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, 603-607 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2007. Vol. 357, no 3, 603-607 p.
Bioactivation of vitamin D3, 25-Hydroxylation, Hepatocytes, Expression, Transcriptional regulation, Osteomalacia
IdentifiersURN: urn:nbn:se:uu:diva-97880DOI: 10.1016/j.bbrc.2007.03.177ISI: 000246382700006PubMedID: 17445763OAI: oai:DiVA.org:uu-97880DiVA: diva2:172975