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CYP7B1-mediated metabolism of dehydroepiandrosterone and 5alpha-androstane-3beta,17beta-diol--potential role(s) for estrogen signaling
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.
2008 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 275, no 8, 1778-1789 p.Article in journal (Refereed) Published
Abstract [en]

CYP7B1, a cytochrome P450 enzyme, metabolizes several steroids involved in hormonal signaling including 5 alpha-androstane-3 beta,17 beta-diol (3 beta-Adiol), an estrogen receptor agonist, and dehydroepiandrosterone, a precursor for sex hormones. Previous studies have suggested that CYP7B1-dependent metabolism involving dehydroepiandrosterone or 3 beta-Adiol may play an important role for estrogen receptor beta-mediated signaling. However, conflicting data are reported regarding the influence of different CYP7B1-related steroids on estrogen receptor beta activation. In the present study, we investigated CYP7B1-mediated conversions of dehydroepiandrosterone and 3 beta-Adiol in porcine microsomes and human kidney cells. As part of these studies, we compared the effects of 3 beta-Adiol (a CYP7B1 substrate) and 7 alpha-hydroxy-dehydroepiandrosterone (a CYP7B1 product) on estrogen receptor beta activation. The data obtained indicated that 3 beta-Adiol is a more efficient activator, thus lending support to the notion that CYP7B1 catalysis may decrease estrogen receptor beta activation. Our data on metabolism indicate that the efficiencies of CYP7B1-mediated hydroxylations of dehydroepiandrosterone and 3 beta-Adiol are very similar. The enzyme catalyzed both reactions at a similar rate and the K-cat/K-m values were in the same order of magnitude. A high dehydroepiandrosterone/3 beta-Adiol ratio in the incubation mixtures, similar to the ratio of these steroids in many human tissues, strongly suppressed CYP7B1-mediated 3 beta-Adiol metabolism. As the efficiencies of CYP7B1-mediated hydroxylation of dehydroepiandrosterone and 3 beta-Adiol are similar, we propose that varying steroid concentrations may be the most important factor determining the rate of CYP7B1-mediated metabolism of dehydroepiandrosterone or 3 beta-Adiol. Consequently, tissue-specific steroid concentrations may have a strong impact on CYP7B1-dependent catalysis and thus on the levels of different CYP7B1-related steroids that can influence estrogen receptor beta signaling.

Place, publisher, year, edition, pages
2008. Vol. 275, no 8, 1778-1789 p.
Keyword [en]
cytochrome P450, estrogen receptor, hydroxylase, sex hormone, steroid metabolism
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-17120DOI: 10.1111/j.1742-4658.2008.06336.xISI: 000254499500017PubMedID: 18331353OAI: oai:DiVA.org:uu-17120DiVA: diva2:44891
Available from: 2008-06-17 Created: 2008-06-17 Last updated: 2017-12-08Bibliographically 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

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