Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J Clin Invest 2006 Jun;116(6):1703-12
Date
05/13/2006Pubmed ID
16691293Pubmed Central ID
PMC1459072DOI
10.1172/JCI27793Scopus ID
2-s2.0-33745217611 (requires institutional sign-in at Scopus site) 219 CitationsAbstract
The balance between bioactivation and degradation of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is critical for ensuring appropriate biological effects of vitamin D. Cytochrome P450, family 24-mediated (CYP24-mediated) 24-hydroxylation of 1,25(OH)2D3 is an important step in the catabolism of 1,25(OH)2D3. The enzyme is directly regulated by vitamin D receptor (VDR), and it is expressed mainly in the kidney, where VDR is also abundant. A recent report suggests that activation of steroid and xenobiotic receptor (SXR) also enhances the expression of CYP24, providing a new molecular mechanism of drug-induced osteomalacia. However, here we showed that activation of SXR did not induce CYP24 expression in vitro and in vivo, nor did it transactivate the CYP24 promoter. Instead, SXR inhibited VDR-mediated CYP24 promoter activity, and CYP24 expression was very low in tissues containing high levels of SXR, including the small intestine. Moreover, 1,25(OH)2D3-induced CYP24 expression was enhanced in mice lacking the SXR ortholog pregnane X receptor, and treatment of humans with the SXR agonist rifampicin had no effect on intestinal CYP24 expression, despite demonstration of marked CYP3A4 induction. Combined with our previous findings that CYP3A4, not CYP24, plays the dominant role in hydroxylation of 1,25(OH)2D3 in human liver and intestine, our results indicate that SXR has a dual role in mediating vitamin D catabolism and drug-induced osteomalacia.
Author List
Zhou C, Assem M, Tay JC, Watkins PB, Blumberg B, Schuetz EG, Thummel KEAuthor
Mahfoud Assem PharmD Associate Professor in the School of Pharmacy Administration department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBone Density Conservation Agents
Calcitriol
Cell Line
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System
Gene Expression Regulation
Genes, Reporter
Humans
Ligands
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Osteomalacia
Promoter Regions, Genetic
Receptors, Calcitriol
Receptors, Steroid
Response Elements
Signal Transduction
Steroid Hydroxylases
Tissue Distribution
Vitamin D3 24-Hydroxylase
