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Heterotropic activation of flavonoids on cytochrome P450 3A4: a case example of alleviating dronedarone-induced cytotoxicity
Toxicology Letters ( IF 3.5 ) Pub Date : 2020-02-01 , DOI: 10.1016/j.toxlet.2019.11.016
Jie Bai 1 , Li Li 1 , Shengyu Zhao 1 , Xiaoqing Fan 1 , Jie Zhang 1 , Minwan Hu 1 , Yonghui Chen 1 , Yanhong Sun 1 , Baolian Wang 1 , Jing Jin 1 , Xiaojian Wang 1 , Dan Zhang 1 , Jinping Hu 1 , Yan Li 1
Affiliation  

The clinical drug-drug interactions mediated by heterotropic activation on cytochrome P450 (CYP450) kinetics, especially CYP3A4, have received wide concern in recent years. Flavonoids, a group of important natural substances with various pharmacological activities, distribute widely among vegetables, fruits and herbs. The frequent and numerous uses of flavonoids may increase the risk of food/herb-drug interactions. However, little is known about activation effects of flavonoids on CYP3A4. The aim of this study was to investigate activation of CYP3A4 by flavonoids, explore the molecular mechanism, and assess the biological effects on dronedarone (DND) induced toxicity. The results showed that flavone, tangeretin, sinensetin and 6-hydroxyflavone increased the cell viability by decreasing DND-induced cytotoxicity. These four flavonoids could activate the metabolism of DND in hamster pharmacokinetics study. Furthermore, both molecular docking and circular dichroism analysis partially illustrated the molecular mechanism of heterotropic activation. Finally, the pharmacophore model suggested B aromatic ring, hydrophobic groups at 7-position and hydrogen bond acceptors at 4-position may play a vital role in activation of flavonoids on CYP3A4. Taken together, our findings would provide useful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions in humans.

中文翻译:

黄酮类化合物对细胞色素 P450 3A4 的异向激活:减轻决奈达隆诱导的细胞毒性的一个案例

近年来,由细胞色素 P450 (CYP450) 动力学,尤其是 CYP3A4 的异向激活介导的临床药物相互作用受到广泛关注。黄酮类化合物是一组具有多种药理活性的重要天然物质,广泛分布于蔬菜、水果和药材中。类黄酮的频繁和大量使用可能会增加食物/草药-药物相互作用的风险。然而,对黄酮类化合物对 CYP3A4 的激活作用知之甚少。本研究的目的是研究黄酮类化合物对 CYP3A4 的激活,探索分子机制,并评估对决奈达隆 (DND) 诱导毒性的生物学效应。结果表明,黄酮、橘皮素、正藤素和 6-羟基黄酮通过降低 DND 诱导的细胞毒性来增加细胞活力。在仓鼠药代动力学研究中,这四种黄酮类化合物可以激活DND的代谢。此外,分子对接和圆二色性分析部分说明了异向激活的分子机制。最后,药效团模型表明 B 芳环、7 位疏水基团和 4 位氢键受体可能在 CYP3A4 上黄酮类化合物的活化中起重要作用。总之,我们的研究结果将为预测人类中含有类黄酮的食物/草药-药物相互作用的潜在风险提供有用的信息。7 位疏水基团和 4 位氢键受体可能在 CYP3A4 上黄酮类化合物的活化中起重要作用。总之,我们的研究结果将为预测人类中含有类黄酮的食物/草药-药物相互作用的潜在风险提供有用的信息。7 位疏水基团和 4 位氢键受体可能在 CYP3A4 上黄酮类化合物的活化中起重要作用。总之,我们的研究结果将为预测人类中含有类黄酮的食物/草药-药物相互作用的潜在风险提供有用的信息。
更新日期:2020-02-01
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