The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2020-09-01
Date Acceptance
2020-06-30
Citation
Journal of Steroid Biochemistry and Molecular Biology, 2020, 202
ISSN
0960-0760
Publisher
Elsevier
Journal / Book Title
Journal of Steroid Biochemistry and Molecular Biology
Volume
202
Copyright Statement
© 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/32629108
PII: S0960-0760(20)30249-1
Subjects
11-ketoetiocholanolone
11-ketotestosterone
11-oxygenated androgens
19-CARBON STEROIDS
3-ALPHA-HYDROXYSTEROID DEHYDROGENASES
5-BETA-REDUCED STEROIDS
AKR1C1-AKR1C4
ANDROGENS
Biochemistry & Molecular Biology
C19 STEROIDS
Endocrinology & Metabolism
Life Sciences & Biomedicine
METABOLISM
Science & Technology
steroid 5 alpha-reductase
steroid 5 beta-reductase
STEROID 5-ALPHA-REDUCTASE
steroid metabolism
SUBSTRATE-SPECIFICITY
SUPERFAMILY
Publication Status
Published
Coverage Spatial
England
Article Number
105724
Date Publish Online
2020-07-03