PXR variants: the impact on drug metabolism and therapeutic responses.
PXR variants: the impact on drug metabolism and therapeutic responses.
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DOI：
10.1016/j.apsb.2016.07.002
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发表时间：
2016-09
影响因子：
14.5
通讯作者：
Chen, Taosheng
中科院分区：
文献类型：
--
作者：
Brewer, C. Trent;Chen, Taosheng
妊娠X受体（PXR）在介导药物代谢酶和转运体的异体诱导中发挥着重要而多样的作用。PXR存在多种蛋白异构体，它们对靶基因具有不同的转录活性；转录变体3 （PXR3）和4 （PXR4）不诱导靶基因表达，而转录变体1 （PXR1）和2 （PXR2）通过激活靶基因表达来响应激动剂。PXR蛋白变体在蛋白相互作用方面也表现出差异；PXR1与p53相互作用，而PXR3则不会。此外，编码这些蛋白异构体的PXR转录本变体受变体各自启动子的甲基化和缺失的差异调节，并且它们在各种人类癌症以及癌组织中的表达与邻近正常组织相比有所不同。PXR1和PXR4 mRNA在癌组织中被甲基化下调，当异位过表达时对细胞增殖有不同的影响。为了预测PXR转录本变异表达对癌变、治疗反应和毒性发展的影响，还需要更多详细和比较的机制研究。PXR诱导药物代谢酶和转运体，并具有多种转录变体，如PXR1， PXR2， PXR3和PXR4，它们对激动剂有反应，与其他蛋白质相互作用，并以不同的方式影响细胞功能。需要进一步的研究来预测PXR变异对癌变、治疗反应和毒性的影响。
The pregnane X receptor (PXR) plays an important and diverse role in mediating xenobiotic induction of drug-metabolizing enzymes and transporters. Several protein isoforms of PXR exist, and they have differential transcriptional activity upon target genes; transcript variants 3 (PXR3) and 4 (PXR4) do not induce target gene expression, whereas transcript variants 1 (PXR1) and 2 (PXR2) respond to agonist by activating target gene expression. PXR protein variants also display differences in protein–protein interactions; PXR1 interacts with p53, whereas PXR3 does not. Furthermore, the transcript variants of PXR that encode these protein isoforms are differentially regulated by methylation and deletions in the respective promoters of the variants, and their expression differs in various human cancers and also in cancerous tissue compared to adjacent normal tissues. PXR1 and PXR4 mRNA are downregulated by methylation in cancerous tissue and have divergent effects on cellular proliferation when ectopically overexpressed. Additional detailed and comparative mechanistic studies are required to predict the effect of PXR transcript variant expression on carcinogenesis, therapeutic response, and the development of toxicity. PXR induces drug-metabolizing enzymes and transporters, and has multiple transcript variants, such as PXR1, PXR2, PXR3, and PXR4, which respond to agonists, interact with other proteins, and affect cellular function differently. Further studies are required to predict the effect of PXR variants on carcinogenesis, therapeutic response, and toxicity.
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