA4 is a major C19 adrenal steroid and is metabolised to active androgens. 11KT is a partial agonist and 11KDHT a full agonist, comparable to DHT at 1 nM. 11OHA4 and downstream 11β-hydroxyl metabolites are novel substrates for 11βHSD2. 11OHA4, 11OHT, 11KA4 and 11KT are novel substrates for SRD5A. Abstract: 11β-Hydroxyandrostenedione (11OHA4), a major C19 steroid produced by the adrenal, was first reported in the 1950s. Initially the subject of numerous studies, interest dwindled due to the apparent lack of physiological function and, by the end of the century, 11OHA4 was no longer considered as an adrenal C19 steroid. Our recent studies, however, showed that 11OHA4 is the precursor to novel active androgens which include 11-ketodihydrotestosterone (11KDHT) which has been implicated in prostate cancer, thereby renewing interest in 11OHA4. In this paper we review the biosynthesis and downstream metabolism of 11OHA4. We discuss the extra-adrenal biosynthesis of 11OHA4 in humans and in other species, highlighting the well-documented role of 11OHA4 in the testes of male fish in which the steroid functions as an active androgen. Finally, we discuss the physiological relevance of 11OHA4 metabolism in castration resistant prostate cancer and outline future prospects.