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Regulation of human CYP27A1 by estrogens and androgens in HepG2 and prostate cells
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.
2007 (English)In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 462, no 1, 13-20 p.Article in journal (Refereed) Published
Abstract [en]

The regulation of the human CYP27A1 gene by estrogens and androgens was studied in human liver-derived HepG2 and prostate cells. Our results show that the promoter activity, enzymatic activity and mRNA levels of CYP27A1 in HepG2 cells are downregulated by estrogen in presence of ERα or ERβ. Similar effects by estrogen were found in RWPE-1 prostate cells. In contrast, estrogen markedly upregulated the transcriptional activity of CYP27A1 in LNCaP prostate cancer cells. 5α-Dihydrotestosterone and androgen receptor upregulated the transcriptional activity of CYP27A1 in HepG2 cells. Progressive deletion experiments indicate that the ERβ-mediated effects in HepG2 and LNCaP cells are conferred to the same region (−451/+42) whereas ERα-mediated effects on this promoter are more complex. The results indicate that the stimulating effect of androgen in HepG2 cells is conferred to a region upstream from –792 in the CYP27A1 promoter. In summary, we have identified the human CYP27A1 gene as a target for estrogens and androgens. The results imply that expression of CYP27A1 may be affected by endogenous sex hormones and pharmacological compounds with estrogenic or androgenic effects.

Place, publisher, year, edition, pages
2007. Vol. 462, no 1, 13-20 p.
Keyword [en]
Transcriptional regulation, Sterol 27-hydroxylase, Vitamin D3 25-hydroxylase, Cholesterol homeostasis, Activation of vitamin D3
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95812DOI: 10.1016/j.abb.2007.04.001ISI: 000246900900002PubMedID: 17482558OAI: oai:DiVA.org:uu-95812DiVA: diva2:170157
Available from: 2007-04-27 Created: 2007-04-27 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Hormonal Regulation of the Human CYP27A1 and CYP7B1 Genes
Open this publication in new window or tab >>Hormonal Regulation of the Human CYP27A1 and CYP7B1 Genes
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

CYP27A1 and CYP7B1 are widely expressed in various human tissues and are two key enzymes involved in the pathways for conversion of cholesterol to bile acids. Also, CYP27A1 is involved in bioactivation of vitamin D3 and CYP7B1 plays a role in 7alpha-hydroxylation of dehydroepiandrosterone and other steroids. Both enzymes have been reported to be relevant to prostate cell proliferation. The current study examines the hormonal regulation of CYP27A1 and CYP7B1.

CYP7B1 was shown to be regulated by estrogens and androgens in human embryonic kidney HEK293 and prostate cancer LNCaP cells. Quantitation of CYP7B1 mRNA in adult and fetal human tissues showed markedly higher CYP7B1 mRNA levels in fetal tissues compared with the corresponding adult ones, except in the liver. This indicates a tissue-specific, developmental regulation of CYP7B1 and suggests an important function for this enzyme in fetal life. CYP7B1 regulation by estrogens may be of importance in fetal development and in other processes where CYP7B1 is involved, including cholesterol homeostasis, cellular proliferation, and CNS function. The regulation of CYP7B1 by sex hormones also suggests an important role for CYP7B1 in balancing prostate hormone levels in human cells.

Results show that CYP27A1 can be regulated by dexamethasone, growth hormone, IGF-1, PMA, estrogens and androgens in liver-derived HepG2 cells. Dexamethasone, growth hormone and IGF-1 stimulated the promoter and endogenous activity of CYP27A1, whereas thyroid hormones and PMA inhibited CYP27A1. The regulatory effects of estrogens and androgens are different depending on the cell types. Thus, the results imply that human CYP27A1 gene is a target for estrogens and androgens, and the expression of CYP27A1 may be affected by endogenous sex hormones and pharmacological compounds with estrogenic or androgenic effects.

The mechanism for the dexamethasone-induced effect on the human CYP27A1 promoter was examined. A GRE was identified important for GR-mediated regulation of CYP27A1 transcriptional activity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 56
Keyword
Pharmaceutical biochemistry, CYP27A1, CYP7B1, cholesterol, estrogen, androgen, prostate, glucocorticoid receptor, fetal development, Farmaceutisk biokemi
Identifiers
urn:nbn:se:uu:diva-7837 (URN)978-91-554-6876-7 (ISBN)
Public defence
2007-05-22, C2:301, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2007-04-27 Created: 2007-04-27Bibliographically approved

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Norlin, MariaWikvall, Kjell

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