C11-hydroxy and C11-oxo C19 and C21 Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors
"> Figure 1
<p>C11-oxy C<sub>21</sub> backdoor pathway and 11β-hydroxyandrostenedione (11OHA4) pathway. The interconversion of C11-hydroxy and C11-oxo steroids catalysed by 11β-hydroxysteroid dehydrogenase isozymes (11βHSD1/2). C11-oxy C<sub>21</sub> backdoor pathway, dashed line; 11OHA4 pathway, solid line. <b>Steroids:</b> 11βOHP4, 11β-hydroxyprogesterone; 11βOHDHP4, 11β-hydroxydihydroprogesterone; 11KP4, 11-ketoprogesterone; 11KDHP4, 11-ketodihydroprogesterone; 3,11-diOHDHP4, 5α-pregnan-3α,11β-diol-20-one; alfaxalone, 5α-pregnan-3α-ol-11,20-dione; 21dF, 21-deoxycortisol; 21dE, 21-deoxycortisone; 11OHPdione, 5α-pregnan-11β,17α-diol-3,20-dione; 11KPdione, 5α-pregnan-17α-ol-3,11,20-trione; 11OHPdiol, 5α-pregnan-3α,11β,17α-triol-20-one; 11KPdiol, 5α-pregnan-3α,17α-diol-11,20-dione; 11OHA4, 11β-hydroxyandrostenedione; 11KA4, 11-ketoandrostenedione; 11OHT, 11β-hydroxytestosterone; 11KT, 11-ketotestosterone; 11OH5αdione, 5α-androstan-11β-ol-3,17-dione; 11K5αdione, 5α-androstane-3,11,17-trione; 11OHDHT, 11β-hydroxydihydrotestosterone; 11KDHT, 11-ketodihydrotestosterone; 11OHAST, 11β-hydroxyandrosterone; 11KAST, 11-ketoandrosterone; 11OH3αdiol, 11β-hydroxyandrostanediol; 11K3αdiol, 11-ketoandrostanediol. <b>Enzymes:</b> 11βHSD1, 11β-hydroxysteroid dehydrogenase 1; 11βHSD2, 11β-hydroxysteroid dehydrogenase 2; CYP17A1, cytochrome P450 17α-hydroxylase/17,20-lyase; SRD5A, 5α-reductase; 3αHSD, 3α-hydroxysteroid dehydrogenase; 17βHSD, 17β-hydroxysteroid dehydrogenase.</p> "> Figure 2
<p>Conversion of C11-hydroxy steroids by 11βHSD2 after 24 h. (<b>A</b>) C11-hydroxy C<sub>19</sub> substrates were added at a concentration of 1 µM, while 10 µM of 11OH3αdiol (shaded area) was added due to inadequate ionization during analysis. Results from this reaction are indicated on the right <span class="html-italic">y</span>-axis. (<b>B</b>) A total of 1 µM of the substrate was used to evaluate all C11-hydroxy C<sub>21</sub> steroid conversions. Solid bars, substrate; patterned bars, product. Unpaired <span class="html-italic">t</span>-tests were utilised to determine statistical significance between the substrate concentration added (0 h) and the substrate concentration remaining (24 h). §, not significant; *, <span class="html-italic">p</span> < 0.05; ***, <span class="html-italic">p</span> < 0.001; ****, <span class="html-italic">p</span> < 0.0001.</p> "> Figure 3
<p>Conversion of C11-oxo steroids by 11βHSD1 after 24h. (<b>A</b>) C11-oxo C<sub>19</sub> substrates were added at a concentration of 1 µM, while 10 µM of 11K3αdiol (shaded area) was added due to inadequate ionization during analysis. Results from this reaction are indicated on the right <span class="html-italic">y</span>-axis. (<b>B</b>) A total of 1 µM of the substrate was used to evaluate all C11-oxo C<sub>21</sub> steroid conversions. Solid bars, substrate; patterned bars, product. Unpaired <span class="html-italic">t</span>-tests were utilised to determine statistical significance between the substrate concentration added (0 h) and the substrate concentration remaining (24 h). §, not significant; *, <span class="html-italic">p</span> < 0.05; **, <span class="html-italic">p</span> < 0.005; ***, <span class="html-italic">p</span> < 0.001; ****, <span class="html-italic">p</span> < 0.0001.</p> ">
