非诺贝特对小异二聚体伴侣(SHP)和细胞色素P450 (CYP) 2D6表达的影响。

Drug metabolism letters Pub Date : 2017-11-17 DOI:10.2174/1872312811666170407164631

Rebecca Kent, Hyunyoung Jeong

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引用次数: 3

摘要

背景:细胞色素P450 (CYP) 2D6是一种主要的药物代谢酶，负责消除25%的上市药物。我们最近发现SHP是CYP2D6表达的负调节因子，并表明改变SHP表达的因素影响CYP2D6的表达。非诺贝特是一种过氧化物酶体增殖物激活受体α(PPARα)的激动剂，此前有报道称其可上调小鼠肝脏中SHP的表达。本研究的目的是确定非诺贝特是否通过上调SHP表达来降低CYP2D6的表达。方法:给cyp2d6人源化转基因小鼠非诺贝特(100 mg/kg/天，腹腔注射5天)或对照物。测定肝脏CYP2D6、SHP mRNA及蛋白表达水平。结果:结果显示，虽然各组间SHP mRNA水平没有差异，但非诺贝特处理小鼠的SHP蛋白水平增加了2倍。尽管SHP蛋白水平升高，但CYP2D6在mRNA或蛋白水平上的表达并未降低。在非诺贝特处理的人肝细胞中也观察到类似的结果。瞬时转染和启动子报告子实验的结果表明，PPARα可以反激活CYP2D6启动子，这表明非诺贝特对CYP2D6下调的缺失可能部分是由于PPARα激活了CYP2D6启动子。结论:这些结果表明非诺贝特对CYP2D6表达的影响很小，但增加了SHP的表达。

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Effects of Fenofibrate on the Expression of Small Heterodimer Partner (SHP) and Cytochrome P450 (CYP) 2D6.

Background: Cytochrome P450 (CYP) 2D6 is a major drug-metabolizing enzyme, responsible for eliminating 25% of marketed drugs. We recently identified SHP as a negative regulator of CYP2D6 expression and showed that factors that alter SHP expression influence CYP2D6 expression. Fenofibrate, an agonist of peroxisome proliferator-activated receptor α(PPARα), has been previously reported to upregulate SHP expression in the mouse liver. The objective of this study was to determine whether fenofibrate decreases CYP2D6 expression via upregulating SHP expression.

Methods: CYP2D6-humanized transgenic mice were administered with fenofibrate (100 mg/kg/day intraperitoneally for 5 days) or vehicle control. Hepatic mRNA and protein expression levels of CYP2D6 and SHP were measured.

Results: Results showed that while mRNA levels of SHP did not differ between the groups, protein levels of SHP increased by 2-fold in fenofibrate-treated mice. Despite the increased SHP protein levels, CYP2D6 expression did not decrease at the mRNA or protein levels. Similar results were observed in human hepatocytes treated with fenofibrate. Results from transient transfection and promoter reporter assays indicate that PPARα can transactivate CYP2D6 promoter, suggesting that the lack of CYP2D6 downregulation by fenofibrate may be in part due to the activation of CYP2D6 promoter by PPARα.

Conclusion: These results indicate that fenofibrate has minimal effects on CYP2D6 expression despite increased SHP expression.

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来源期刊

Drug metabolism letters Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

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期刊介绍： Drug Metabolism Letters publishes letters and research articles on major advances in all areas of drug metabolism and disposition. The emphasis is on publishing quality papers very rapidly by taking full advantage of the Internet technology both for the submission and review of manuscripts. The journal covers the following areas: In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites.