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       【摘要】 
       目的介绍中草药化学成分对细胞色素P3A4亚型影响。方法查阅国内外近年来关于中草药化学成分对细胞色素CYP3A4亚型影响的有关文献并进行综述。结果多种中草药及成分能够抑制或诱导细胞色素CYP3A4亚型，从而影响合用药物的代谢，导致药物相互作用的发生甚至不良反应的发生。结论应重视一些中草药配伍其它药物对细胞色素CYP3A4亚型的影响及所引起的药物相互作用和形成机制的研究，促进临床合理用药，提高中草药的有效性和安全性。
       【关键词】  细胞色素P450酶； 中草药； 药物相互作用； 合理用药
       Review on the Effect of Chinese Herbal Medicine on CYP3A4 Isoforms of Cytochrome p450 System
       Yin Yongqin, Shen Zhibin
       Department of Traditional Chinese Medicine, Guangdong Pharmacological University, Guangzhou 510006,China
       Abstract：ObjectiveTo introduce the effect of chemical instituents from Chinese herbal medicine on CYP3A4 isoform of cytochrome P450 system. MethodsTo summarize related literature about Chinese herbal medicine on CYP3A4 isoform of cytochrome P450 system in recent years at home and abroad.ResultsSome Chinese herbal medicine can reduce or induce CYP3A4 isoform of cytochrome P450. Consequently it affected  combined drug metabolism and resulted in drug interaction. ConclusionWe should pay attention to the effect of some Chinese herbal medicine on CYP3A4 isoform of cytochrome P450 system and corresponding drug interaction and the correlated mechanism， in order to ensure the efficiency and safety of Chinese herbal medicine.
       Key words：Cytochrome P450 (CYP);   Chinese herbal medicine;   Drug interaction;   Rational use of medicine
       
       美国的一项研究表明，住院患者的严重不良反应发生率为6．7％，因药物相互作用的致死率已排名住院患者死亡原因的第4～5位。了解不同药物对代谢酶的调节及预测可能的代谢性药物相互作用，并以体外研究所得数据为进一步的临床试验设计提供有价值的信息，降低临床试验的成本及风险，避免因药物代谢性相互作用而引起的不良反应的发生。中药化学成分复杂，它的成分代谢多数情况下是通过细胞色素P450酶(CYP)代谢同时能够抑制或诱导CYP活性发生改变。人类细胞色素P450 (CYP 450) 是存在于肝脏微粒体混合功能氧化酶系的主要成分。我们综述了药物体外代谢研究试验中不用中药及化学成分对P3A4的影响，指导临床合理用药和中西药物相互作用研究中的应用。
       1  中草药对CYP3A4的影响
        中药配伍理论研究中，因为中药强调合并用药，方剂以复方为主，含有多种中药，因此中药配伍存在与P450酶有关的中药间相互作用的机会可能更多;同时中药不论其成分多么复杂，但在体内起作用的物质基础仍然属于化合物范畴，既然是化合物，则同样面临着机体对其的处置即P450酶的代谢。这样中药配伍就符合基于药物代谢酶产生药物相互作用的两个基本要素，即药物对P450酶产生影响，进一步受到影响的P450酶再作用于药物，改变药物的代谢特征，这就是基于P450酶的药物相互作用的分子基础。基于这种推论，我们对影响CYP3A4作用的中药进行总结。见表1。表1  中草药对CYP3A4的影响（略）
       2  中草药化学成分对CYP3A4的影响
        中药同西药相比向来被认为使用安全，不良反应少，但由于中药所含的化学成分复杂，因此对酶的影响更具多样性，所以对中草药成分对CYP3A4的影响进行总结。见表2。表2  中草药化学成分对CYP3A4的影响（略）
        通过对作用于细胞色素CYP3A4的中草药和化学成分总结，将会为临床中药物配伍提供参考，减少毒副作用，提高用药安全。
       【参考文献】
         　　［1］岩城正宏. 各种未成熟柑橘类果实对CYP3A4及P-糖蛋白活性的影响［J］. 国际中医中药杂志, 2006, 28(6):365.
       