Abstract
:1. Introduction
2. Results
2.1. The Interconversion of C11-oxy C19 and C11-oxy C21 Steroids by the 11βHSD Isoforms
2.1.1. Conversion of C11-Hydroxy Steroids by 11βHSD2
2.1.2. Conversion of C11-oxo Steroids by 11βHSD1
2.2. Agonistic and Antagonistic Activity of C11-oxy Steroids towards Nuclear Steroid Receptors
2.2.1. Agonistic and Antagonistic Activity towards the AR
2.2.2. Agonistic and Antagonistic Activity towards the PRA
2.2.3. Agonistic and Antagonist Activity towards the PRB
3. Discussion
4. Materials and Methods
4.1. Materials
Cell Models and Vector Constructs
4.2. 11βHSD Steroidogenic Assays
4.2.1. Substrate Addition
4.2.2. Steroid Extraction
4.2.3. Separation and Quantification by UPC2-MS/MS
4.3. Receptor Assays
4.4. Statistical Analyses
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Androgens | Progestogens | ||
---|---|---|---|
A4 | androstenedione | P4 | progesterone |
11OHA4 | 11β-hydroxyandrostenedione | 11αOHP4 | 11α-hydroxyprogesterone |
11KA4 | 11-ketoandrostenedione | 11βOHP4 | 11β-hydroxyprogesterone |
T | testosterone | 11KP4 | 11-ketoprogesterone |
11OHT | 11β-hydroxytestosterone | 11αOHDHP4 | 11α-hydroxydihydroprogesterone |
11KT | 11-ketotestosterone | 11βOHDHP4 | 11β-hydroxydihydroprogesterone |
5αdione | 5α-androstanedione | 11KDHP4 | 11-ketodihydroprogesterone |
11OH5αdione | 5α-androstan-11β-ol-3,17-dione | 3,11-diOHDHP4 | 5α-pregnan-3α,11β-diol-20-one |
11K5αdione | 5α-androstane-3,11,17-trione | alfaxalone | 5α-pregnan-3α-ol-11,20-dione |
DHT | dihydrotestosterone | 17OHP4 | 17α-hydroxyprogesterone |
11OHDHT | 11β-hydroxydihydrotestosterone | 21dF | 21-deoxycortisol |
11KDHT | 11-ketodihydrotestosterone | 21dE | 21-deoxycortisone |
AST | androsterone | 11OHPdione | 5α-pregnan-11β,17α-diol-3,20-dione |
11OHAST | 11β-hydroxyandrosterone | 11KPdione | 5α-pregnan-17α-ol-3,11,20-trione |
11KAST | 11-ketoandrosterone | 11OHPdiol | 5α-pregnan-3α,11β,17α-triol-20-one |
11OH3αdiol | 11β-hydroxyandrostanediol | 11KPdiol | 5α-pregnan-3α,17α-diol-11,20-dione |
11K3αdiol | 11-ketoandrostanediol |
(A) | |||||||||
---|---|---|---|---|---|---|---|---|---|
10 nM | 100 nM | 1 µM | |||||||
Steroid | % Induction | ±SEM | Statistical Significance | % Induction | ±SEM | Statistical Significance | % Induction | ±SEM | Statistical Significance |
T | 3.18 | 1.29 | - | 35.1 | 9.66 | - | 100 | 16.6 | - |
DHT | 30.4 | 9.92 | * | 141 | 35.7 | **** | 161 | 22.4 | **** |
11KT | 1.81 | 0.71 | § | 15.0 | 4.52 | § | 148 | 25.6 | **** |
11KDHT | 6.59 | 1.2 | § | 78.0 | 11.6 | *** | 191 | 45.9 | **** |
11OHDHT | 1.63 | 0.49 | § | 10.7 | 4.53 | * | 153 | 49.1 | **** |
(B) | |||||||||
1 µM | 10 µM | ||||||||
Steroid | % Induction | ±SEM | Statistical Significance | % Induction | ±SEM | Statistical Significance | |||
T | 100 | 2.86 | - | 100 | 2.86 | - | |||
Bicalutamide | 71.0 | 3.95 | § | 11.3 | 1.55 | **** | |||
11OHA4 | 103 | 11.5 | § | 62.1 | 7.53 | * | |||
11OH5αdione | 103 | 15.4 | § | 68.5 | 8.35 | * | |||
11αOHP4 | 94.7 | 13.2 | § | 23.3 | 0.15 | **** | |||
11αOHDHP4 | 90.9 | 3.41 | § | 24.2 | 10.7 | **** | |||
11βOHP4 | 57.5 | 8.01 | ** | 7.60 | 1.5 | **** | |||
11βOHDHP4 | 76.2 | 11.6 | § | 18.4 | 0.88 | **** | |||
11KP4 | 76.3 | 15.2 | § | 25.7 | 4.25 | **** | |||
11KDHP4 | 75.1 | 22 | § | 34.9 | 9.73 | **** | |||
21dE | 110 | 11.3 | § | 68.8 | 4 | * | |||
