期刊
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
卷 202, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2020.105724
关键词
11-oxygenated androgens; 11-ketotestosterone; steroid 5 beta-reductase; steroid 5 alpha-reductase; 11-ketoetiocholanolone; steroid metabolism
资金
- Wellcome Trust [WT209492/Z/17/Z]
- Academy of Medical Sciences UK [NAF0041002]
- National Research Foundation (NRF) of South Africa [111622]
- SARChI DST/NRF [82813]
- European Society of Endocrinology (ESE)
- Medical Research Council, UK [MR/P011462/1]
- NIHR Oxford Biomedical Research Centre
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust [BRC-1215-20009]
- University of Birmingham [BRC-1215-20009]
- MRC [MR/P011462/1] Funding Source: UKRI
Testosterone and its 5 alpha-reduced form, 5 alpha-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, 110-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 5 alpha or 50-reduction commitment step. We show that inactivation of 11-ketotestosterone is predominantly driven by AKR1D1, which efficiently catalyses the 50-reduction of 11-ketotestosterone, committing it to a metabolic pathway that terminates in 11-ketoetiocholanolone. We demonstrate that 5 alpha-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.
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