C11-hydroxy and C11-oxo C<sub>19</sub> and C<sub>21</sub> Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors
C11-oxy C<sub>19</sub> and C11-oxy C<sub>21</sub> steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation of C11-oxy steroids by 11β-hydroxysteroid dehydrogenase (11βHSD) interconversion a...
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| Format: | Article |
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/1/101 |
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| author | Rachelle Gent Desmaré Van Rooyen Stephen L. Atkin Amanda C. Swart |
| author_facet | Rachelle Gent Desmaré Van Rooyen Stephen L. Atkin Amanda C. Swart |
| author_sort | Rachelle Gent |
| collection | DOAJ |
| description | C11-oxy C<sub>19</sub> and C11-oxy C<sub>21</sub> steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation of C11-oxy steroids by 11β-hydroxysteroid dehydrogenase (11βHSD) interconversion and potential agonist and antagonist activity associated with the androgen (AR) and progesterone receptors (PRA and PRB). Steroid conversions were investigated in transiently transfected HEK293 cells expressing 11βHSD1 and 11βHSD2, while CV1 cells were utilised for agonist and antagonist assays. The conversion of C11-hydroxy steroids to C11-oxo steroids by 11βHSD2 occurred more readily than the reverse reaction catalysed by 11βHSD1, while the interconversion of C11-oxy C<sub>19</sub> steroids was more efficient than C11-oxy C<sub>21</sub> steroids. Furthermore, 11-ketodihydrotestosterone (11KDHT), 11-ketotestosterone (11KT) and 11β-hydroxydihydrotestosterone (11OHDHT) were AR agonists, while only progestogens, 11β-hydroxyprogesterone (11βOHP4), 11β-hydroxydihydroprogesterone (11βOHDHP4), 11α-hydroxyprogesterone (11αOHP4), 11α-hydroxydihydroprogesterone (11αOHDHP4), 11-ketoprogesterone (11KP4), 5α-pregnan-17α-diol-3,11,20-trione (11KPdione) and 21-deoxycortisone (21dE) exhibited antagonist activity. C11-hydroxy C<sub>21</sub> steroids, 11βOHP4, 11βOHDHP4 and 11αOHP4 exhibited PRA and PRB agonistic activity, while only C11-oxo steroids, 11KP4 and 11-ketoandrostanediol (11K3αdiol) demonstrated PRB agonism. While no steroids antagonised the PRA, 11OHA4, 11β-hydroxytestosterone (11OHT), 11KT and 11KDHT exhibited PRB antagonism. The regulatory role of 11βHSD isozymes impacting receptor activation is clear—C11-oxo androgens exhibit AR agonist activity; only C11-hydroxy progestogens exhibit PRA and PRB agonist activity. Regulation by the downstream metabolites of active C11-oxy steroids at the receptor level is apparent—C11-hydroxy and C11-oxo metabolites antagonize the AR and PRB, progestogens the former, androgens the latter. The findings highlight the intricate interplay between receptors and active as well as “inactive” C11-oxy steroids, suggesting novel regulatory tiers. |
| first_indexed | 2024-03-08T15:06:42Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T15:06:42Z |
| publishDate | 2023-12-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-bf0390691433485985ee442e867a70e82024-01-10T14:58:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0125110110.3390/ijms25010101C11-hydroxy and C11-oxo C<sub>19</sub> and C<sub>21</sub> Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid ReceptorsRachelle Gent0Desmaré Van Rooyen1Stephen L. Atkin2Amanda C. Swart3Department of Biochemistry, Stellenbosch University, Stellenbosch 7600, South AfricaDepartment of Biochemistry, Stellenbosch University, Stellenbosch 7600, South AfricaSchool of Postgraduate Studies and Research, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, BahrainDepartment of Biochemistry, Stellenbosch University, Stellenbosch 7600, South AfricaC11-oxy C<sub>19</sub> and C11-oxy C<sub>21</sub> steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation of C11-oxy