Logo: to the web site of Uppsala University

uu.sePublications from Uppsala University
Change search
Link to record
Permanent link

Direct link
Ellfolk, Maria
Publications (2 of 2) Show all publications
Norlin, M., Lundqvist, J., Ellfolk, M., Hellström Pigg, M., Gustafsson, J. & Wikvall, K. (2017). Drug-mediated gene regulation of vitamin D3 metabolism in primary human dermal fibroblasts. Basic & Clinical Pharmacology & Toxicology, 120(1), 59-63
Open this publication in new window or tab >>Drug-mediated gene regulation of vitamin D3 metabolism in primary human dermal fibroblasts
Show others...
2017 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 120, no 1, p. 59-63Article in journal (Refereed) Published
Abstract [en]

Vitamin D metabolism was studied in primary human dermal fibroblasts with focus on drug-mediated gene regulation related to adverse side effects of antiretroviral drugs used in HIV therapy. The fibroblasts expressed mRNA for cytochrome P450 (CYP) enzymes catalysing bioactivating (CYP2R1, CYP27A1 and CYP27B1) and catabolic reactions (CYP24A1). The cells produced both 25-hydroxyvitamin D3 and 1a,25-dihydroxyvitamin D3. The results demonstrate that primary dermal fibroblasts have an active vitamin D3 metabolising system. High incidence of low bone mineral density is a concern for HIV-infected patients treated with antiretroviral drugs. Osteomalacia and severe vitamin D deficiency have been reported. We investigated whether drug-mediated gene regulation could be a possible mechanism behind these adverse drug effects. Fibroblasts were treated with different drugs used in HIV therapy and the 1a,25-dihydroxyvitamin D3 levels and relative mRNA-levels for crucial enzymes were determined. Efavirenz, stavudine and ritonavir significantly downregulated the bioactivating CYP2R1 and upregulated the catabolic CYP24A1. The drugs reduced bioactivating enzyme activities and cellular levels of 1a,25-dihydroxyvitamin D3. The current results indicate that effects on gene expression may lead to disturbed vitamin D-metabolism and decreased cellular levels of active vitamin D3. The data are consistent with the impaired bone health in patients treated with certain antiretroviral drugs.

National Category
Basic Medicine
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-319044 (URN)10.1111/bcpt.12641 (DOI)000394527200009 ()27404500 (PubMedID)
Available from: 2017-03-30 Created: 2017-03-30 Last updated: 2018-01-13Bibliographically approved
Hosseinpour, F., Ellfolk, M., Norlin, M. & Wikvall, K. (2007). Phenobarbital suppresses vitamin D3 25-hydroxylase expression: A potential new mechanism for drug-induced osteomalacia. Biochemical and Biophysical Research Communications - BBRC, 357(3), 603-607
Open this publication in new window or tab >>Phenobarbital suppresses vitamin D3 25-hydroxylase expression: A potential new mechanism for drug-induced osteomalacia
2007 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 357, no 3, p. 603-607Article in journal (Refereed) Published
Abstract [en]

Prolonged therapy with phenobarbital may cause vitamin D deficiency or osteomalacia. In the current study, we propose a novel mechanism for drug-induced osteomalacia involving impaired bioactivation of vitamin D3 due to decreased 25-hydroxylation of vitamin D3 in liver. The present data, using the pig as model, demonstrate direct effects by phenobarbital on the expression of CYP27A1 and CYP2D25, two important 25-hydroxylases. Treatment by phenobarbital markedly reduced the rate of 25-hydroxylation by primary hepatocytes and suppressed the cellular CYP27A1 mRNA levels. The rate of 25-hydroxylation by two different purified 25-hydroxylases, microsomal CYP2D25, and mitochondrial CYP27A1, respectively, was dose-dependently inhibited by phenobarbital. Reporter assay experiments in liver-derived HepG2 cells revealed a marked PXR-mediated transcriptional downregulation of the CYP2D25 promoter. In addition, the data indicate that phenobarbital might affect the mRNA stability of CYP2D25. Taken together, the data suggest that vitamin D3 25-hydroxylation may be suppressed by phenobarbital. A downregulation of 25-hydroxylation by phenobarbital may explain, at least in part, the increased risk of osteomalacia, bone loss, and fractures in long-term phenobarbital therapy.

Keywords
Bioactivation of vitamin D3, 25-Hydroxylation, Hepatocytes, Expression, Transcriptional regulation, Osteomalacia
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-97880 (URN)10.1016/j.bbrc.2007.03.177 (DOI)000246382700006 ()17445763 (PubMedID)
Available from: 2008-11-28 Created: 2008-11-28 Last updated: 2018-01-13Bibliographically approved
Organisations

Search in DiVA

Show all publications