Genetic profiling defines the xenobiotic gene network controlled by the nuclear receptor pregnane X receptor
Genetic profiling defines the xenobiotic gene network controlled by the nuclear receptor pregnane X receptor
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DOI：
10.1210/me.2002-0421
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发表时间：
2003-07-01
影响因子：
--
通讯作者：
Evans, RM
中科院分区：
文献类型：
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作者：
Rosenfeld, JM;Vargas, R;Evans, RM
孤儿核受体孕烷 X 受体 (PXR) 对于肝异生酶（包括细胞色素 3A 同工酶）的转录调节至关重要。这些酶对于大多数内源性甾醇代谢物（内生素）和多种外来化合物（异生素）的分解代谢和清除至关重要，这些外来化合物包括药物、农药和通过饮食和环境暴露而遇到的毒素。为了探索 PXR 在哺乳动物异生素反应中更广泛的作用，我们对来自 PXR 敲除小鼠和表达组成型活性变体 VP-hPXR 的小鼠的肝脏样本进行了独特的微阵列基因分析。这种基因引导的表达分析能够靶向和限制 PXR 对肝脏的反应，并且没有药物及其代谢物引起的副作用。与药理学研究一样，受体依赖性基因包括 I 相和 II 相代谢酶，以及作为主要 PXR 靶点的某些药物和阴离子转运蛋白。此外，对遗传和药理学阵列数据的比较分析揭示了代表外源反应的遗传描述的核心网络。
The orphan nuclear receptor pregnane X receptor (PXR) is essential for the transcriptional regulation of hepatic xenobiotic enzymes including the cytochrome 3A isoenzymes. These enzymes are central to the catabolism and clearance of most endogenous sterol metabolites (endobiotics) and a vast diversity of foreign compounds (xenobiotics) including pharmaceuticals, pesticides, and toxins encountered through diet and environmental exposure. To explore a broader role of PXR in the mammalian xenobiotic response, we have conducted a unique microarray gene profiling analysis on liver samples derived from PXR knockout mice and mice expressing a constitutively active variant, VP-hPXR. This genetically guided expression analysis enables targeting and restriction of the PXR response to liver, and is devoid of side effects resulting from drugs and their metabolites. As with pharmacological studies, receptor-dependent genes include both phase I and phase II metabolic enzymes, as well as certain drug and anion transporters as principal PXR targets. Moreover, comparative analysis of data from both genetic and pharmacological arrays reveals a core network that represents a genetic description of the xenobiotic response.