Down M J, Arkle S, Mills J J
Department of Pharmacology, School of Pharmacy and Biomedical Sciences, St Michaels Building, University of Portsmouth, White Swan Road, Portsmouth, UK.
Arch Biochem Biophys. 2007 Jan 1;457(1):105-10. doi: 10.1016/j.abb.2006.09.017. Epub 2006 Oct 6.
This study reports that dexamethasone (DEX) significantly induces CYP3A11, CYP3A13 and CYP3A25 mRNA expression in male and female 4 days, 3 weeks and 18 weeks old C57BL/6J mice. Furthermore, CYP3A activity, as measured by erythromycin-N-demethylation, is also significantly increased. PXR, RXRalpha and CAR are known to be involved in the induction of CYP3As. Here we report nuclear receptors PXR and RXRalpha but not CAR demonstrate gender- and age-dependent expression. Also, treatment of C57BL/6J mice with DEX induces PXR but not RXRalpha or CAR. In summary, we demonstrate DEX is not only able to up-regulate CYP3A expression and activity, but also the nuclear receptor PXR through which it may exert this effect. Furthermore, the gender- and age-dependent pattern of basal PXR and RXRalpha expression is similar to the 3 CYP3As analysed.
本研究报告称，地塞米松（DEX）可显著诱导4日龄、3周龄和18周龄雄性及雌性C57BL/6J小鼠体内CYP3A11、CYP3A13和CYP3A25 mRNA的表达。此外，通过红霉素-N-脱甲基化测定的CYP3A活性也显著增加。已知孕烷X受体（PXR）、视黄酸X受体α（RXRα）和组成型雄烷受体（CAR）参与CYP3A的诱导过程。在此我们报告，核受体PXR和RXRα而非CAR呈现出性别和年龄依赖性表达。此外，用DEX处理C57BL/6J小鼠可诱导PXR表达，但不诱导RXRα或CAR表达。总之，我们证明DEX不仅能够上调CYP3A的表达和活性，还能上调核受体PXR，其可能通过PXR发挥这一作用。此外，基础PXR和RXRα表达的性别和年龄依赖性模式与所分析的3种CYP3A相似。
