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Metabolism of a novel side chain modified Delta 8(14)-15-ketosterol, a potential cholesterol lowering drug: 28-hydroxylation by CYP27A1
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry. (Steroid P450)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry. (Steroid P450)
Avd. för klinisk kemi, KI, Huddinge, Sverige.
Department of clinical chemistry and toxicology, University of Texas medical branch, Galveston, USA.
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2008 (English)In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1388-1918, Vol. 1781, no 8, 383-390 p.Article in journal (Refereed) Published
Abstract [en]

The synthetic inhibitors of sterol biosynthesis, 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one and 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one, are of interest as potential cholesterol lowering drugs. Rapid metabolism of synthetic 15-ketosterols may lead to a decrease, or loss, of their potency to affect lipid metabolism. 3beta-Hydroxy-5alpha-cholest-8(14)-en-15-one is reported to be rapidly side chain oxygenated by rat liver mitochondria. In an attempt to reduce this metabolism, the novel side chain modified 15-ketosterol 3beta-Hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one was synthesized. We have examined the metabolism by recombinant human CYP27A1 of this novel side chain modified 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one and compared the rate of metabolism with that of the previously described 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one. Both sterols were found to be efficiently metabolized by recombinant human CYP27A1. None of the two 15-ketosterols was significantly metabolized by microsomal 7alpha-hydroxylation. Interestingly, CYP27A1-mediated product formation was much lower with the side chain modified 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one than with the previously described 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one. A surprising finding was that this novel side chain modified sterol was metabolized mainly in the C-28 position by CYP27A1. The data on 28-hydroxylation by human CYP27A1 provide new insights on the catalytic properties and substrate specificity of this enzyme. The finding that 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one with a modified side chain is metabolized at a dramatically slower rate than the previously described 15-ketosterol with unmodified side chain may be important for future development of synthetic cholesterol lowering sterols.

Place, publisher, year, edition, pages
2008. Vol. 1781, no 8, 383-390 p.
Keyword [en]
human CYP27A1, 27-hydroxylation, 28-hydroxylation, inhibitors of sterol biosynthesis, cholesterol lowering drug
National Category
Pharmaceutical Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-100754DOI: 10.1016/j.bbalip.2008.05.009ISI: 000259058900004PubMedID: 18603016OAI: oai:DiVA.org:uu-100754DiVA: diva2:210977
Available from: 2009-04-07 Created: 2009-04-07 Last updated: 2011-03-03Bibliographically 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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