11KPdione | 92.7 | 14.7 | § | 38.8 | 6.6 | **** | |||
P4 | 22.3 | 5.11 | **** | 9.93 | 3.29 | **** | |||
17OHP4 | 72.2 | 13.1 | § | 10.8 | 1.15 | **** |
10 nM | 100 nM | 1 µM | |||||||
---|---|---|---|---|---|---|---|---|---|
Steroid | % Induction | ±SEM | Statistical Significance | % Induction | ±SEM | Statistical Significance | % Induction | ±SEM | Statistical Significance |
P4 | 83.9 | 12.7 | - | 93.9 | 9.22 | - | 100 | 12.4 | - |
17OHP4 | 47.5 | 2.04 | **** | 50.5 | 1.52 | **** | 55.4 | 2.22 | **** |
11βOHP4 | 62.3 | 10.6 | ** | 68.7 | 7.87 | *** | 91.6 | 12.6 | § |
11βOHDHP4 | 48.6 | 3.29 | **** | 51.0 | 2.54 | **** | 73.4 | 12.1 | *** |
11αOHP4 | 49.9 | 4.69 | **** | 55.4 | 5.42 | **** | 67.4 | 8.52 | **** |
(A) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
10 nM | 100 nM | 1 µM | ||||||||||
Steroid | % Induction | ±SEM | Statistical Significance | % Induction | ±SEM | Statistical Significance | % Induction | ±SEM | Statistical Significance | |||
P4 | 43.5 | 2.42 | - | 87.4 | 14.2 | - | 100 | 23.9 | - | |||
17OHP4 | 13.1 | 0.90 | *** | 15.1 | 1.15 | **** | 35.4 | 5.04 | **** | |||
11βOHP4 | 25.0 | 5.79 | § | 113 | 10.5 | ** | 124 | 16.2 | * | |||
11βOHDHP4 | 13.9 | 0.72 | ** | 21.7 | 4.83 | **** | 80.7 | 22.2 | * | |||
11KP4 | 13.8 | 0.37 | ** | 14.9 | 0.96 | **** | 31.4 | 5.55 | **** | |||
11αOHP4 | 12.7 | 1.32 | *** | 17.2 | 3.03 | **** | 45.4 | 6.88 | **** | |||
11K3αdiol | 41.2 | 27.9 | § | 45.3 | 32.9 | **** | 57.4 | 19.6 | **** | |||
(B) | ||||||||||||
10 nM | 100 nM | 1 µM | 10 µM | |||||||||
Steroid | % Induction | ±SEM | Statistical Significance | % Induction | ±SEM | Statistical Significance | % Induction | ±SEM | Statistical Significance | % Induction | ±SEM | Statistical Significance |
P4 | 100 | 2.9 | - | 100 | 2.9 | - | 100 | 2.9 | - | 100 | 2.9 | - |
RU486 | 99.3 | 2.21 | § | 11.7 | 0.75 | **** | 10.5 | 0.39 | **** | 9.64 | 0.21 | **** |
A4 | 51.9 | 8.81 | **** | 44.7 | 5.04 | **** | 47.7 | 7.64 | **** | 29.7 | 5.11 | **** |
T | 82.9 | 18 | § | 64.5 | 8.95 | ** | 48.4 | 8.92 | **** | 34.9 | 1.02 | **** |
DHT | 72.1 | 1.19 | * | 65.5 | 4.75 | ** | 55.8 | 3.36 | *** | 34.6 | 0.86 | **** |
5αdione | 74.7 | 4.02 | * | 56.5 | 2.13 | *** | 68.9 | 4.63 | ** | 38.0 | 5.47 | **** |
11OHA4 | 51.2 | 8.18 | **** | 48.5 | 6.87 | **** | 56.6 | 10.3 | *** | 30.6 | 1.29 | **** |
11OHT | 62.5 | 2.51 | ** | 68.5 | 6.68 | ** | 66.0 | 8.73 | ** | 48.4 | 5.92 | **** |
11KT | 69.1 | 14.4 | ** | 78.2 | 16.7 | § | 61.4 | 8.77 | ** | 35.6 | 1.83 | **** |
11KDHT | 85.9 | 10.9 | § | 85.0 | 11.7 | § | 74.4 | 5 | * | 45.0 | 2.5 | **** |
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Gent, R.; Van Rooyen, D.; Atkin, S.L.; Swart, A.C. C11-hydroxy and C11-oxo C19 and C21 Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors. Int. J. Mol. Sci. 2024, 25, 101. https://doi.org/10.3390/ijms25010101
Gent R, Van Rooyen D, Atkin SL, Swart AC. C11-hydroxy and C11-oxo C19 and C21 Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors. International Journal of Molecular Sciences. 2024; 25(1):101. https://doi.org/10.3390/ijms25010101
Chicago/Turabian StyleGent, Rachelle, Desmaré Van Rooyen, Stephen L. Atkin, and Amanda C. Swart. 2024. "C11-hydroxy and C11-oxo C19 and C21 Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors" International Journal of Molecular Sciences 25, no. 1: 101. https://doi.org/10.3390/ijms25010101