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Effects of CYP7B1-related steroids on androgen receptor activation in different cell lines
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.
2012 (English)In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1388-1918, Vol. 1821, no 7, 973-979 p.Article in journal (Refereed) Published
Abstract [en]

The widely expressed steroid hydroxylase CYP7B1 is involved in metabolism of a number of steroids reported to influence estrogen and androgen signaling. Several studies by us and other investigators have linked this enzyme to effects on estrogen receptor activation. In a previous report we examined the effect of CYP7B1-mediated hormone metabolism for estrogen-mediated response in kidney-derived HEK293 cells. In the current study we used an androgen response element (ARE) reporter system to examine androgen-dependent response of some CYP7B1 substrates and CYP7B1-formed metabolites in several cell lines derived from different tissues. The results indicate significantly lower androgen receptor activation by CYP7B1-formed steroid metabolites than by the corresponding steroid substrates, suggesting that CYP7B1-mediated catalysis may decrease some androgenic responses. Thus, CYP7B1-dependent metabolism may be of importance not only for estrogenic signaling but also for androgenic. This finding, that CYP7B1 activity may be a regulator of androgenic signaling by converting AR ligands into less active metabolites, is also supported by real-time RT-PCR experiment where a CYP7B1 substrate, but not the corresponding product, was able to stimulate known androgen-sensitive genes. Furthermore, our data indicate that the effects of some steroids on hormone response element reporter systems are cell line-specific. For instance, despite transfection of the same reporter systems, 5-androstene-3β,17β-diol strongly activates an androgen-dependent response element in prostate cancer cells whereas it elicits only ER-dependent responses in kidney HEK293 cells. Potential roles of cell-specific metabolism or comodulator expression for the observed differences are discussed.

Place, publisher, year, edition, pages
2012. Vol. 1821, no 7, 973-979 p.
Keyword [en]
Androgen, CYP7B1, Hydroxylation, AR-mediated response, Steroid metabolism
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-151739DOI: 10.1016/j.bbalip.2012.03.007ISI: 000305359200004OAI: oai:DiVA.org:uu-151739DiVA: diva2:411163
Available from: 2011-04-16 Created: 2011-04-16 Last updated: 2012-08-01Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 146
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
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)
Swedish Research Council
Available from: 2011-05-20 Created: 2011-04-16 Last updated: 2011-07-01Bibliographically approved

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