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Cited by 67Prostate Cancer Treatment and ResearchHormonal and reproductive studiesAdrenal Hormones and Disorders

Profiling adrenal 11β-hydroxyandrostenedione metabolites in prostate cancer cells, tissue and plasma: UPC2-MS/MS quantification of 11β-hydroxytestosterone, 11keto-testosterone and 11keto-dihydrotestosterone

du Toit, Therina, Bloem, Liezl M., Quanson, Jonathan L., Ehlers, Riaan, Serafin, Antonio M., Swart, Amanda C.·2017·The Journal of Steroid Biochemistry and Molecular Biology
DOI 10.1016/j.jsbmb.2016.06.009
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Abstract

Adrenal C 19 steroids serve as precursors to active androgens in the prostate. Androstenedione (A4), 11β-hydroxyandrostenedione (11OHA4) and 11β-hydroxytestosterone (11OHT) are metabolised to potent androgen receptor (AR) agonists, dihydrotestosterone (DHT), 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT). The identification of 11OHA4 metabolites, 11KT and 11KDHT, as active androgens has placed a new perspective on adrenal C11-oxy C 19 steroids and their contribution to prostate cancer (PCa). We investigated adrenal androgen metabolism in normal epithelial prostate (PNT2) cells and in androgen-dependent prostate cancer (LNCaP) cells. We also analysed steroid profiles in PCa tissue and plasma, determining the presence of the C 19 steroids and their derivatives using ultra-performance liquid chromatography (UHPLC)- and ultra-performance convergence chromatography tandem mass spectrometry (UPC 2-MS/MS). In PNT2 cells, sixty percent A4 (60%) was primarily metabolised to 5α-androstanedione (5αDIONE) (40%), testosterone (T) (10%), and androsterone (AST) (10%). T (30%) was primarily metabolised to DHT (10%) while low levels of A4, 5αDIONE and 3αADIOL (≈20%) were detected. Conjugated steroids were not detected and downstream products were present at <0.05μM. Only 20% of 11OHA4 and 11OHT were metabolised with the former yielding 11keto-androstenedione (11KA4), 11KDHT and 11β-hydroxy-5α-androstanedione (11OH-5αDIONE) and the latter yielding 11OHA4, 11KT and 11KDHT with downstream products <0.03μM. In LNCaP cells, A4 (90%) was metabolised to AST-glucuronide via the alternative pathway while T was detected as T-glucuronide with negligible conversion to downstream products. 11OHA4 (80%) and 11OHT (60%) were predominantly metabolised to 11KA4 and 11KT and in both assays more than 50% of 11KT was detected in the unconjugated form. In tissue, we detected C11-oxy C 19 metabolites at significantly higher levels than the C 19 steroids, with unconjugated 11KDHT, 11KT and 11OHA4 levels ranging between 13 and 37.5ng/g. Analyses of total steroid levels in plasma showed significant levels of 11OHA4 (≈230-440nM), 11KT (≈250-390nM) and 11KDHT (≈19nM). DHT levels (<0.14nM) were significantly lower. In summary, 11β-hydroxysteroid dehydrogenase type 2 activity in PNT2 cells was substantially lower than in LNCaP cells, reflected in the conversion of 11OHA4 and 11OHT. Enzyme substrate preferences suggest that the alternate pathway is dominant in normal prostate cells. Glucuronidation activity was not detected in PNT2 cells and while all T derivatives were efficiently conjugated in LNCaP cells, 11KT was not. Substantial 11KT levels were also detected in both PCa tissue and plasma. 11OHA4 therefore presents a significant androgen precursor and its downstream metabolism to 11KT and 11KDHT as well as its presence in PCa tissue and plasma substantiate the importance of this adrenal androgen.

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  • The levels of 11-oxygenated androgens were higher than those of the classical androgens in tissue from two patients with prostate cancer.

    “Indeed, a recent study showed that the levels of these 11-oxygenated androgens were higher than those of the classical androgens in tissue from two patients with prostate cancer (du Toit et al., 2017).”

    From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as du Toit et al., 2017

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Authors
du Toit, T., Bloem, L. M., Quanson, J. L., Ehlers, R., Serafin, A. M., & Swart, A. C.
Affiliations
Stellenbosch University (ZA)
Corresponding author
Swart, Amanda C.
ORCID
Venue
The Journal of Steroid Biochemistry and Molecular Biology
Publisher
Elsevier BV
Published
2017-02
Volume
166
Pages
54-67
ISSN
0960-0760 (ISSN-L)
DOI
10.1016/j.jsbmb.2016.06.009
OpenAlex
W2462363595
Cited by
67
References
71
Citations by year
2026: 1 · 2025: 3 · 2024: 3 · 2023: 9 · 2022: 4 · 2021: 6 · 2020: 8 · 2019: 12 · 2018: 10 · 2017: 10 · 2016: 1
FWCI
9.83
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Research Foundation, CANSA
  • University of Stellenbosch
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
11β-hydroxyandrostenedione, 11β-hydroxytestosterone, 11-ketotestosterone, prostate cancer, androgen metabolism, androgen receptor agonists, androstenedione, dihydrotestosterone, androsterone, LNCaP cells
MeSH terms
Adrenal Glands, Aged, Androgens, Androstenedione, Humans, Hydroxytestosterones, Male, Prostatic Neoplasms, Dihydrotestosterone, Steroids, Testosterone, Gene Expression Regulation, Neoplastic, Disease Progression, Glucuronic Acid, Cell Line, Tumor, Tandem Mass Spectrometry

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