PDF(Pubmed)
Abstract：
Cathine is the stable form of cathinone, the major active compound found in khat (Catha edulis Forsk) plant. Khat was found to inhibit major phase I drug metabolizing cytochrome P450 (CYP) enzyme activities in vitro and in vivo. With the upsurge of khat consumption and the potential use of cathine to combat obesity, efforts should be channelled into understanding potential cathine-drug interactions, which have been rather limited. The present study aimed to assess CYPs activity and inhibition by cathine in a high-throughput in vitro fluorescence-based enzyme assay and molecular docking analysis to identify how cathine interacts within various CYPs\' active sites. The half maximal inhibitory concentration (IC50) values of cathine determined for CYP2A6 and CYP3A4 were 80 and 90 μM, while CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2 and CYP3A5 showed no significant inhibition. Furthermore, in Ki analysis, the Lineweaver-Burk plots depicted non-competitive mixed inhibition of cathine on both CYP2A6 and CYP3A4 with Ki value of 63 and 100 μM, respectively. Cathine showed negligible time-dependent inhibition on CYPs. Further, molecular docking studies showed that cathine was bound to CYP2A6 via hydrophobic, hydrogen and π-stacking interactions and formed hydrophobic and hydrogen bonds with active site residues in CYP3A4. Both molecular docking prediction and in vitro outcome are in agreement, granting more detailed insights for predicting CYPs metabolism besides the possible cathine-drug interactions. Cathine-drug interactions may occur with concomitant consumption of khat or cathine-containing products with medications metabolized by CYP2A6 and CYP3A4.
摘要：
卡西酮是卡西酮的稳定形式，在卡塔（CathaedulisForsk）植物中发现的主要活性化合物。发现Khat在体外和体内抑制主要的I相药物代谢细胞色素P450（CYP）酶活性。随着阿拉伯茶消费的激增和卡西汀用于对抗肥胖的潜在用途，应该努力理解潜在的阴极-药物相互作用，这是相当有限的。本研究旨在通过高通量体外基于荧光的酶测定和分子对接分析来评估CYPs的活性和Cathine的抑制作用，以确定Cathine如何在各种CYPs活性位点内相互作用。CYP2A6和CYP3A4测定的阴极的半最大抑制浓度（IC50）值为80和90μM，而CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6、CYP2E1、CYP2J2和CYP3A5无明显抑制作用。此外，在Ki分析中，Lineweaver-Burk图描绘了对CYP2A6和CYP3A4的非竞争性混合抑制，Ki值为63和100μM，分别。Cathine对CYPs的时间依赖性抑制作用可忽略不计。Further,分子对接研究表明，阴极通过疏水与CYP2A6结合，CYP3A4中的氢和π堆积相互作用，并与活性位点残基形成疏水和氢键。分子对接预测和体外结果一致，除了可能的阴极-药物相互作用外，还为预测CYPs代谢提供更详细的见解。与CYP2A6和CYP3A4代谢的药物同时食用khat或含cathine的产品可能会发生Cathine-药物相互作用。
