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张远冬,刘学庆,郭延垒,张有金,石亮,王二豪,于超.大鼠肝微粒体法评价20种中药有效成分对CYP2C9酶的作用[J].陆军军医大学学报(原第三军医大学学报),2013,35(24 ):2654-2658. Zhang Yuandong,Liu Xueqing,Guo Yanlei,Zhang Youjin,Shi Liang,Wang Erhao,Yu Chao.Effects of 20 active ingredients of traditional Chinese herbs on CYP2C9 activities in rat liver microsomes[J].J Amry Med Univ (J Third Mil Med Univ),2013,35(24 ):2654-2658.
张远冬, 刘学庆, 郭延垒, et al. Effects of 20 active ingredients of traditional Chinese herbs on CYP2C9 activities in rat liver microsomes[J]. Journal of Army Medical University, 2013, 35(24): 2654-2658.
张远冬,刘学庆,郭延垒,张有金,石亮,王二豪,于超.大鼠肝微粒体法评价20种中药有效成分对CYP2C9酶的作用[J].陆军军医大学学报(原第三军医大学学报),2013,35(24 ):2654-2658. Zhang Yuandong,Liu Xueqing,Guo Yanlei,Zhang Youjin,Shi Liang,Wang Erhao,Yu Chao.Effects of 20 active ingredients of traditional Chinese herbs on CYP2C9 activities in rat liver microsomes[J].J Amry Med Univ (J Third Mil Med Univ),2013,35(24 ):2654-2658. DOI:
张远冬, 刘学庆, 郭延垒, et al. Effects of 20 active ingredients of traditional Chinese herbs on CYP2C9 activities in rat liver microsomes[J]. Journal of Army Medical University, 2013, 35(24): 2654-2658. DOI:
目的 建立体外大鼠肝微粒体中CYP2C9酶活性测定方法,并以此方法评价20种中药有效成分单体对大鼠CYP2C9酶的作用。 方法 以双氯芬酸(Diclofenac)为探针,在实验组大鼠肝微粒体孵育体系中加入20种中药有效成分单体,在37 ℃水浴温孵15 min后冰乙腈终止反应,HPLC测定各孵育体系中探针药物的代谢产物4′-羟基双氯芬酸的转化率,并与对照组比较其差异来评价各有效成分对CYP2C9酶活性的作用。 结果 4′-羟基双氯芬酸、双氯芬酸及其内标香豆素三者分离良好且无其他内源性物质干扰;动力学考察表明双氯芬酸在0.25 mg/mL的大鼠肝微粒体体系中孵育15 min,测得酶动力学参数V
max
为0.145 6 nmol/(min·mg),K
m
为8.270 μmol/L;抑制实验考察发现:黄芩素、蛇床子素、大黄素、獐牙菜苦苷、淫羊藿苷、白藜芦醇实验组中4′-羟基双氯芬酸转化率分别为(402.60±10.58)、(210.90±10.26)、(414.46±10.32)、(509.83±26.45)、(355.44±15.87)、(387.34±22.16)pmol/(min·mg),显著低于对照组[(735.80±17.27)pmol/(min·mg),P0.05
]
,其他中药成分实验组与对照组比较,其转化率无统计学差异。 结论 建立了中药有效成分对CYP2C9酶作用的体外大鼠肝微粒体研究方法,并初步评价了黄芩素、蛇床子素、大黄素、獐牙菜苦苷、淫羊藿苷、白藜芦醇对CYP2C9具有抑制作用,在临床联合用药中需注意其可能引起的药物-药物相互作用。
Objective To establish a method for evaluating the activity of cytochrome P450 2C9 (CYP2C9) using diclofenac as the probe compound in rat liver microsomes (RLMs) in vitro
and to investigate the impact of 20 active ingredients of traditional Chinese herbs on CYP2C9 activity. Methods Diclofenac and 20 active ingredients of traditi
onal Chinese herbs were incubated with RLMs for 15 min at 37 ℃
and the reaction was terminated by cold acetonitrile. The conversion ratio of 4′-hydroxydiclofenac was determined by HPLC. Finally
the effects of the 20 active ingredients of traditional Chinese herbs on CYP2C9 activities were evaluated by comparison of the conversion ratio with control group. Results 4′-hydroxydiclofenac
diclofenac and coumarin were perfectly separated. After diclofenac incubation with 0.25 mg/mL RLM for 15 min
the kinetic parameters were revealed
V
max
0.145 6 nmol/(min·mg) and K
m
8.270 μmol/L. Among the 20 active ingredients
baicalein
cnidiadin
emodin
swertiamarin
icariin
and resveratrol displayed strong inhibition on CYP2C9 with the conversion ratio of 402.60±10.58
210.90±10.26
414.46±10.32
509.83±26.45
355.44±15.87
and 387.34±22.16 pmol/(min·mg)
respectively
which were significantly lower than that of control group 735.80±17.27 pmol/(min·mg) (P0.05). Conclusion The method for evaluating influences of active ingredients of traditional Chinese herbs on CYP2C9 activity in RLMs in vitro is successfully established. Baicalein
cnidiadin
emodin
swertiamarin
icariin
and resveratrol inhibit CYP2C9 activity in vitro
indicating that we should pay attention to drug-drug interactions of these active ingredients when they are used concomitantly with other drugs in clinical practice.
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