[Inhibitory effect of flavonoids from Scutellariae Radix on human cytochrome P450 1A].
[Inhibitory effect of flavonoids from Scutellariae Radix on human cytochrome P450 1A].
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DOI：
10.19540/j.cnki.cjcmm.20181128.005
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发表时间：
2019-02-01
期刊：
影响因子：
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通讯作者：
Yang, Ling
中科院分区：
文献类型：
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作者：
Tu, Dong-Zhu;Ma, Hong-Ying;Yang, Ling
研究了8种天然黄酮类化合物对肿瘤化学预防靶点细胞色素P4501 A（CYP 1A）的抑制作用。在本研究中，非那西丁被用作CYP 1A的探针底物，而人肝微粒体和重组人CYP 1A酶被用作酶源。液相色谱-串联质谱法用于监测非那西丁的O-脱乙基代谢产物对乙酰氨基酚的形成速率。根据对乙酰氨基酚生成速率的变化绘制剂量依赖性抑制曲线，并测定IC_（50）。采用抑制动力学分析和对接模拟方法研究了汉黄芩素（Wogonin）对CYP 1A的抑制模式和机制，并测定了其对CYP 1A 1和CYP 1A 2的抑制常数（Ki）。结果表明，汉黄芩素、7-甲氧基黄烷酮和木芙蓉素A对CYP 1A有较强的抑制作用（IC_（50）100 μ mol·L~（-1））。进一步的研究表明汉黄芩素对其他人CYP酶有微弱的抑制作用，提示它可作为开发CYP 1A特异性抑制剂的先导化合物。抑制动力学分析表明，汉黄芩素对CYP 1A 1和CYP 1A 2的非那西丁O-去乙基化反应具有竞争性抑制作用，Ki值分别为0.118和0.262 μ mol·L~（-1）。分子对接表明汉黄芩素与CYP 1A 1和CYP 1A 2通过疏水和π-π相互作用，与CYP 1A 1中的Ser 120和Ser 116通过氢键相互作用。本研究结果表明，黄芪中的部分黄酮类化合物对CYP 1A有较强的抑制作用，而汉黄芩素是最有效的CYP 1A抑制剂，对CYP 1A的选择性相对较高。
This study investigated the inhibitory effect of eight natural flavonoids in Chinese herb Scutellariae Radix on huamn cytochrome P450 1 A(CYP1 A), a key cancer chemo-preventive target. In this study, phenacetin was used as a probe substrate for CYP1 A, while human liver microsomes and recombinant human CYP1 A enzymes were used as enzyme sources. Liquid chromatography-tandem mass spectrometry was used to monitor the formation rates of acetaminophen, the O-deethylated metabolite of phenacetin. The dose-dependent inhibition curves were depicted based on the changes of the formation rates of acetaminophen, while the IC_(50) were determined. Inhibition kinetic analyses and docking simulations were used to investigate the inhibition modes and mechanism of wogonin(the most potent CYP1 A inhibitor in this herb), while the inhibition constants(K_i) of wogonin against both CYP1 A1 and CYP1 A2 were determined. Among all tested flavonoids, wogonin, 7-methoxyflavanone and oroxylin A displayed a strong inhibitory effect on CYP1 A(IC_(50)100 mumol·L~(-1)). Further investigations demonstrated that wogonin had a weak inhibitory effect on other human CYP enzymes, suggesting that it could be used as a lead compound for the development of specific inhibitors of CYP1 A. Furthermore, the inhibition kinetic analyses clearly demonstrated that wogonin could strongly inhibit phenacetin O-deethylation in both CYP1 A1 and CYP1 A2 in a competitive manner, with K_i values at 0.118 and 0.262 mumol·L~(-1), respectively. Molecular docking demonstrated that wogonin could strongly interact with CYP1 A1 and CYP1 A2 via hydrophobic and pi-pi interactions, as well as Ser120 and Ser116 in CYP1 A1 via hydrogen-bonding. In conclusion, this study found that some flavonoids in Scutellariae Radix displayed a strong inhibitory effect on CYP1 A, while wogonin is the most potent CYP1 A inhibitor with a relatively high selectivity towards CYP1 A over other human CYPs.