       ［2］Subehan, Usia T, Iwata H, et al. Mechanism-based inhibition of CYP3A4 and CYP2D6 by Indonesian medicinal plants［J］. J. Ethnopharmacol., 2006, 105(3): 449.
       
       ［3］Venkataramanan R, Ramachandran V, Komoroski BJ, et a1, Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures［J］. Drug Metab. Dispos., 2000, 28(11):1270.
       
       ［4］Paolini M, Pozzetti L, Sapone A, et a1. Effect of licorice and glycyrrhizin on murine liver CYP-dependent monooxy-genases［J］. Life Sci., 1998, 62(6):571.
       
       ［5］Budzinski J, Foster B, Vandenhoek S, et al. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures［J］. Phytomedicine, 2000, 74:273.
       
       ［6］Pekthong D, Martin H, Abadie C, et al. Differential inhibition of rat and human hepatic cytochrome P450 by Andrographis paniculata extract and andrographolide［J］. J. Ethnopharmacol., 2008, 115(3): 432.
       
       ［7］贾敬亮，徐丽娜，杜金粱，等. 连翘苷对原代大鼠肝细胞CYP3A1的影响［J］. 黑龙江畜牧兽医, 2008,10:84.
       
       ［8］石井贤二, 等. 抑制CYP3A4活性的绿茶成分［J］. 国际中医中药杂志,2006,28(1):49.
       
       ［9］Fan L, Wang G, Wang LS, et al. Herbal medicine Yin Zhi Huang induces CYP3A4-mediated sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole［J］. Acta Pharmacol Sin, 2007, 28(10):1685.
       
       ［10］Uchida S, Yamada H, Li XD, et al. Effects of Ginkgo Biloba Extract on Pharmacokinetics and Pharmacodynamics of Tolbutamide and Midazolam in Healthy Volunteers［J］. J Clin Pharmacol, 2006, 46(11):1290.
       
       ［11］Liu KH, Kim MJ, Jeon BH, Shon JH, et al. Inhibition of human cytochrome P450 isoforms and NADPH-CYP reductase in vitro by 15 herbal medicines, including Epimedii herba［J］. J. Clin. Pharm. Ther., 2006, 31(1): 83.
       
       ［12］Anderson GD, Rosito G, Mohustsy MA, et al. Drug interaction potential of soy extract and Panax ginseng［J］. J. Clin. Pharmacol., 2003, 43(6):643.
       
       ［13］Hellum BH, Nilsen OG . In vitro inhibition of CYP3A4 metabolism and P-glycoprotein-mediated transport by trade herbal products［J］. Basic. Clin. Pharmacol. Toxicol., 2008, 102(5):466.
       
       ［14］岩城正宏. 各种未成熟柑橘类果实对CYP3A4及P-糖蛋白活性的影响［J］. 国际中医中药杂志, 2006, 28(6):365.
       
       ［15］董海燕, 邵敬伟, 王涛, 等. 四种抗癌中药提取物对大鼠肝CYP3A酶活性及mRNA表达的影响［J］. 中药材, 2008, 31(1):68.
       
       ［16］Usia T, Iwata H, Hiratsuka A, et al. CYP3A4 and CYP2D6 inhibitory activities of Indonesian medicinal plants［J］. Phytomedicine, 2006, 13(1-2): 67.
       
       ［17］Iwata H, Tezuka Y, Kadota S, et al. Metabolism-dependent inhibition of CYP3A4 and CYP2D6 by extracts from 26 herbal medicines［J］. J. Trad. Med., 2004, 21(6):281.
       
       ［18］Iwata H, Tezuka Y, Usia T, et al. Inhibition of human liver microsomal CYP3A4 and CYP2D6 by extracts from 78 herbal medicines［J］. J. Trad. Med., 2004, 21(1):42.
       
       ［19］Subehan, Zaidi SF, Kadota S, et al. Inhibition on human liver cytochrome P450 3A4 by constituents of fennel (Foeniculum vulgare): identification and characterization of a mechanism-based inactivator［J］. J. Agric. Food Chem., 2007, 55(25):10162.
       
