Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia.
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.
Zhou
Changcheng
C
Department of Pharmaceutics, University of Washington, Seattle, Washington 98195-7610, USA.
Assem
Mahfoud
M
Tay
Jessica C
JC
Watkins
Paul B
PB
Blumberg
Bruce
B
Schuetz
Erin G
EG
Thummel
Kenneth E
KE
D000818:Animals; D050071:Bone Density Conservation Agents; D002117:Calcitriol / Q000378:metabolism; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010018:Osteomalacia / Q000139:chemically induced* / Q000378:metabolism; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction / Q000502:physiology*; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D065668:Vitamin D3 24-Hydroxylase
D050071:Bone Density Conservation Agents; D008024:Ligands; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol