Modulation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) activation by ursolic acid (UA) attenuates rifampin-isoniazid cytotoxicity
Modulation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) activation by ursolic acid (UA) attenuates rifampin-isoniazid cytotoxicity
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DOI：
10.1016/j.phymed.2017.09.016
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发表时间：
2017-12-01
期刊：
影响因子：
7.9
通讯作者：
Yun-Ping, Lim
中科院分区：
文献类型：
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作者：
Hsiao-Yun, Chang;Chao-Jung, Chen;Yun-Ping, Lim
背景：细胞色素P450酶转录诱导剂与治疗药物之间的相互作用可通过拮抗核受体孕烷X受体(PXR，NR1I2)的激活而被阻止，从而提高治疗效果。目的：本研究旨在确定广泛分布的五环三萜乌索酸(UA)可能是PXR及其姊妹受体雄烷组成受体(CAR，NR1I3)的有效拮抗剂。方法：利用肝癌细胞株HepG2，分别评价PXR和CAR靶基因CYP3A4和CYP2B6的启动活性。在一个分化的HepaRG细胞系中检测了细胞色素P3A4和细胞色素P4P2B6的催化活性、基因表达和蛋白表达。结果：瞬时转染实验表明，UA能有效抑制利福平(RIF)和Citco(人CAR激动剂)介导的CYP3A4和CYP2B6启动子活性。这些抑制作用与细胞色素P3A4和细胞色素P450 2B6的表达和催化活性密切相关。此外，联合调节因子与PXR的相互作用以及CYP3A4启动子活性和CYP3A4启动子异生反应元件(翻转重复序列6，ER6)的转录复合体分别在UA存在下被破坏。UA对PXR有拮抗作用，并能逆转RIF诱导的异烟肼(INH)的细胞毒作用。综上所述，UA可抑制PXR和CAR的反式激活作用，降低细胞色素P3A4和细胞色素P42B6的表达和功能。结论：UA可能是减少CYP酶转录诱导剂与治疗药物之间潜在危险相互作用的有效药物。
Background: Interactions between transcriptional inducers of cytochrome P450 (CYP450) enzymes and therapeutic drugs may be prevented by antagonizing the activation of a nuclear receptor (NR), pregnane X receptor (PXR, NR1I2), thus improving therapeutic efficacy.Purpose: In the present study, we aim to identify that ursolic acid (UA), a widely distributed pentacyclic triterpene, may act as an effective antagonist of PXR and its sister NR receptor, constitutive androstane receptor (CAR, NR1I3).Methods: The hepatocellular carcinoma cell line, HepG2, was used to evaluate the promoter activity of PXR and CAR target genes, CYP3A4 and CYP2B6, respectively. Catalytic activities, mRNA, and protein expression of CYP3A4 and CYP2B6 were evaluated in a differentiated HepaRG cell line. Coregulation of PXR with coregulators on CYP3A4 promoter response elements was also been characterized.Results: Transient transfection assays showed that UA effectively attenuated CYP3A4 and CYP2B6 promoter activities mediated by rifampin (RIF, human PXR agonist) and CITCO (human CAR agonist). These inhibitory effects were well correlated with the expression and catalytic activities of CYP3A4 and CYP2B6. Furthermore, the interaction of co-regulators with PXR and the transcriptional complexes in the CYP3A4 promoter activity and CYP3A4 promoter xenobiotic response element (everted repeat 6, ER6), respectively, were disrupted in the presence of UA. UA showed an antagonistic effect against PXR, and reversed the cytotoxic effects of isoniazid (INH) induced by RIF. Taken together, these results show that UA inhibits the transactivation effects of PXR and CAR, and reduces the expression and function of CYP3A4 and CYP2B6.Conclusion: The present study suggests that UA could be a powerful agent for reducing potentially dangerous interactions between transcriptional inducers of CYP enzymes and therapeutic drugs.