       ［20］Piver B, Berthou F, Dreano Y, et al. Inhibition of CYP3A, CYP1A and CYP2E1 activities by resveratrol and other non volatile red wine components ［J］. Toxicol. Lett., 2001, 125(1-3):83.
       
       ［21］Yu C, Ye S, Sun H, Liu Y, et al. PXR-mediated transcriptional activation of CYP3A4 by cryptotanshinone and tanshinone IIA ［J］. Chem. Biol. Interact. 2009, 177(1):58.
       
       ［22］Subehan S, Kadota S, Tezuka Y. In vitro mechanism-based inactivation of cytochrome P450 3A4 by a new constituent of Cinnamomum burmani ［J］. Planta. Med., 2008, 74(12):1474.
       
       ［23］Girennavar B, Jayaprakasha GK, Patil BS. Potent inhibition of human cytochrome P450 3A4, 2D6, and 2C9 isoenzymes by grapefruit juice and its furocoumarins［J］. J. Food Sci., 2007, 72(8): C417.
       
       ［24］Ho PC, Saville DJ, Wanwimolruk S. Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds ［J］. J. Pharm. Pharm. Sci., 2001, 4(3):217.
       
       ［25］Tsukamoto S, Aburatani M, Yoshida T, et al. CYP3A4 inhibitors isolated from Licorice［J］. Biol. Pharm. Bull., 2005, 28(10):2000.
       
       ［26］Tsukamoto S, Aburatani M, Yoshida T, et al. CYP3A4 inhibitors isolated from Licorice［J］. Biol. Pharm. Bull., 2005, 28(10):2000.
       
       ［27］Lee JY, Duke RK, Tran VH, et al. Hyperforin and its analogues inhibit CYP3A4 enzyme activity ［J］. Phytochemistry, 2006, 67(23): 2550.
       
       ［28］Henderson GL, Harkey MR, Gershwin ME, et al. Effects of ginseng components on c-DNA-expressed cytochrome P450 enzyme catalytic activity［J］. Life Sci., 1999, 65(15):PL209.
       
       ［29］Bhardwaj RK, Glaeser H, Becquemont L, et al. Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4 ［J］. J. Pharmacol. Exp. Ther., 2002, 302(2):645.
       
       ［30］Subehan, Usia T, Kadota S, et al. Constituents of Zingiber aromaticum and their CYP3A4 and CYP2D6 inhibitory activity ［J］. Chem. Pharm. Bull. (Tokyo), 2005, 53(3):333.
       
       ［31］Dreiseitel A, Schreier P, Oehme A , et al. Anthocyanins and their metabolites are weak inhibitors of cytochrome P450 3A4 ［J］. Mol. Nutr. Food Res., 2008, 52(12) :1428.
       
       ［32］Singh YN. Potential for interaction of kava and St. John"s wort with drugs［J］. J. Ethnopharmacol., 2005, 100(1-2): 108.
       
       ［33］Appiah-Opong R, Commandeur JN, van Vugt-Lussenburg B, et al. Inhibition of human recombinant cytochrome P450s by curcumin and curcumin decomposition products ［J］. Toxicology, 2007, 235(1-2):83.
       
       ［34］Chow HH, Hakim IA, Vining DR, et al. Effects of repeated green tea catechin administration on human cytochrome P450 activity ［J］. Cancer Epidemiol. Biomarkers Prev., 2006, 15(12): 2473.
       
       ［35］Ganzera M, Schneider P, Stuppner H. Inhibitory effects of the essential oil of chamomile (Matricaria recutita L.) and its major constituents on human cytochrome P450 enzymes ［J］. Life Sci., 2006, 78(8): 856.
       
       ［36］Takahashi E, Fujita K, Kamataki T, et al. Inhibition of human cytochrome P450 1B1, 1A1 and 1A2 by antigenotoxic compounds, purpurin and alizarin［J］. Mutat. Res., 2002, 508(1-2):147.
       
       ［37］Julsing MK, Vasilev NP, Schneidman-Duhovny D, et al. Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation［J］. Eur. J. Med. Chem., 2008, 43(6): 1171.
       
