Role of NF-κB in regulation of PXR-mediated gene expression -: A mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents
Role of NF-κB in regulation of PXR-mediated gene expression -: A mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents
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DOI：
10.1074/jbc.m601302200
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发表时间：
2006-06-30
影响因子：
4.8
通讯作者：
Tian, Yanan
中科院分区：
文献类型：
--
作者：
Gu, Xinsheng;Ke, Sui;Tian, Yanan
长期以来，人们观察到炎症反应和感染会降低人类和实验动物的药物代谢能力。细胞色素P-450 3A4 cyp304参与了目前超过50%的处方药的代谢，cyp3a4的表达受妊娠X受体（PXR）的转录调控，PXR是一种配体依赖性转录因子。在本研究中，我们报道了脂多糖和肿瘤坏死因子- α激活NF-kappa B通过NF-kappa B与PXR的相互作用在抑制cyp3a4中起关键作用。类视黄醇X受体复合物。nf - κ B特异性抑制因子SRI κ B α对nf - κ B的抑制逆转了脂多糖和肿瘤坏死因子α的抑制作用。此外，我们发现NF-kappa B p65破坏了PXR的关联。RXR α复合物与DNA序列，由电泳迁移迁移试验和染色质免疫沉淀试验确定。NF-kappa B p65直接与RXR α的DNA结合域相互作用，可能阻止RXR α与共识DNA序列的结合，从而抑制PXR的转激活。RXR复合物。nf - κ B活化的这种抑制机制可能扩展到其他核受体调控的系统，其中RXR α是二聚化伙伴。
It is a long-standing observation that inflammatory responses and infections decrease drug metabolism capacity in human and experimental animals. Cytochrome P-450 3A4 cyp304 is responsible for the metabolism of over 50% of current prescription drugs, and cyp3a4 expression is transcriptionally regulated by pregnane X receptor (PXR), which is a ligand-dependent transcription factor. In this study, we report that NF-kappa B activation by lipopolysaccharide and tumor necrosis factor-alpha plays a pivotal role in the suppression of cyp3a4 through interactions of NF-kappa B with the PXR . retinoid X receptor (RXR) complex. Inhibition of NF-kappa B by NF-kappa B-specific suppressor SRI kappa B alpha reversed the suppressive effects of lipopolysaccharide and tumor necrosis factor-alpha. Furthermore, we showed that NF-kappa B p65 disrupted the association of the PXR . RXR alpha complex with DNA sequences as determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assays. NF-kappa B p65 directly interacted with the DNA-binding domain of RXR alpha and may prevent its binding to the consensus DNA sequences, thus inhibiting the transactivation by the PXR . RXR alpha complex. This mechanism of suppression by NF-kappa B activation may be extended to other nuclear receptor-regulated systems where RXR alpha is a dimerization partner.