Lin Fei, Lin Xinhua, Wang Xuewen, Mei Guanghui, Chen Bing, Yao Hong, Huang Lingyi
Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China.
Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China.
Front Pharmacol. 2023 Feb 15;14:1108867. doi: 10.3389/fphar.2023.1108867. eCollection 2023.
Hieron is a traditional Chinese herbal medicine, the ethyl acetate extract from (SDEA) showed favorable anticancer potentials. However, the effect of SDEA on human cytochrome P450 enzymes (CYP450) remains unclear. To predict the herb-drug interaction (HDI) and lay the groundwork for further clinical trials, the inhibitory effect of SDEA and its four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) on seven CYP450 isoforms were investigated by using the established CYP450 cocktail assay based on LC-MS/MS. Appropriate substrates for seven tested CYP450 isoforms were selected to establish a reliable cocktail CYP450 assay based on LC-MS/MS. The contents of four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) in SDEA were determined as well. Then, the validated CYP450 cocktail assay was applied to test the inhibitory potential of SDEA and four constituents on CYP450 isoforms. SDEA showed strong inhibitory effect on CYP2C9 and CYP2C8 (IC ≈ 1 μg/ml), moderate inhibitory effect against CYP2C19, CYP2E1 and CYP3A (IC < 10 μg/ml). Among the four constituents, Amentoflavone had the highest content in the extract (13.65%) and strongest inhibitory effect (IC < 5 μM), especially for CYP2C9, CYP2C8 and CYP3A. Amentoflavone also showed time-dependent inhibition on CYP2C19 and CYP2D6. Apigenin and Palmatine both showed concentration-dependent inhibition. Apigenin inhibited CYP1A2, CYP2C8, CYP2C9, CYP2E1 and CYP3A. Palmatine inhibited CYP3A and had a weak inhibitory effect on CYP2E1. As for Delicaflavone, which has the potential to develop as an anti-cancer agent, showed no obvious inhibitory effect on CYP450 enzymes. Amentoflavone may be one of the main reasons for the inhibition of SDEA on CYP450 enzymes, the potential HDI should be considered when SDEA or Amentoflavone were used with other clinical drugs. On the contrast, Delicaflavone is more suitable to develop as a drug for clinical use, considering the low level of CYP450 metabolic inhibition.
喜树是一种传统的中草药，其乙酸乙酯提取物（SDEA）显示出良好的抗癌潜力。然而，SDEA对人细胞色素P450酶（CYP450）的影响仍不清楚。为了预测草药-药物相互作用（HDI）并为进一步的临床试验奠定基础，采用基于液相色谱-串联质谱（LC-MS/MS）的已建立的CYP450鸡尾酒法，研究了SDEA及其四种成分（穗花杉双黄酮、巴马汀、芹菜素、精致黄酮）对七种CYP450亚型的抑制作用。选择七种受试CYP450亚型的合适底物，建立基于LC-MS/MS的可靠的CYP450鸡尾酒法。同时测定了SDEA中四种成分（穗花杉双黄酮、巴马汀、芹菜素、精致黄酮）的含量。然后，将经过验证的CYP450鸡尾酒法应用于测试SDEA和四种成分对CYP450亚型的抑制潜力。SDEA对CYP2C9和CYP2C8表现出强烈的抑制作用（IC≈1μg/ml），对CYP2C19、CYP2E1和CYP3A表现出中等抑制作用（IC<10μg/ml）。在这四种成分中，穗花杉双黄酮在提取物中的含量最高（13.65%），抑制作用最强（IC<5μM），尤其是对CYP2C9、CYP2C8和CYP3A。穗花杉双黄酮对CYP2C19和CYP2D6也表现出时间依赖性抑制。芹菜素和巴马汀均表现出浓度依赖性抑制。芹菜素抑制CYP1A2、CYP2C8、CYP2C9、CYP2E1和CYP3A。巴马汀抑制CYP3A，对CYP2E1有较弱的抑制作用。至于有潜力开发为抗癌药物的精致黄酮，对CYP450酶没有明显的抑制作用。穗花杉双黄酮可能是SDEA抑制CYP450酶的主要原因之一，当SDEA或穗花杉双黄酮与其他临床药物合用时，应考虑潜在的HDI。相比之下，考虑到CYP450代谢抑制水平较低，精致黄酮更适合开发为临床用药。
