Nuclear xenobiotic receptor pregnane X receptor locks corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) onto the CYP24A1 promoter to attenuate vitamin D3 activation.
We have studied the molecular mechanism by which the nuclear xenobiotic receptors pregnane X receptor (PXR) and constitutive active/androstane receptor (CAR) regulate transcription of the vitamin D(3) 24-hydroxylase (CYP24A1) gene. In the absence of vitamin D(3), PXR activates the CYP24A1 gene by directly binding to and transactivating vitamin D-response elements (VDREs) within its promoter. Vitamin D(3) activates the CYP24A1 promoter by dissociating the corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) from the vitamin D receptor (VDR) on those VDREs. PXR strongly represses vitamin D(3) activation of the CYP24A1 gene, in which PXR indirectly binds to and prevents vitamin D(3)-dependent dissociation of SMRT from the CYP24A1 promoter. The degree of the PXR-mediated locking of SMRT depends on the relative concentration of vitamin D(3) to the human PXR activator rifampicin; SMRT increased its dissociation as this ratio increased. CAR is also found to prevent dissociation of SMRT from the CYP24A1 promoter. Thus, our present study defines the novel molecular mechanism by which PXR and CAR mediate drug interactions with vitamin D(3) to regulate the CYP24A1 gene. Pxr(+/+) and Pxr(-/-) mice were continuously treated with mouse PXR activator PCN to evaluate the hypothesis that induction of the Cyp24a1 gene is responsible for the loss of bone mineral density often observed in patients treated continuously with PXR-activating drugs. PCN-dependent loss of mineral density is observed in the metaphyseal bones of only the Pxr(+/+) mice. This loss, however, does not correlate with the expression levels of the Cyp24a1 gene in these mice.
Konno
Yoshihiro
Y
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Kodama
Susumu
S
Moore
Rick
R
Kamiya
Nobuhiro
N
Negishi
Masahiko
M
D000818:Animals; D002762:Cholecalciferol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D056985:Nuclear Receptor Co-Repressor 2; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000502:physiology; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000235:genetics*; D014407:Tumor Cells, Cultured; D065668:Vitamin D3 24-Hydroxylase; D015262:Xenobiotics / Q000494:pharmacology
D004268:DNA-Binding Proteins; C539130:NCOR2 protein, human; C539131:Ncor2 protein, mouse; D056985:Nuclear Receptor Co-Repressor 2; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D015262:Xenobiotics; D002762:Cholecalciferol; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase