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1α,25-Dihydroxyvitamin D3 affects hormone production and expression of steroidogenic enzymes in human adrenocortical NCI-H295R cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2010 (English)In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1801, no 9, 1056-1062 p.Article in journal (Refereed) Published
Abstract [en]

The current study presents data indicating that 1 alpha,25-dihydroxyvitamin D-3 affects the production of hormones and expression of crucial steroidogenic enzymes in the human adrenocortical cell line NCI-H295R. This cell line is widely used as a model for adrenal steroidogenesis. Treatment of the cells with 1 alpha,25-dihydroxyvitamin D-3 suppressed the levels of corticosterone, aldosterone, DHEA, DHEA-sulfate and androstenedione in the culture medium. In order to study the mechanisms behind this suppression of hormone production, we investigated the effects of 1 alpha,25-dihydroxyvitamin D-3 on important genes and enzymes controlling the biosynthesis of adrenal hormones. The mRNA levels were decreased for CYP21A2 while they were increased for CYP11A1 and CYP17A1. No significant changes were observed in mRNA for CYP11B1, CYP11B2 or 3 beta-hydroxysteroid dehydrogenase (3 beta HSD). In similarity with the effects on mRNA levels, also the endogenous enzyme activity of CYP21A2 decreased after treatment with 1 alpha,25-dihydroxyvitamin D3. Interestingly, the two CYP17A1-mediated activities were influenced reciprocally the 17 alpha-hydroxylase activity increased whereas the 17,20-lyase activity decreased. The current data indicate that the 1 alpha,25-dihydroxyvitamin D-3-mediated decrease in corticosterone and androgen production is due to suppression of the 21-hydroxylase activity by CYP21A2 and the 17,20-lyase activity by CYP17A1, respectively. In conclusion, the current study reports novel findings on 1 alpha,25-dihydroxyvitamin D-3-mediated effects on hormone production and regulation of genes and enzymes involved in steroidogenesis in the adrenocortical NCI-H295R cell line, a model for human adrenal cortex.

Place, publisher, year, edition, pages
2010. Vol. 1801, no 9, 1056-1062 p.
Keyword [en]
Steroidogenesis, Calcitriol, 1 alpha, 25-dihydroxyvitamin D-3, Regulation
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-135611DOI: 10.1016/j.bbalip.2010.04.009ISI: 000280627800008PubMedID: 20420936OAI: oai:DiVA.org:uu-135611DiVA: diva2:375289
Available from: 2010-12-07 Created: 2010-12-07 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Enzymatic Regulation of Steroidogenesis and Nuclear Receptor Activation: Special Focus on Vitamin D and Sex Hormones
Open this publication in new window or tab >>Enzymatic Regulation of Steroidogenesis and Nuclear Receptor Activation: Special Focus on Vitamin D and Sex Hormones
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Enzyme-catalyzed reactions are important to regulate steroidogenesis and nuclear receptor activation. The present investigation examines the role of steroid metabolism catalyzed by CYP7B1 for regulation of hormone receptor activation and the effects of vitamin D on enzymatic regulation of steroidogenesis.

The study reports data indicating that CYP7B1 can regulate estrogenic signaling by converting estrogens into inactive or less active metabolites. Similar results were obtained for CYP7B1-mediated metabolism of some androgen receptor ligands, indicating that CYP7B1 can be involved also in the regulation of androgenic signaling. CYP7B1 substrates and metabolites were found to exert androgenic effects in a cell line-specific manner. Furthermore, cell line differences were observed in the expression pattern for androgen receptor comodulators.

This thesis reports that 1α,25-dihydroxyvitamin D3 alters the gene expression and enzyme activity of CYP21A2 and CYP17A1 leading to suppressed production of aldosterone, dehydroepiandrosterone and androstenedione in adrenocortical cells. These are novel findings on vitamin D action.

A mechanism is reported for the vitamin D-mediated regulation of the CYP21A2 gene. Data indicate that vitamin D receptor interacting repressor (VDIR) and Williams syndrome transcription factor (WSTF) are key comodulators in this novel vitamin D receptor (VDR)-mediated mechanism. Furthermore, the results indicate that altered expression levels of VDIR and WSTF can shift the suppressing effect of vitamin D to a stimulatory effect. Also, epigenetic components were found to be involved in the effects of vitamin D on CYP21A2 transcriptional rate. In addition, a functional vitamin D response element was identified in the CYP21A2 promoter.

This study also reports that 1α,25-dihydroxyvitamin D3 affects sex hormone production in a tissue-specific way. Gene expression and enzyme activity of aromatase were found to be downregulated in cells derived from breast, but not in cells derived from prostate and adrenal cortex. The production of estradiol and dihydrotestosterone was altered in a tissue-selective manner following vitamin D treatment. These findings are of importance for the discussion on vitamin D as a potential anti-breast cancer agent.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 55 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 146
Keyword
adrenal steroidogenesis, CYP7B1, vitamin D, calcitriol, enzymatic regulation, transcriptional regulation, CYP21A2, aromatase, sex hormone, estrogen, androgen, nuclear receptor
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Biochemistry
Identifiers
urn:nbn:se:uu:diva-151740 (URN)978-91-554-8093-6 (ISBN)
Public defence
2011-06-10, Uppsala Biomedical Center, room C4:301, Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Funder
Swedish Research Council
Available from: 2011-05-20 Created: 2011-04-16 Last updated: 2011-07-01Bibliographically approved

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Lundqvist, JohanNorlin, MariaWikvall, Kjell

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