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Effects of CYP7B1-mediated catalysis on estrogen receptor activation.
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, 1090-1097 p.Article in journal (Refereed) Published
Abstract [en]

Most of the many biological effects of estrogens are mediated via the estrogen receptors ER alpha and beta. The current study examines the role of CYP7B1-mediated catalysis for activation of ER. Several reports suggest that CYP7B1 may be important for hormonal action but previously published studies are contradictory concerning the manner in which CYP7B1 affects ER beta-mediated response. In the current study, we examined effects of several CYP7B1-related steroids on ER activation, using an estrogen response element (ERE) reporter system. Our studies showed significant stimulation of ER by 5-androstene-3 beta,17 beta-diol (Aene-diol) and 5 alpha-androstane-3 beta,17 beta-diol (3 beta-Adiol). In contrast, the CYP7B1-formed metabolites from these steroids did not activate the receptor, indicating that CYP7B1-mediated metabolism abolishes the ER-stimulating effect of these compounds. The mRNA level of HEM45, a gene known to be stimulated by estrogens, was strongly up-regulated by Aene-diol but not by its CYP7B1-formed metabolite, further supporting this concept. We did not observe stimulation by dehydroepiandrosterone (DHEA) or 7 alpha-hydroxy-DHEA, previously suggested to affect ER beta-mediated response. As part of these studies we examined metabolism of Aene-diol in pig liver which is high in CYP7B1 content These experiments indicate that CYP7B1-mediated metabolism of Aene-diol is of a similar rate as the metabolism of the well-known CYP7B1 substrates DHEA and 3 beta-Adiol. CYP7B1-mediated metabolism of 3 beta-Adiol has been proposed to influence ER beta-mediated growth suppression. Our results indicate that Aene-diol also might be important for ER-related pathways. Our data indicate that low concentrations of Aene-diol can trigger ER-mediated response equally well for both ER alpha and beta and that CYP7B1-mediated conversion of Aene-diol into a 7 alpha-hydroxymetabolite will result in loss of action.

Place, publisher, year, edition, pages
2010. Vol. 1801, no 9, 1090-1097 p.
Keyword [en]
CYP7B1, estrogen, hydroxylation, steroid metabolism, ER-mediated response
National Category
Pharmaceutical Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-100776DOI: 10.1016/j.bbalip.2010.05.011ISI: 000280627800012PubMedID: 20553962OAI: oai:DiVA.org:uu-100776DiVA: diva2:210974
Available from: 2009-04-07 Created: 2009-04-07 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Steroid-Metabolizing Cytochrome P450 (CYP) Enzymes in the Maintenance of Cholesterol and Sex Hormone Levels
Open this publication in new window or tab >>Steroid-Metabolizing Cytochrome P450 (CYP) Enzymes in the Maintenance of Cholesterol and Sex Hormone Levels
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The enzymes CYP27A1 and CYP7B1 are widely expressed in various human tissues and perform catalytic reactions in cholesterol homeostasis and endocrine signaling.

We have investigated the metabolism of a synthetic oxysterol. In this study, we show that CYP27A1 is the enzyme responsible for a 28-hydroxylation of this oxysterol and that the rate of CYP27A1-mediated metabolism is relatively slow. This may give an explanation for the prolonged inhibitory effects on cholesterol biosynthesis that have been shown for this oxysterol. The current study contributes to the knowledge of synthetically produced oxysterols and their potential use as cholesterol lowering drugs.

In two studies we investigated CYP7B1-mediated metabolism of different sex hormones. Our data indicate that CYP7B1 may carry out a previously unknown catalytic reaction involving an androgen. Taken together the data suggest that varying steroid concentrations in cells and tissues may be important for CYP7B1-dependent metabolism of sex hormones and sex hormone precursors. CYP7B1-mediated hydroxylation of sex hormones may influence the cellular levels of these steroids and may be a potential pathway for elimination of the steroids from the cell.

Some known CYP7B1 substrates are agonists for ERα and ERβ but the reported role(s) of CYP7B1 for ER action are not fully understood. In the last study we investigated the role(s) of CYP7B1-mediated metabolism for ER-mediated action. Our data indicate that CYP7B1-mediated conversion of steroids that affect ER-mediated response into their 7α-hydroxymetabolites will result in loss of action. This indicates that CYP7B1 may have an important role for regulation of ER-mediated processes in the body.

In summary, results from this thesis contribute to the knowledge on the metabolism of synthetic oxysterols of potential use as cholesterol lowering drugs and the role(s) of CYP7B1-mediated metabolism for processes related to the functions of sex hormones.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 96
Keyword
CYP27A1, CYP7B1, cytochrome P450, estrogen receptor, androgen receptor, cholesterol, sex hormone, hydroxylation, steroid metabolism, regulation of steroid levels
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Biochemistry
Identifiers
urn:nbn:se:uu:diva-100787 (URN)978-91-554-7518-5 (ISBN)
Public defence
2009-05-27, C8:301, BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Note
Disputationsordförande; Professor Eva Brittebo, Inst. för Biovetenskap, Avd. för Toxikologi, Uppsala Universitet, Uppsala Betygsnämndens ledamöten; Docent Lena Ekström, Inst. för Laboratoriemedicin, Avd. för Klinisk Kemi, Karolinska Universitetssjukhuset, Huddinge Docent Ulf Diczfaluzy, Inst. för Laboratoriemedicin, Avd. för Klinisk Kemi, Karolinska Universitetssjukhuset, Huddinge Professor Agneta Oskarsson, Inst. BVF, Avd. för farmakologi och toxikologi, SLU, UppsalaAvailable from: 2009-05-06 Created: 2009-04-07 Last updated: 2011-05-05Bibliographically approved
2. 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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