The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1. Issue 202 (September 2020)

• Record Type: Journal Article
• Authors: Barnard, Lise; Nikolaou, Nikolaos; Louw, Carla; Schiffer, Lina; Gibson, Hylton; Gilligan, Lorna C.; Gangitano, Elena; Snoep, Jacky; Arlt, Wiebke; Tomlinson, Jeremy W.; Storbeck, Karl-Heinz
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 202(2020)
• Publication Date: 2020-09
• Subjects: 11KA4 11-ketoandrostenedione -- 11KAn 11-ketoandrosterone -- 11K-5α-dione 11K-5α-androstanedione -- 11K-5α-DHT 11-keto-5α-dihydrotestosterone -- 11K-5β-dione 11-keto-5β-androstanedione -- 11K-5β-DHT 11-keto-5β-dihydrotestosterone -- 11KEdiol 11-ketoetiocholanediol -- 11KEt 11-ketoetiocholanolone -- 11KT 11-ketotestosterone -- 11OHA4 11β-hydroxyandrostenedione -- 11OHAn 11β-hydroxyandrosterone -- 11OHEt 11β-hydroxyetiocholanolone -- 11OHT 11β-hydroxytestosterone -- HSD17B2 17β-hydroxysteroid dehydrogenase type 2 -- 5α-DHT 5α-dihydrotestosterone -- 5α-dione 5α-androstanedione -- 5β-DHT 5β-dihydrotestosterone -- 5β-dione 5β-androstanedione -- A4 androstenedione -- Adiol androstanediol -- AKR1C3 17β-hydroxysteroid dehydrogenase type 5 -- AKR1C4 3α-hydroxysteroid dehydrogenase type 1 -- AKR1D1 aldo-keto reductase family member 1 type D1 -- An androsterone -- AR androgen receptor -- CYP11B1 cytochrome P450 11β-hydroxylase -- Ediol etiocholanediol -- Et etiocholanolone -- SRD5A1 steroid 5α-reductase type 1 -- SRD5A2 steroid 5α-reductase type 2 -- T testosterone -- UHPSFC-MS/MS ultra-high performance supercritical fluid chromatography tandem mass spectrometry; 11-oxygenated androgens -- 11-ketotestosterone -- steroid 5β-reductase -- steroid 5α-reductase -- 11-ketoetiocholanolone -- steroid metabolism; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2020.105724
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: 11-ketotestosterone is efficiently 5β -reduced by AKR1D1. SRD5A2, but not SRD5A1 catalyses the 5α-reduction of 11-ketotestosterone. Metabolism of 11-ketotestosterone overlaps with cortisone metabolism. 11-ketoandrosterone is a urinary marker of 11-ketotestosterone. Abstract: Testosterone and its 5α-reduced form, 5α-dihydrotestosterone, were previously thought to represent the only active androgens in humans. However, recent studies have shown that the potent androgen, 11-ketotestosterone, derived from the adrenal androgen precursor, 11β-hydroxyandrostenedione, may in fact serve as the primary androgen in healthy women. Yet, despite recent renewed interest in these steroids, their downstream metabolism has remained undetermined. We therefore set out to investigate the metabolism of 11-ketotestosterone by characterising the 5α- or 5β-reduction commitment step. We show that inactivation of 11-ketotestosterone is predominantly driven by AKR1D1, which efficiently catalyses the 5β-reduction of 11-ketotestosterone, committing it to a metabolic pathway that terminates in 11-ketoetiocholanolone. We demonstrate that 5α-reduction of 11-ketotestosterone is catalysed by SRD5A2, but not SRD5A1, and terminates in 11-ketoandrosterone, but is only responsible for a minority of 11-ketotestosterone inactivation. However, as 11-ketoetiocholanolone is also generated by the metabolism of the glucocorticoid cortisone, 11-ketoandrosterone should be considered a more specific urinary marker of 11-ketotestosterone production.