Lou Dan, Bao Su-Su, Li Ying-Hui, Lin Qian-Meng, Yang Su-Fen, He Jia-Yang
The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
Eur J Drug Metab Pharmacokinet. 2019 Oct;44(5):611-618. doi: 10.1007/s13318-019-00546-y.
Myricetin is a flavonoid compound that is abundant in teas, red wine, berries, herbs and vegetables with a variety of pharmacological properties such as antioxidant, anti-inflammatory and anti-cancer effects. Although there are in vitro studies showing that myricetin inhibits human cytochrome P450 (CYP) 2D6 and CYP3A, the inhibitory mechanisms of myricetin on CYP enzymes are still unclear. The aim of this study was to evaluate the inhibitory effects of myricetin on human and rat CYPs, including CYP3A2/3A4, CYP2B1/2B6, CYP2C9/2C11 and CYP2D1/2D6.
This study was performed to investigate the inhibitory effects of myricetin on human CYP3A4, CYP2B6, CYP2C9, CYP2D6 and rat CYP3A2, CYP2B1, CYP2C11, CYP2D1 through the cocktail approach using ultra-performance liquid chromatography tandem mass spectrometry. Typical probe substrates were used as follows-midazolam for CYP3A2/3A4, dextromethorphan for CYP2D1/2D6, tolbutamide for CYP2C9/2C11, and bupropion for CYP2B1/2B6.
The results of this study showed that myricetin might not be a time-dependent inhibitor. Moreover, myricetin inhibited CYP3A4 in an uncompetitive way with an inhibition constant (K) value of 143.1 μM. It was also a noncompetitive inhibitor of CYP2C9 and CYP2D6 with K values of 31.12 and 53.44 μM and a competitive inhibitor of CYP2B1 with a K value of 69.70 μM, as well as a mixed inhibitor of CYP3A2, CYP2C11 and CYP2D1with K values of 37.57, 14.88 and 17.39 μM, respectively.
In conclusion, this study indicates that myricetin inhibited CYP3A4/3A2, CYP2C9/2C11, CYP2D6/2D1 and CYP2B1 by various mechanisms with different K values. Given that our experiments are established in vitro, further in vivo work is needed to confirm the interaction between myricetin and CYP enzymes, thus providing better guidance for the safe clinical use of myricetin.
杨梅素是一种黄酮类化合物，在茶、红酒、浆果、草药和蔬菜中含量丰富，具有多种药理特性，如抗氧化、抗炎和抗癌作用。尽管有体外研究表明杨梅素可抑制人细胞色素P450（CYP）2D6和CYP3A，但杨梅素对CYP酶的抑制机制仍不清楚。本研究的目的是评估杨梅素对人和大鼠CYP酶的抑制作用，包括CYP3A2/3A4、CYP2B1/2B6、CYP2C9/2C11和CYP2D1/2D6。
本研究采用超高效液相色谱串联质谱联用的鸡尾酒法，研究杨梅素对人CYP3A4、CYP2B6、CYP2C9、CYP2D6以及大鼠CYP3A2、CYP2B1、CYP2C11、CYP2D1的抑制作用。使用的典型探针底物如下：咪达唑仑用于检测CYP3A2/3A4，右美沙芬用于检测CYP2D1/2D6，甲苯磺丁脲用于检测CYP2C9/2C11，安非他酮用于检测CYP2B1/2B6。
本研究结果表明，杨梅素可能不是时间依赖性抑制剂。此外，杨梅素以非竞争性方式抑制CYP3A4，抑制常数（K）值为143.1μM。它也是CYP2C9和CYP2D6的非竞争性抑制剂，K值分别为31.12和53.44μM，是CYP2B1的竞争性抑制剂，K值为69.70μM，还是CYP3A2、CYP2C11和CYP2D1的混合型抑制剂，K值分别为37.57、14.88和17.39μM。
总之，本研究表明杨梅素通过不同机制、以不同K值抑制CYP3A4/3A2、CYP2C9/2C11、CYP2D6/2D1和CYP2B1。鉴于我们的实验是在体外进行的，需要进一步开展体内研究以确认杨梅素与CYP酶之间的相互作用，从而为杨梅素的安全临床应用提供更好的指导。
