The DOI matches its OpenAlex record; 51 of the 51 references it cites were found in a registry or an index.
Possible involvement of pregnane X receptor–enhanced CYP24 expression in drug-induced osteomalacia
Open accessAbstract
Vitamin D controls calcium homeostasis and the development and maintenance of bones through vitamin D receptor activation. Prolonged therapy with rifampicin or phenobarbital has been shown to cause vitamin D deficiency or osteomalacia, particularly in patients with marginal vitamin D stores. However, the molecular mechanism of this process is unknown. Here we show that these drugs lead to the upregulation of 25-hydroxyvitamin D(3)-24-hydroxylase (CYP24) gene expression through the activation of the nuclear receptor pregnane X receptor (PXR; NR1I2). CYP24 is a mitochondrial enzyme responsible for inactivating vitamin D metabolites. CYP24 mRNA is upregulated in vivo in mice by pregnenolone 16alpha-carbonitrile and dexamethasone, 2 murine PXR agonists, and in vitro in human hepatocytes by rifampicin and hyperforin, 2 human PXR agonists. Moreover, rifampicin increased 24-hydroxylase activity in these cells, while, in vivo in mice, pregnenolone 16alpha-carbonitrile increased the plasma concentration of 24,25-dihydroxyvitamin D(3). Transfection of PXR in human embryonic kidney cells resulted in rifampicin-mediated induction of CYP24 mRNA. Analysis of the human CYP24 promoter showed that PXR transactivates the sequence between -326 and -142. We demonstrated that PXR binds to and transactivates the 2 proximal vitamin D-responsive elements of the human CYP24 promoter. These data suggest that xenobiotics and drugs can modulate CYP24 gene expression and alter vitamin D(3) hormonal activity and calcium homeostasis through the activation of PXR.
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Cites
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Organotypic liver culture models: meeting current challenges in toxicity testing
LeCluyse, E. L., Witek, R. P., Andersen, M. E., & Powers, M. J. (2012) · Critical Reviews in Toxicology · doi:10.3109/10408444.2012.682115 · Cited by 363
Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects
di Masi, A., Marinis, E. D., Ascenzi, P., & Marino, M. (2009) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2009.04.002 · Cited by 288
Zhou, C. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27793 · Cited by 256
Pathophysiology and treatment of osteoporosis: Challenges for clinical practice in older people
Barnsley, J., Buckland, G., Chan, P. E., Ong, A., Ramos, A. S., Baxter, M., Laskou, F., Dennison, E. M., Cooper, C., & Patel, H. P. (2021) · Aging Clinical and Experimental Research · doi:10.1007/s40520-021-01817-y · Cited by 199
Metadata
- Authors
- Pascussi, J., Robert, A., Nguyen, T. M., Walrant-Debray, O., Garabédian, M., Martin, P. G. P., Pineau, T., Saric, J., Navarro, F., Maurel, P., & Vilarem, M.
- Venue
- Journal of Clinical Investigation
- Publisher
- American Society for Clinical Investigation
- Published
- 2005-01-03
- Volume
- 115
- Issue
- 1
- Pages
- 177-186
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2160202028
- Cited by
- 317
- References
- 51
- FWCI
- 13.78
- Type
- journal article
- Language
- en
- Open access
- bronze
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- CoChat. (2026). Citation check: Possible involvement of pregnane X receptor–enhanced CYP24 expression in drug-induced osteomalacia. https://app.cochat.ai/papers/10.1172/jci200521867
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- Pascussi, J., Robert, A., Nguyen, T. M., Walrant-Debray, O., Garabédian, M., Martin, P. G. P., Pineau, T., Saric, J., Navarro, F., Maurel, P., & Vilarem, M. (2005). Possible involvement of pregnane X receptor–enhanced CYP24 expression in drug-induced osteomalacia. Journal of Clinical Investigation. https://doi.org/10.1172/jci200521867
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