NCOA6 可差异调控 CYP2C9 和 CYP3A4 基因的表达。
NCOA6 differentially regulates the expression of the CYP2C9 and CYP3A4 genes.
机构信息
Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709, United States.
出版信息
Pharmacol Res. 2011 May;63(5):405-13. doi: 10.1016/j.phrs.2011.01.013. Epub 2011 Feb 1.
CYP2Cs and CYP3A4 sub families of enzymes of the Cytochrome P450 super family metabolize clinically prescribed therapeutics. Constitutive and induced expressions of these enzymes are under the control of HNF4α and rifampicin activated PXR. In the present study, we show a mechanism for ligand dependent synergistic cross talk between PXR and HNF4α. Two-hybrid screening identified NCOA6 as a HNF4α interacting protein. NCOA6 was also found to interact with PXR through the first LXXLL motif in GST pull down and mammalian two hybrid assays. NCOA6 enhances the synergistic activation of CYP2C9 and CYP3A4 promoter activity by PXR and HNF4α in the presence of rifampicin. However silencing NCOA6 abrogated the synergistic activation and induction of CYP2C9 by PXR-HNF4α but not of CYP3A4. ChIP analysis revealed that NCOA6 could bridge HNF4α and PXR binding sites of the CYP2C9 promoter. Our results indicate that NCOA6 is responsible for the synergistic activation of CYP2C9 by HNF4α and PXR and NCOA6 differentially regulates CYP2C9 and CYP3A4 gene expression though both the genes are regulated by the same nuclear receptors.
细胞色素 P450 超级家族的 CYP2C 和 CYP3A4 亚家族酶代谢临床规定的治疗药物。这些酶的组成型和诱导表达受 HNF4α 和利福平激活的 PXR 控制。在本研究中，我们展示了 PXR 和 HNF4α 之间配体依赖性协同交叉对话的机制。双杂交筛选鉴定 NCOA6 为 HNF4α 相互作用蛋白。通过 GST 下拉和哺乳动物双杂交测定，还发现 NCOA6 通过第一个 LXXLL 基序与 PXR 相互作用。在利福平存在的情况下，NCOA6 增强了 PXR 和 HNF4α 对 CYP2C9 和 CYP3A4 启动子活性的协同激活。然而，沉默 NCOA6 消除了 PXR-HNF4α 的协同激活和 CYP2C9 的诱导，但不消除 CYP3A4。ChIP 分析显示，NCOA6 可以桥接 CYP2C9 启动子的 HNF4α 和 PXR 结合位点。我们的结果表明，NCOA6 负责 HNF4α 和 PXR 对 CYP2C9 的协同激活，并且 NCOA6 通过相同的核受体调节 CYP2C9 和 CYP3A4 基因表达，但通过不同的机制调节这两个基因。
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