Scutellarin Mediates Cytochrome P450 3A4 and 2C19 Expression via Pregnane X Receptor and Constitutive Androstane Receptor.

IF 2.4 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current molecular pharmacology Pub Date : 2023-01-01 DOI:10.2174/1874467215666220823123852

Hangxing Huang, Change Cao, Zhimin Miao, Xiaoli Yang, Yong Lai

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引用次数: 0

Abstract

Background: Breviscapine is a flavonoid extracted from Erigeron breviscapus (Vant.) Hand.-Mazz., and mainly contains scutellarin. Nuclear receptors play important roles in regulating transporter and drug metabolic enzymes.

Objective: To investigate the regulatory effects of scutellarin on CYP3A4 and 2C19 in HepG2 and Caco-2 cells based on nuclear receptors PXR and CAR.

Methods: The proteins and mRNA levels of CYP3A4 and CYP2C19 treated with scutellarin were detected by Western Blot and RT-qPCR. Using assays of the dual-luciferase reporter, promoter sequences containing hPXR and hCAR protein recognition and binding regulatory elements CYP3A4 and CYP2C19 were inserted upstream of the reporter gene, and the expression vector and the reporter vector were cotransfected into HepG2 and Caco-2 cells.

Results: Scutellarin inhibited mRNA of CYP3A4 and PXR, and promoted mRNA expression of CYP2C19 and CAR in RT-qPCR results. Western-blot results showed scutellarin inhibited the expression of CYP3A4 and promoted the expression of CYP2C19. The dual-luciferase reporter genes showed that scutellarin enhanced the expression level of CYP2C19, and when its concentration was 40 and 80μmol/L, CYP3A4 was significantly increased.

Conclusion: Scutellarin down-regulates CYP3A4 through PXR, and its mechanism may work by up-regulating CAR, binding to PXR to inhibit PXR-mediated expression of CYP3A4. Scutellarin up-regulates CYP2C19 through CAR.

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黄芩苷通过孕烷X受体和构形雄烷受体介导细胞色素P450 3A4和2C19的表达。

背景:灯盏花素是从灯盏花(Erigeron breviscapus)中提取的一种黄酮类化合物。Hand.-Mazz。，主要含有黄芩苷。核受体在转运体和药物代谢酶的调控中发挥着重要作用。目的:探讨黄芩苷对HepG2和Caco-2细胞CYP3A4和2C19的调节作用。方法:采用Western Blot和RT-qPCR方法检测黄芩苷处理后细胞中CYP3A4和CYP2C19蛋白及mRNA水平。通过双荧光素酶报告基因检测，将含有hPXR和hCAR蛋白识别及结合调控元件CYP3A4和CYP2C19的启动子序列插入报告基因上游，将表达载体和报告载体共转染HepG2和Caco-2细胞。结果:在RT-qPCR结果中，黄芩苷抑制CYP3A4和PXR mRNA表达，促进CYP2C19和CAR mRNA表达。Western-blot结果显示，黄芩苷抑制CYP3A4的表达，促进CYP2C19的表达。双荧光素酶报告基因结果显示，黄芩苷提高了CYP2C19的表达水平，当黄芩苷浓度为40和80μmol/L时，CYP3A4的表达量显著增加。结论:黄芩苷通过PXR下调CYP3A4，其机制可能是通过上调CAR，结合PXR抑制PXR介导的CYP3A4表达。黄芩苷通过CAR上调CYP2C19。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current molecular pharmacology Pharmacology, Toxicology and Pharmaceutics-Drug Discovery

CiteScore

4.90

自引率

3.70%

发文量

112

期刊介绍： Current Molecular Pharmacology aims to publish the latest developments in cellular and molecular pharmacology with a major emphasis on the mechanism of action of novel drugs under development, innovative pharmacological technologies, cell signaling, transduction pathway analysis, genomics, proteomics, and metabonomics applications to drug action. An additional focus will be the way in which normal biological function is illuminated by knowledge of the action of drugs at the cellular and molecular level. The journal publishes full-length/mini reviews, original research articles and thematic issues on molecular pharmacology. Current Molecular Pharmacology is an essential journal for every scientist who is involved in drug design and discovery, target identification, target validation, preclinical and clinical development of drugs therapeutically useful in human disease.