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中药有效成分对细胞色素P450酶的抑制活性评价
引用本文:艾常虹,孙汉雄,李桦,庄笑梅,董德利.中药有效成分对细胞色素P450酶的抑制活性评价[J].中国药理学通报,2011,27(4):519-523.
作者姓名:艾常虹  孙汉雄  李桦  庄笑梅  董德利
作者单位:1. 军事医学科学院毒物药物研究所,北京,100850;哈尔滨医科大学药学院,黑龙江,哈尔滨,150081
2. 军事医学科学院毒物药物研究所,北京,100850
3. 哈尔滨医科大学药学院,黑龙江,哈尔滨,150081
基金项目:国家科技重大专项重大新药创制项目
摘    要:目的评价10个中药有效成分对人肝微粒体5种CYP同工酶(CYP1A2、2C9、2C19、2D6和3A4)的抑制活性,为临床合理用药提供参考。方法在混合人肝微粒体孵育体系中,分别以非那西丁O-脱乙基、甲苯磺丁脲4-羟基化、奥美拉唑5-羟基化、右美沙芬O-脱甲基化和咪达唑仑1'-羟基化反应为5种同工酶代谢活性的标志,用阳性抑制剂对试验体系进行验证。应用LC-MS检测受试物对探针底物代谢产物生成量的影响,得到抑制率并计算IC50。结果柚皮素是CYP2C19的强抑制剂和1A2的中等抑制剂(IC50为0.43和4.79μmol.L-1)。异鼠李素是CYP1A2、2C9和2C19的中等抑制剂,IC50分别为5.36、1.40和3.28μmol.L-1。大黄酸对CYP1A2和3A4的IC50分别为8.32和2.50μmol.L-1,为中等抑制剂。喜树碱是CYP2C9和2C19的中等抑制剂(IC50为2.01和2.48μmol.L-1)。金雀花碱、小檗碱和齐墩果酸抑制CYP2C9、2D6和2C19的IC50分别为8.13、4.69和3.56μmol.L-1,为中等抑制剂。结论柚皮素、异鼠李素、金雀花碱、盐酸小檗碱、喜树碱、大黄酸和齐墩果酸对CYP同工酶有不同程度的抑制作用,在临床应用时应注意可能的药-药相互作用。

关 键 词:中药有效成分  细胞色素P450  抑制  肝微粒体  药-药相互作用  混合探针底物法

In vitro inhibition of cytochrome P450 activities by active constituents of Chinese herbal drugs
AI Chang-hong,SUN Han-xiong,LI Hua,ZHUANG Xiao-mei,DONG De-li.In vitro inhibition of cytochrome P450 activities by active constituents of Chinese herbal drugs[J].Chinese Pharmacological Bulletin,2011,27(4):519-523.
Authors:AI Chang-hong  SUN Han-xiong  LI Hua  ZHUANG Xiao-mei  DONG De-li
Institution:AI Chang-hong1,2,SUN Han-xiong1,LI Hua1,ZHUANG Xiao-mei1,DONG De-li2(1.Institute of Pharmacology and Toxicology,Academy of Military Medical Sciences,Beijing 100850,China,2.Dept of Pharmacology,Haerbin Medical University,Haerbin 150081,China)
Abstract:Aim To evaluate the inhibitory effects of 10 herbal active constituents on 5 CYP isoforms in vitro in human liver microsomes(HLM).Methods The metabolic activities of CYP1A2,2C9,2C19,2D6 and 3A4 were measured in HLM by the cocktail substrate assay using phenacetin-O-deethylation,tolbutamide methyl hydroxylation,omeprazole 5-hydroxylation,dextromethorphan-O-demethylation and midazolam 1′-hydroxylation as marked reactions.A panel of known specific CYP inhibitors was applied to validate the HLM incubation system.The metabolite formation of the probe substrates in incubates were quantified by a LC-MS method.The inhibitory curves were obtained for each herbal constituent and the corresponding IC50 values were calculated.Results Among the 10 active constituents tested,naringenin was found to be a strong inhibitor on CYP2C19 with IC50 of 0.43 μmol·L-1 and a moderate inhibitor of CYP1A2(IC50 4.79 μmol·L-1).Isorhamnetin was a moderate inhibitor for CYP1A2,2C9 and 2C19 with IC50 of 5.36,1.40 and 3.28 μmol·L-1,respectively.The IC50 values of rhein on CYP1A2 and 3A4 were 8.32 and 2.50 μmol·L-1,suggesting that it was a moderate inhibitor for these two isoforms.Camptothecin was also a moderate inhibitor for CYP2C9 and 2C19(IC50 2.01 and 2.48 μmol·L-1).Other three active constituents,cytosine,berberine and oleanolic acid inhibited CYP2C9,2D6 and 2C19 with IC50 of 8.13,4.69 and 3.56 μmol·L-1,respectively.While no significant inhibitory effects were observed for chlorogenic acid,ferulic acid and puerarin.Conclusions Naringenin,isorhamnetin,camptothecin,cytosine,berberine,rhein and oleanolic acid have inhibitory effects on the metabolic activities of different CYP isoforms in HLM.There may be potential drug interactions clinically when these active constituents are used concomitantly with drugs that are metabolized primarily by the CYP isoforms.
Keywords:herbal active constituents  cytochrome P450  inhibition  liver microsomes  drug-drug interaction  cocktail substrate assay  
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