Flavonoids activate pregnane x receptor-mediated CYP3A4 gene expression by inhibiting cyclin-dependent kinases in HepG2 liver carcinoma cells.
Flavonoids activate pregnane x receptor-mediated CYP3A4 gene expression by inhibiting cyclin-dependent kinases in HepG2 liver carcinoma cells.
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DOI：
10.1186/1471-2091-11-23
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发表时间：
2010-06-16
期刊：
影响因子：
--
通讯作者：
Chen T
中科院分区：
文献类型：
--
作者：
Dong H;Lin W;Wu J;Chen T
药物代谢酶细胞色素P450 3A4（CYP3A4）的表达受藜芦烷×受体（PXR）调节，PXR受多种信号通路（包括细胞周期蛋白依赖性激酶（Cdk）通路）调节。通常被人类作为膳食成分消耗的黄酮类化合物已经显示出调节各种信号传导途径（例如，抑制Cdks）。黄酮类化合物也被证明可以诱导CYP的表达，但其潜在的作用机制尚不清楚。在这里，我们报告的机制负责类黄酮介导的PXR激活和表达。在一个基于细胞的筛选设计，以确定化合物激活PXR介导的CYP3A4基因表达的HepG2人癌细胞，我们确定了几种黄酮类化合物，如木犀草素和芹菜素，作为PXR激活剂。类黄酮没有直接结合PXR，这表明类黄酮介导的PXR激活可能是另一种机制。与类黄酮的Cdk5抑制作用一致，Cdk5和p35（激活Cdk5所需的非细胞周期蛋白调节亚基）在HepG2中表达。Cdk5的激活减弱PXR介导的CYP3A4表达，而其下调增强它。Cdk5介导的CYP3A4启动子活性的下调被黄酮类化合物恢复，表明黄酮类化合物通过灭活Cdk5激活PXR。体外激酶试验表明，Cdk5直接磷酸化PXR。Cdk激酶谱分析表明，芹菜素抑制多种Cdk，这表明几种Cdk可能参与类黄酮激活PXR。我们的研究结果首次将类黄酮对Cdks表达的刺激作用与其对Cdks的抑制作用联系起来，通过PXR介导的机制。这些结果可能具有重要的影响，药物的药代动力学与草药治疗和草药药物相互作用。
The expression of the drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is regulated by the pregnane × receptor (PXR), which is modulated by numerous signaling pathways, including the cyclin-dependent kinase (Cdk) pathway. Flavonoids, commonly consumed by humans as dietary constituents, have been shown to modulate various signaling pathways (e.g., inhibiting Cdks). Flavonoids have also been shown to induce CYPs expression, but the underlying mechanism of action is unknown. Here, we report the mechanism responsible for flavonoid-mediated PXR activation and CYP expression. In a cell-based screen designed to identify compounds that activate PXR-mediated CYP3A4 gene expression in HepG2 human carcinoma cells, we identified several flavonoids, such as luteolin and apigenin, as PXR activators. The flavonoids did not directly bind to PXR, suggesting that an alternative mechanism may be responsible for flavonoid-mediated PXR activation. Consistent with the Cdk5-inhibitory effect of flavonoids, Cdk5 and p35 (a non-cyclin regulatory subunit required to activate Cdk5) were expressed in HepG2. The activation of Cdk5 attenuated PXR-mediated CYP3A4 expression whereas its downregulation enhanced it. The Cdk5-mediated downregulation of CYP3A4 promoter activity was restored by flavonoids, suggesting that flavonoids activate PXR by inactivating Cdk5. In vitro kinase assays showed that Cdk5 directly phosphorylates PXR. The Cdk kinase profiling assay showed that apigenin inhibits multiple Cdks, suggesting that several Cdks may be involved in activation of PXR by flavonoids. Our results for the first time link the stimulatory effect of flavonoids on CYP expression to their inhibitory effect on Cdks, through a PXR-mediated mechanism. These results may have important implications on the pharmacokinetics of drugs co-administered with herbal remedy and herbal-drug interactions.
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影响因子：
3.9
作者：
Pondugula, Satyanarayana R.;Brimer-Cline, Cynthia;Chen, Taosheng
通讯作者：
Chen, Taosheng
影响因子：
4.8
作者：
Lin, Wenwei;Wu, Jing;Chen, Taosheng
通讯作者：
Chen, Taosheng
DOI：
10.1124/jpet.104.076331
发表时间：
2005-02-01
影响因子：
3.5
作者：
Ding, XS;Staudinger, JL
通讯作者：
Staudinger, JL
影响因子：
4.5
作者：
Messina, A.;Nannelli, A.;Gervasi, P. G.
通讯作者：
Gervasi, P. G.
影响因子：
5.3
作者：
Kodama, S;Koike, C;Yamamoto, Y
通讯作者：
Yamamoto, Y