Response to Zhou et al.
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《神经病学神经外科学杂志》
INSERM U632, Université Montpellier, Montpellier, France.
Address correspondence to: Jean-Marc Pascussi, INSERM U632, 1919 route de Mende, Montpellier 34293, France. Phone: 33-4-67-61-33-69; Fax: 33-4-67-52-36-81; E-mail: pascussi@montp.inserm.fr.
Osteomalacia is a frequent complication resulting from long-term therapy with drugs such as phenytoin, carbamazepine, and phenobarbital. We have investigated the crosstalk between pregnane X receptor (PXR) and vitamin D receptor (VDR) and have reported that (a) PXR binds to and transactivates vitamin D–responsive elements in the 25-hydroxyvitamin D3-24-hydroxylase (CYP24) promoter, and (b) PXR agonists increase CYP24 mRNA expression in human hepatocytes and mouse kidney (1). Since the CYP24 enzyme converts 1,25-dihydroxyvitamin D3 to inactive metabolites, these observations provide an objective explanation for the induction of osteomalacia by PXR agonists. In their report on this crosstalk in the June issue of the JCI, Zhou et al. (2) concluded instead that CYP24 is not induced but rather downregulated by PXR agonists. These authors observed neither binding to nor transactivation of the CYP24 promoter by PXR, nor did they find induction of CYP24 mRNA in human hepatocytes. As soon as we became aware of this work, we repeated key experiments using extracts from new hepatocyte cultures and new inducers (SR128123 and CITCO). Moreover, we evaluated the constitutive androstane receptor–VDR (CAR-VDR) crosstalk. Our new results fully confirm our previous findings. In human hepatocyte cultures, the CYP24 mRNA level was increased by rifampicin and 2 other PXR agonists, phenobarbital and SR128123. EMSA not only confirmed the binding of PXR to vitamin D–responsive elements–I and –II of CYP24 but also revealed that CAR binds these responsive elements. This last point is consistent with the finding that CITCO, a specific agonist of CAR, was a weak inducer of CYP24 in hepatocytes and that androstanol, an inverse agonist of CAR, inhibited CAR-mediated transactivation of the CYP24 promoter. We believe that these discrepancies between our work and that published by Zhou et al. (2) could be due to methodological differences in hepatocyte cultures (culture medium), transfection assays (cell lines), and EMSA. More work is currently being done to identify the origin of these discrepancies.
References
Pascussi J.M., et al. 2005. Possible involvement of pregnane X receptor–enhanced CYP24 expression in drug-induced osteomalacia. J. Clin. Invest. 115:177–186 doi: 10.1172/JCI200521867.
Zhou C., et al. 2006. Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J. Clin. Invest. 116:1703–1712 doi: 10.1172/JCI27793.(Jean-Marc Pascussi, Patri)
信息仅供参考，不构成任何之建议、推荐或指引。文章版权属于原著作权人，若您认为此文不宜被收录供大家免费阅读，请邮件或电话通知我们，我们收到通知后，会立即将您的作品从本网站删除。Address correspondence to: Jean-Marc Pascussi, INSERM U632, 1919 route de Mende, Montpellier 34293, France. Phone: 33-4-67-61-33-69; Fax: 33-4-67-52-36-81; E-mail: pascussi@montp.inserm.fr.
Osteomalacia is a frequent complication resulting from long-term therapy with drugs such as phenytoin, carbamazepine, and phenobarbital. We have investigated the crosstalk between pregnane X receptor (PXR) and vitamin D receptor (VDR) and have reported that (a) PXR binds to and transactivates vitamin D–responsive elements in the 25-hydroxyvitamin D3-24-hydroxylase (CYP24) promoter, and (b) PXR agonists increase CYP24 mRNA expression in human hepatocytes and mouse kidney (1). Since the CYP24 enzyme converts 1,25-dihydroxyvitamin D3 to inactive metabolites, these observations provide an objective explanation for the induction of osteomalacia by PXR agonists. In their report on this crosstalk in the June issue of the JCI, Zhou et al. (2) concluded instead that CYP24 is not induced but rather downregulated by PXR agonists. These authors observed neither binding to nor transactivation of the CYP24 promoter by PXR, nor did they find induction of CYP24 mRNA in human hepatocytes. As soon as we became aware of this work, we repeated key experiments using extracts from new hepatocyte cultures and new inducers (SR128123 and CITCO). Moreover, we evaluated the constitutive androstane receptor–VDR (CAR-VDR) crosstalk. Our new results fully confirm our previous findings. In human hepatocyte cultures, the CYP24 mRNA level was increased by rifampicin and 2 other PXR agonists, phenobarbital and SR128123. EMSA not only confirmed the binding of PXR to vitamin D–responsive elements–I and –II of CYP24 but also revealed that CAR binds these responsive elements. This last point is consistent with the finding that CITCO, a specific agonist of CAR, was a weak inducer of CYP24 in hepatocytes and that androstanol, an inverse agonist of CAR, inhibited CAR-mediated transactivation of the CYP24 promoter. We believe that these discrepancies between our work and that published by Zhou et al. (2) could be due to methodological differences in hepatocyte cultures (culture medium), transfection assays (cell lines), and EMSA. More work is currently being done to identify the origin of these discrepancies.
References
Pascussi J.M., et al. 2005. Possible involvement of pregnane X receptor–enhanced CYP24 expression in drug-induced osteomalacia. J. Clin. Invest. 115:177–186 doi: 10.1172/JCI200521867.
Zhou C., et al. 2006. Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J. Clin. Invest. 116:1703–1712 doi: 10.1172/JCI27793.(Jean-Marc Pascussi, Patri)
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