The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1

Lise Barnard, Nikolaos Nikolaou, Carla Louw, Lina Schiffer, Hylton Gibson, Lorna Gilligan, Elena Gangitano, Jacky Snoep, Wiebke Arlt, Jeremy Tomlinson, Karl-Heinz Storbeck

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
66 Downloads (Pure)

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.
Original languageEnglish
Article number105724
JournalThe Journal of Steroid Biochemistry and Molecular Biology
Volume202
Early online date3 Jul 2020
DOIs
Publication statusPublished - Sep 2020

Bibliographical note

Funding Information:
This work was supported by the Wellcome Trust (Investigator Grant WT209492/Z/17/Z , to W.A.), the Academy of Medical Sciences UK (Newton Advanced Fellowship NAF0041002 , to K.-H.S), the National Research Foundation (NRF) of South Africa ( 111622 , to L.B), SARChI DST/NRF grant ( 82813 , to J.S), the European Society of Endocrinology (ESE) (Short-Term Fellowship to E.G), the Medical Research Council, UK (programme grant to J.W.T. MR/P011462/1 ), and the NIHR Oxford Biomedical Research Centre (J.W.T.). W.A. receives support from the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (Grant Reference Number BRC-1215-20009). The views expressed are those of the author(s) and not necessarily those of the NIHR UK, the Department of Health and Social Care UK or the NRF of South Africa.

Publisher Copyright:
© 2020 The Authors

Keywords

  • 11-ketoetiocholanolone
  • 11-ketotestosterone
  • 11-oxygenated androgens
  • steroid 5α-reductase
  • steroid 5β-reductase
  • steroid metabolism

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Fingerprint

Dive into the research topics of 'The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1'. Together they form a unique fingerprint.

Cite this