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目的研究天然黄酮类化合物对CYP3A4的抑制活性并通过定性及三维定量分析两种方法挖掘天然黄酮结构中抑制CYP3A4活性的关键因素。方法利用睾酮特征代谢反应表征人肝微粒体中CYP3A4的活性。在此体系中,首先选取较高浓度初筛25种黄酮类化合物的抑制活性。对于抑制活性超过50%的化合物,进行多浓度测试以获得IC50值。最后分别采用定性和三维定量两种方式分析黄酮结构与CYP3A4抑制之间的相关性。结果初筛实验表明,黄酮苷元类化合物中的黄芩素、异鼠李素、山奈酚、白杨素、木犀草素、芹菜素、槲皮素、柚皮素以及豆蔻明9个化合物对CYP3A4表现出最强抑制作用。除了异鼠李素之外,另外8个化合物的抑制百分比高达90%。黄酮类化合物中主要是取代基的类型、羟基的数量和位置以及碳1、2位双键影响对CYP3A4的抑制活性。建立了预测性较好的反映黄酮结构及对CYP3A4抑制活性的定量计算模型。结论本文发现了黄酮类化合物抑制CYP3A4活性的关键结构特征,同时建立了可以用于黄酮类化合物抑制CYP3A4活性的计算化学模型。
Objective To study the inhibitory activity of natural flavonoids on CYP3A4 and explore the key factors inhibiting the activity of CYP3A4 in natural flavonoids by qualitative and quantitative three-dimensional analysis. Methods The CYP3A4 activity in human liver microsomes was characterized by the characteristic metabolic reaction of testosterone. In this system, we first choose the higher concentration of 25 kinds of flavonoid screening activity. For compounds that inhibit activity by more than 50%, multiple concentration tests were performed to obtain IC50 values. Finally, qualitative and quantitative three-dimensional quantitative analysis of flavonoids and CYP3A4 inhibition of the correlation between. Results The preliminary screening experiments showed that CYP3A4 was found in the flavonoid aglycone compounds such as baicalein, isorhamnetin, kaempferol, chrysin, luteolin, apigenin, quercetin, naringin and 9 compounds of cardamom The strongest inhibitory effect. In addition to isorhamnetin, the other eight compounds have a percent inhibition of up to 90%. Flavonoids are mainly the type of substituents, the number and position of hydroxyl groups and the inhibitory activity of CYP3A4 on the carbon double bond. A quantitative predictive model of flavonoid structure and its inhibitory activity against CYP3A4 was established. Conclusions The key structural features of flavonoids inhibiting CYP3A4 activity were found in this paper. At the same time, a computational chemistry model was established for the inhibition of CYP3A4 activity by flavonoids.