The far and distal enhancers in the CYP3A4 gene co-ordinate the proximal promoter in responding similarly to the pregnane X receptor but differentially to hepatocyte nuclear factor-4α
The far and distal enhancers in the CYP3A4 gene co-ordinate the proximal promoter in responding similarly to the pregnane X receptor but differentially to hepatocyte nuclear factor-4α
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DOI：
10.1042/bj20070613
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发表时间：
2008-01-01
影响因子：
4.1
通讯作者：
Yan, Bingfang
中科院分区：
文献类型：
--
作者：
Liu, Fu-Jun;Song, Xiulong;Yan, Bingfang
CYP3A4（细胞色素P450 3A4）参与超过50%的药物和其他外源性物质的代谢。 CYP3A4 的表达是由许多结构不同的化合物诱导的。 PXR（孕烷X受体）被认为是诱导的关键调节因子，PXR介导的CYP3A4基因反式激活是通过远端模块与近端启动子的协调机制实现的。最近，发现一个far模块支持CYP3A4的组成型表达。远模块与远端模块一样，在结构上由 PXR 响应元件 (F-ER6) 和 HNF-4 α（肝细胞核受体 4 α）识别的元件聚集而成。我们假设 far 模块支持 CYP3A4 基因的 PXR 反式激活。与假设一致，远模块与 CYP3A4 近端启动子的融合显着增加了利福平诱导的报告基因活性。当远端和远端模块都融合到近端启动子时，这种增加会协同增强。然而，当 F-ER6 被破坏时，这种增加显着减少。染色质免疫沉淀检测到远模块中存在 PXR。有趣的是，HNF-4α增加了远端-近端融合启动子的活性，但降低了远端-近端融合启动子的活性。鉴于 CYP3A4 的诱导代表了一种重要的解毒机制，支持 PXR 反式激活的功能冗余和协同相互作用表明远侧和远端模块确保了化学损伤期间 CYP3A4 的诱导。对 HNF-4 α 反应的差异表明诱导的强度是通过各种转录网络控制的。
CYP3A4 (cytochrome P450 3A4) is involved in the metabolism of more than 50 % of drugs and other xenobiotics. The expression of CYP3A4 is induced by many structurally dissimilar compounds. The PXR (pregnane X receptor) is recognized as a key regulator for the induction, and the PXR-directed transactivation of the CYP3A4 gene is achieved through a coordinated mechanism of the distal module with the proximal promoter. Recently, a far module was found to support constitutive expression of CYP3A4. The far module, like the distal module, is structurally clustered by a PXR response element (F-ER6) and elements recognized by HNF-4 alpha (hepatocyte nuclear receptor-4 alpha). We hypothesized that the far module supports PXR transactivation of the CYP3A4 gene. Consistent with the hypothesis, fusion of the far module to the proximal promoter of CYP3A4 markedly increased rifampicin-induced reporter activity. The increase was synergistically enhanced when both the far and distal modules were fused to the proximal promoter. The increase, however, was significantly reduced when the F-ER6 was disrupted. Chromatin immunoprecipitation detected the presence of PXR in the far module. Interestingly, HNF-4 alpha increased the activity of the distal-proximal fused promoter, but decreased the activity of the far-proximal fused promoter. Given the fact that induction of CYP3A4 represents an important detoxification mechanism, the functional redundancy and synergistic interaction in supporting PXR transactivation suggest that the far and distal modules ensure the induction of CYP3A4 during chemical insults. The difference in responding to HNF-4 alpha suggests that the magnitude of the induction is under control through various transcriptional networks.