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CYP7B1-mediated metabolism of 5 alfa-androstane-3 alfa,17 beta-diol (3 alfa-Adiol): A novel pathway for potential regulation of the cellular levels of androgens and neurosteroids
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Steroid P450)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Steroid P450)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farm farmakologi, Prostaglandingruppen)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Steroid P450)
2009 (English)In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1791, no 12, 1206-1215 p.Article in journal (Refereed) Published
Abstract [en]

The current study presents data indicating that 5alfa-androstane-3alfa,17beta-diol (3alfa-Adiol) undergoes a previously unknown metabolism into hydroxymetabolites, catalyzed by CYP7B1. 3alfa-Adiol is an androgenic steroid which serves as a source for the potent androgen dihydrotestosterone and also can modulate gamma-amino butyric acid A (GABAA) receptor function in the brain. The steroid hydroxylase CYP7B1 is known to metabolize cholesterol derivatives, sex hormone precursors and certain estrogens, but has previously not been thought to act on androgens or 3a-hydroxylated steroids. 3alfa-Adiol was found to undergo NADPH-dependent metabolism into 6- and 7-hydroxymetabolites in incubations with porcine microsomes and human kidney-derived HEK293 cells, which are high in CYP7B1 content. This metabolism was suppressed by addition of steroids known to be metabolized by CYP7B1. Also, recombinant expression of human CYP7B1 in HEK293 cells significantly increased the rate of 3alfa-Adiol hydroxylation. In addition, 3alfa-Adiol significantly suppressed CYP7B1-mediated catalytic reactions, in a way as would be expected for substrates that compete for the same enzyme. The present results indicate that CYP7B1-mediated catalysis may play a role for control of the cellular levels of androgens, not only of estrogens. These findings suggest a previously unknown mechanism for metabolic elimination of 3alfa-Adiol which may impact intracellular levels of dihydrotestosterone and GABAA-modulating steroids.

Place, publisher, year, edition, pages
2009. Vol. 1791, no 12, 1206-1215 p.
Keyword [en]
CYP7B1, 5alfa-androstane-3alfa, 17beta-diol, steroid metabolism, androgen, neurosteroid
National Category
Pharmaceutical Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-100768DOI: 10.1016/j.bbalip.2009.08.010ISI: 000272070700012PubMedID: 19732851OAI: oai:DiVA.org:uu-100768DiVA: diva2:210973
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

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Norlin, Maria

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