The role of the dioxin-responsive element cluster between the Cyp1a1 and Cyp1a2 loci in aryl hydrocarbon receptor biology
The role of the dioxin-responsive element cluster between the Cyp1a1 and Cyp1a2 loci in aryl hydrocarbon receptor biology
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DOI：
10.1073/pnas.0809613106
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发表时间：
2009-03-24
影响因子：
11.1
通讯作者：
Bradfield, Christopher A.
中科院分区：
文献类型：
--
作者：
Nukaya, Manabu;Moran, Susan;Bradfield, Christopher A.
芳烃受体（AHR）在2，3，7，8-四氯二苯并-p-二恶英（二恶英）肝毒性、外源性物质代谢调节和肝血管发育中起着重要作用。这些过程中的每一个似乎都依赖于AHR与基因组内的二恶英反应元件（DREs）的结合。Cyp1a1和Cyp1a2基因座代表被认为在AHR生物学中发挥重要作用的连锁基因。在小鼠中，8个DRE位于Cyp1a1和Cyp1a2基因之间的14-kb基因间区域。这些DRE中的7个，统称为DRE簇（DREC），位于Cyp1a1转录起始位点上游1.4 kb和Cyp1a2起始位点上游12.6 kb。为了研究DREC在AHR生物学各个方面的作用，我们通过同源重组产生了DREC缺陷小鼠模型。使用这个小鼠模型，我们证明了DREC控制Cyp1a1和Cyp1a2基因在体内的适应性上调。使用选定的方面作为终点的急性肝损伤，我们还表明，DREC裸小鼠更敏感的二恶英诱导的肝毒性比WT小鼠。使用Cyp1a1和Cyp1a2基因敲除小鼠进行的平行毒理学研究结果支持以下观察结果：这些P450的上调不是二恶英肝毒性许多方面的原因。最后，我们观察到DREC敲除小鼠静脉导管（DV）的正常闭合。鉴于100%的专利DV在Ahr基因敲除小鼠，这些结果表明，Cyp1a1和Cyp1a2在AHR介导的血管发育中不起主导作用。
The aryl hydrocarbon receptor (AHR) plays a central role in 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) hepatotoxicity, regulation of xenobiotic metabolism, and hepatovascular development. Each of these processes appears to be dependent on binding of the AHR to dioxin-responsive elements (DREs) within the genome. The Cyp1a1 and Cyp1a2 loci represent linked genes thought to play important roles in AHR biology. In the mouse, 8 DREs are located in the 14-kb intergenic region between the Cyp1a1 and Cyp1a2 genes. Seven of these DREs, collectively known as the DRE cluster (DREC), are located 1.4 kb upstream of the Cyp1a1 transcriptional start site and 12.6 kb upstream of the Cyp1a2 start site. To investigate the role of the DREC in each aspect of AHR biology, we generated a DREC-deficient mouse model through homologous recombination. Using this mouse model, we demonstrate that the DREC controls the adaptive up-regulation of both Cyp1a1 and Cyp1a2 genes in vivo. Using selected aspects of acute hepatic injury as endpoints, we also demonstrate that DREC null mice are more sensitive to dioxin-induced hepatotoxicity than WT mice. The results of parallel toxicologic studies using individual Cyp1a1 and Cyp1a2 null mice support the observation that up-regulation of these P450s is not the cause of many aspects of dioxin hepatotoxicity. Finally, we observed normal closure of the ductus venosus (DV) in DREC null mice. Given the 100% penetrance of patent DV in Ahr null mice, these results indicate that Cyp1a1 and Cyp1a2 do not play a dominant role in AHR-mediated vascular development.