steroids by 11β-hydroxysteroid dehydrogenase (11βHSD) interconversion and potential agonist and antagonist activity associated with the androgen (AR) and progesterone receptors (PRA and PRB). Steroid conversions were investigated in transiently transfected HEK293 cells expressing 11βHSD1 and 11βHSD2, while CV1 cells were utilised for agonist and antagonist assays. The conversion of C11-hydroxy steroids to C11-oxo steroids by 11βHSD2 occurred more readily than the reverse reaction catalysed by 11βHSD1, while the interconversion of C11-oxy C<sub>19</sub> steroids was more efficient than C11-oxy C<sub>21</sub> steroids. Furthermore, 11-ketodihydrotestosterone (11KDHT), 11-ketotestosterone (11KT) and 11β-hydroxydihydrotestosterone (11OHDHT) were AR agonists, while only progestogens, 11β-hydroxyprogesterone (11βOHP4), 11β-hydroxydihydroprogesterone (11βOHDHP4), 11α-hydroxyprogesterone (11αOHP4), 11α-hydroxydihydroprogesterone (11αOHDHP4), 11-ketoprogesterone (11KP4), 5α-pregnan-17α-diol-3,11,20-trione (11KPdione) and 21-deoxycortisone (21dE) exhibited antagonist activity. C11-hydroxy C<sub>21</sub> steroids, 11βOHP4, 11βOHDHP4 and 11αOHP4 exhibited PRA and PRB agonistic activity, while only C11-oxo steroids, 11KP4 and 11-ketoandrostanediol (11K3αdiol) demonstrated PRB agonism. While no steroids antagonised the PRA, 11OHA4, 11β-hydroxytestosterone (11OHT), 11KT and 11KDHT exhibited PRB antagonism. The regulatory role of 11βHSD isozymes impacting receptor activation is clear—C11-oxo androgens exhibit AR agonist activity; only C11-hydroxy progestogens exhibit PRA and PRB agonist activity. Regulation by the downstream metabolites of active C11-oxy steroids at the receptor level is apparent—C11-hydroxy and C11-oxo metabolites antagonize the AR and PRB, progestogens the former, androgens the latter. The findings highlight the intricate interplay between receptors and active as well as “inactive” C11-oxy steroids, suggesting novel regulatory tiers.https://www.mdpi.com/1422-0067/25/1/10111β-hydroxysteroid dehydrogenase (HSD11B)11β-hydroxyandrostenedione (11OHA4)11β-hydroxyprogesterone (11OHP4)adrenal steroidogenesisandrogen receptor (AR)castration-resistant prostate cancer (CRPC) |
| spellingShingle | Rachelle Gent Desmaré Van Rooyen Stephen L. Atkin Amanda C. Swart C11-hydroxy and C11-oxo C<sub>19</sub> and C<sub>21</sub> Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors International Journal of Molecular Sciences 11β-hydroxysteroid dehydrogenase (HSD11B) 11β-hydroxyandrostenedione (11OHA4) 11β-hydroxyprogesterone (11OHP4) adrenal steroidogenesis androgen receptor (AR) castration-resistant prostate cancer (CRPC) |
| title | C11-hydroxy and C11-oxo C<sub>19</sub> and C<sub>21</sub> Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors |
| title_full | C11-hydroxy and C11-oxo C<sub>19</sub> and C<sub>21</sub> Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors |
| title_fullStr | C11-hydroxy and C11-oxo C<sub>19</sub> and C<sub>21</sub> Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors |
| title_full_unstemmed | C11-hydroxy and C11-oxo C<sub>19</sub> and C<sub>21</sub> Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors |
| title_short | C11-hydroxy and C11-oxo C<sub>19</sub> and C<sub>21</sub> Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors |
| title_sort | c11 hydroxy and c11 oxo c sub 19 sub and c sub 21 sub steroids pre receptor regulation and interaction with androgen and progesterone steroid receptors |
| topic | 11β-hydroxysteroid dehydrogenase (HSD11B) 11β-hydroxyandrostenedione (11OHA4) 11β-hydroxyprogesterone (11OHP4) adrenal steroidogenesis androgen receptor (AR) castration-resistant prostate cancer (CRPC) |
| url | https://www.mdpi.com/1422-0067/25/1/101 |
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