目的 研究槲皮素、槲皮素-3-O-葡萄糖醛酸苷、异槲皮苷、金丝桃苷和芦丁对人肝微粒体CYP2C19、CYP2D6、CYP3A4、CYP2E1和CYP2C9的体外抑制作用, 并比较槲皮素及其糖苷化合物对CYP酶的抑制程度。方法 采用人肝微粒体、受试黄酮与5种探针底物在还原系统NADPH的作用下, 于37 ℃水浴条件下共同孵育。通过液相色谱-质谱联用分析方法, 测定探针底物的代谢产物生成量, 评价受试化合物对CYP同工酶活性的影响。结果 在人肝微粒体体外孵育反应体系中, 槲皮素对CYP3A4和CYP2C9亚型活性抑制的IC50值分别为13.14和23.09 μmol·L-1, 其他亚型的IC50值均大于100 μmol·L-1。槲皮素-3-O-葡萄糖醛酸苷、异槲皮苷、金丝桃苷和芦丁对这5种酶亚型的IC50值也均大于100 μmol·L-1。结论 槲皮素对CYP3A4和CYP2C9的活性有一定的抑制作用, 而其糖苷类化合物则对这5种酶亚型的活性几乎均没有抑制作用, 槲皮素糖苷化合物发生药物相互作用的可能性较其苷元小。
Abstract
OBJECTIVE To evaluate inhibitory effect of the flavonoids, quercetin and its glycosides, on the activities of human liver microsomes isoforms CYP2C19, CYP2D6, CYP3A4 CYP2E1 and CYP2C9 in vitro for predicting prudential drug-drug interactions in clinical application. METHODS Human liver microsomes and five probes were incubated with tested flavonoids at 37 ℃ in presence of NADPH. The concentrations of produced metabolites in the reaction solution were determined by liquid chromatography/tandem mass spectrometry method, and compared for evaluating the activity of isoenzymes. RESULTS Quercetin inhibited CYP3A4 and CYP2C9 activities with IC50 values of 13.14 and 23.09 μmol·L-1, respectively. While, the quercetin glycosides, quercetin-3-O-glucuronide, isoquercitrin, hyperoside and rutin were found no significant inhibition effects on the five tested enzymes, with IC50 values higher than 100 μmol·L-1. CONCLUSION Quercetin shows moderate inhibition on CYP3A4 and CYP2C9, there is very little inhibition on the other tested flavonoids because sufficiently high levels are not clinically achieved more than 100 μmol·L-1. The quercetin glycoside compounds are less likely to cause potential drug-drug interactions.
关键词
槲皮素 /
糖苷类化合物 /
异槲皮苷 /
金丝桃苷 /
黄酮 /
细胞色素P450 /
药物相互作用
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Key words
quercetin /
glycosides /
isoquercitrin /
hyperoside /
flavonoid /
cytochrome P450 /
drug interaction
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中图分类号：
R285
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参考文献
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脚注
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基金
科技部对欧盟科技合作专项(1108);“重大新药创制”科技重大专项 (2012ZX09301002-001);贵州省毕节市科技局资助项目(毕科合字53)
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