Gambogic acid suppresses cytochrome P450 3A4 by downregulating pregnane X receptor and up-regulating DEC1 in human hepatoma HepG2 cells
Gambogic acid suppresses cytochrome P450 3A4 by downregulating pregnane X receptor and up-regulating DEC1 in human hepatoma HepG2 cells
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DOI：
10.1039/c4tx00239c
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发表时间：
2015-06
影响因子：
2.1
通讯作者：
Wei Liu;Rui Ning;Ruini Chen;Jinhua Hu;Haiyan Gui;Yu-Wen Wang;Jie Liu;G. Hu;Jian Yang;Q. Guo
中科院分区：
文献类型：
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作者：
Wei Liu;Rui Ning;Ruini Chen;Jinhua Hu;Haiyan Gui;Yu-Wen Wang;Jie Liu;G. Hu;Jian Yang;Q. Guo
藤黄酸(GA)被中国食品药品监督管理局批准用于实体瘤患者的II期临床试验。最近，GA和化疗药物的结合代表了一种很有前途的癌症治疗方法。然而，关于赤霉素A对药物代谢酶的影响却知之甚少。在这项研究中，我们首次报道了GA是细胞色素P450 3A4(CYP3A4)酶的有效抑制物，该酶负责超过60%的药物的氧化代谢。经赤霉素A处理后，细胞色素P3A4在mRNA和蛋白水平的表达均下降，酶活性降低。此外，GA对细胞色素P3A4的抑制作用发生在PXR降低之后。PXR基因的敲除降低了细胞色素P3A4的表达水平，而过表达则增加了细胞色素P3A4的mRNA和蛋白水平。GA能显著降低正常细胞和PXR过表达细胞中CYP3A4的表达。同时，分化胚胎软骨细胞基因1(DEC1)的表达在GA处理后迅速增加，随后，细胞色素P3A4的表达持续下降。DEC1的过表达降低了细胞色素P3A4的mRNA和蛋白水平，而DEC1的敲除部分取消了GA诱导的细胞色素P3A4表达的降低。综上所述，我们的数据表明，两个转录因子，PXR和DEC1，参与了GA介导的对HepG2细胞中CYP3A4的抑制。
Gambogic acid (GA) was approved by the Chinese Food and Drug Administration for phase II clinical trials in patients with solid tumors. Recently, combinations of GA and chemotherapeutic agents have represented a promising therapeutic approach for cancer. However, little is known about the effect of GA on drug metabolism enzymes. In this study, we report for the first time that GA is a potent repressor of the cytochrome P450 3A4 (CYP3A4) enzyme, which is responsible for the oxidative metabolism of more than 60% of all pharmaceuticals. After HepG2 cells were treated with GA, the expression of CYP3A4 decreased at both the mRNA and protein levels, and CYP3A4 enzymatic activity was also reduced. Moreover, GA-mediated repression of CYP3A4 occurred after the decrease of PXR. Knockdown of PXR decreased CYP3A4 at the mRNA and protein levels, whereas PXR overexpression increased the CYP3A4 mRNA and protein levels. GA markedly decreased CYP3A4 expression in both normal and PXR overexpressing cells. Meanwhile, differentiated embryonic chondrocyte gene 1 (DEC1) expression rapidly increased in response to GA treatment, and subsequently, CYP3A4 expression continuously decreased. Overexpression of DEC1 decreased CYP3A4 mRNA and protein levels, and knockdown of DEC1 partially abolished the GA-mediated decrease in CYP3A4 expression. Taken together, our data suggest that two transcriptional factors, PXR and DEC1, are involved in the GA-mediated suppression of CYP3A4 in HepG2 cells.