The biologically active forms of vitamin D are broken down to biologically inactive products by the enzyme CYP24, which itself is regulated by the vitamin D receptor (VDR). A 2005 study by another research group that also appeared in the JCI reported that activation of SXR induced CYP24 expression in mice, which would explain an increase in vitamin D breakdown and the resulting osteomalacia observed in individuals taking some SXR-activating antiepileptic drugs or antibiotics. In contrast, the current study by Thummel et al. found that SXR does not induce CYP24 expression in mice to any appreciable extent. Instead, SXR inhibited VDR-mediated CYP24 activity. They also found that treatment of humans with the SXR-activating antibiotic rifampicin had no effect on CYP24 expression, but did increase expression of another enzyme that breaks down vitamin D – CYP3A4. The authors conclude that while SXR negatively regulates CYP24 expression and subsequent vitamin D breakdown, it can also enhance vitamin D hydroxylation and breakdown by inducing the expression of CYP3A4. This explains how SXR activators can cause osteomalacia. The study establishes SXR as a potential therapeutic target for clinical treatment or prevention of osteomalacia.
TITLE: Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia
AUTHOR CONTACT: Kenneth E. Thummel
University of Washington, Seattle, Washington, USA.
Phone: (206) 543-0819; Fax: (206) 543-3204; E-mail: thummel@u-washington.edu .
View the PDF of this article at: https://www.the-jci.org/article.php?id=27793
Journal of Clinical Investigation