Phenobarbital Suppresses Vitamin D3 25-hydroxylase Expression: a Potential New Mechanism for Drug-induced Osteomalacia.
From: Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Box 578, S-751 23 Uppsala, Sweden.
Biochemical and biophysical research communications
- Publish Date: Jun 2007
- ISSN: 0006-291X
- Volume: 357
- Issue: 3
- Pages: 603-7
- Medium: Print
- Language: English
- Citation (JAMA): Hosseinpour Fardin, Ellfolk Maria, Norlin Maria, et al. Phenobarbital Suppresses Vitamin D3 25-hydroxylase Expression: a Potential New Mechanism for Drug-induced Osteomalacia.. Biochem. Biophys. Res. Commun. Jun 2007;357:603-7
Abstract
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 D(3) due to decreased 25-hydroxylation of vitamin D(3) 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 D(3) 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.
Mesh Headings (Keywords): Animals, Anticonvulsants, Cell Line, Tumor, Cells, Cultured, Cytochrome P-450 CYP27A1, Gene Expression Regulation, Enzymologic, Hepatocytes, Humans, Hydroxylation, Luciferases, Microsomes, Liver, Mitochondria, Osteomalacia, Phenobarbital, Promoter Regions (Genetics), RNA, Messenger, Receptors, Cytoplasmic and Nuclear, Recombinant Fusion Proteins, Retinoid X Receptors, Swine, Transcription Factors, Transfection, Vitamin D
Check for Full Text / PubMed Unique Identifier (PMID): 17445763
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