Lim Sharoen Yu Ming, Binti Azidin Athira Rafhana, Ung Yee Tze, Al-Shagga Mustafa, Alshawsh Mohammed Abdullah, Mohamed Zahurin, Ong Chin Eng, Pan Yan
Department of Biomedical Science, The University of Nottingham Malaysia Campus, Jalan Broga, 43500, Semenyih, Selangor Darul Ehsan, Malaysia.
Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
Eur J Drug Metab Pharmacokinet. 2019 Jun;44(3):423-431. doi: 10.1007/s13318-018-0518-2.
A significant number of people worldwide consume khat on daily basis. Long term of khat chewing has shown negative impact on several organ systems. It is likely that these people are co-administered khat preparations and conventional medication, which may lead to khat-drug interactions. This study aimed to reveal the inhibitory potencies of khat ethanol extract (KEE) and its major active ingredient (cathinone) on human cytochrome P450 (CYP) 2C9, CYP2D6, and CYP3A4 enzymes activities, which are collectively responsible for metabolizing 70-80% clinically used drugs.
In vitro fluorescence-based enzyme assays were developed and the CYP enzyme activities were quantified in the presence and absence of KEE and cathinone employing Vivid CYP450 Screening Kits.
KEE inhibited human CYP2C9, CYP2D6, and CYP3A4 enzyme activities with IC of 42, 62, and 18 μg/ml. On the other hand, cathinone showed negligible inhibitory effect on these CYPs. Further experiments with KEE revealed that KEE inhibited CYP2C9 via non-competitive or mixed mode with K of 14.7 μg/ml, CYP2D6 through competitive or mixed mode with K of 17.6 μg/ml, CYP3A4 by mixed inhibition mode with K of 12.1 μg/ml.
Khat-drug interactions are possible due to administration of clinical drugs metabolized by CYP2C9/CYP2D6/CYP3A4 together with khat chewing. Further in vivo studies are required to confirm our findings and identify the causative constituents of these inhibitory effects.
全球有相当数量的人每天都食用巧茶。长期嚼食巧茶已显示出对多个器官系统有负面影响。这些人很可能同时服用巧茶制剂和传统药物，这可能会导致巧茶与药物的相互作用。本研究旨在揭示巧茶乙醇提取物（KEE）及其主要活性成分（去甲伪麻黄碱）对人类细胞色素P450（CYP）2C9、CYP2D6和CYP3A4酶活性的抑制效力，这些酶共同负责代谢70 - 80%的临床使用药物。
开发了基于荧光的体外酶测定法，并使用Vivid CYP450筛选试剂盒在有和没有KEE及去甲伪麻黄碱的情况下对CYP酶活性进行定量。
KEE抑制人类CYP2C9、CYP2D6和CYP3A4酶活性，其半数抑制浓度（IC）分别为42、62和18μg/ml。另一方面，去甲伪麻黄碱对这些细胞色素P450显示出可忽略不计的抑制作用。对KEE的进一步实验表明，KEE通过非竞争性或混合模式抑制CYP2C9，其解离常数（K）为14.7μg/ml；通过竞争性或混合模式抑制CYP2D6，K为17.6μg/ml；通过混合抑制模式抑制CYP3A4，K为12.1μg/ml。
由于同时嚼食巧茶和服用由CYP2C9/CYP2D6/CYP3A4代谢的临床药物，巧茶与药物相互作用是可能的。需要进一步的体内研究来证实我们的发现，并确定这些抑制作用的致病成分。