       ［38］He N, Edeki T. The inhibitory effects of herbal components on CYP2C9 and CYP3A4 catalytic activities in human liver microsomes ［J］. Am. J. Ther., 2004, 11(3): 206.
       
       ［39］Liu Y, Ma H, Zhang JW, et al. Influence of ginsenoside Rh1 and F1 on human cytochrome p450 enzymes［J］. Planta. Med., 2006, 72(2): 126.
       
       ［40］Henderson GL, Harkey MR, Gershwin ME, et al. Effects of ginseng components on c-DNA-expressed cytochrome P450 enzyme catalytic activity［J］. Life Sci., 1999, 65(15):PL209.
       
       ［41］Subehan, Zaidi SF, Kadota S, et al. Inhibition on human liver cytochrome P450 3A4 by constituents of fennel (Foeniculum vulgare): identification and characterization of a mechanism-based inactivator ［J］. J. Agric. Food Chem., 2007, 55(25):10162.
       
       ［42］Appiah-Opong R, Commandeur JN, van Vugt-Lussenburg B, et al. Inhibition of human recombinant cytochrome P450s by curcumin and curcumin decomposition products［J］. Toxicology, 2007, 235(1-2):83.
       
       ［43］Zhang FF, Zheng YF, Zhu HJ, et al. Effects of kaempferol and quercetin on cytochrome 450 activities in primarily cultured rat hepatocytes［J］. Zhe jiang Da Xue Xue Bao Yi Xue Ban, 2006, 35(1): 18.
       
       ［44］Usia T, Watabe T, Kadota S, et al. Mechanism-based inhibition of CYP3A4 by constituents of Zingiber aromaticum ［J］. Biol. Pharm. Bull., 2005, 28(3):495.
       
       ［45］Tsukamoto S, Tomise K, Aburatani M, et al. Isolation of cytochrome P450 inhibitors from strawberry fruit, Fragaria ananassa ［J］. J. Nat. Prod., 2004, 67(11): 1839.
       
       ［46］Fuhr U, Beckmann-Knopp S, Jetter A, et al. The effect of silymarin on oral nifedipine pharmacokinetics［J］. Planta. Med., 2007, 73(14):1429.
       
       ［47］Chatterjee P, Franklin MR. Human cytochrome p450 inhibition and metabolic-intermediate complex formation by goldenseal extract and its methylenedioxyphenyl components［J］. Drug Metab. Dispos., 2003, 31(11):1391.
       
       ［48］Li L, Stanton JD, Tolson AH, et al. Bioactive Terpenoids and Flavonoids from Ginkgo Biloba Extract Induce the Expression of Hepatic Drug-Metabolizing Enzymes through Pregnane X Receptor, Constitutive Androstane Receptor, and Aryl hydrocarbon Receptor-Mediated Pathways［J］. Pharm. Res., 2009, 26(4)：872.
       
       ［49］Qiu F, Zhang R, Sun J et al. Inhibitory effects of seven components of danshen extract on catalytic activity of cytochrome P450 enzyme in human liver microsomes［J］. Drug Metab. Dispos., 2008, 36(7):1308.
       
       ［50］Row EC, Brown SA, Stachulski AV, et al. Design, synthesis and evaluation of furanocoumarin monomers as inhibitors of CYP3A4 ［J］. Org. Biomol. Chem., 2006, 4(8):1604.
       
       ［51］Wen YH, Sahi J, Urda E, et al. Effects of bergamottin on human and monkey drug-metabolizing enzymes in primary cultured hepatocytes［J］. Drug Metab. Dispos., 2002, 30(9):977.
       
       ［52］Fan L, Wang G, Wang LS, et al. Herbal medicine Yin Zhi Huang induces CYP3A4-mediated sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole［J］. Acta Pharmacol Sin, 2007, 28(10):1685.
       
       ［53］Ganzera M, Schneider P, Stuppner H. Inhibitory effects of the essential oil of chamomile (Matricaria recutita L.) and its major constituents on human cytochrome P450 enzymes［J］. Life Sci., 2006, 78(8): 856.
       
       ［54］Usia T, Iwata H, Hiratsuka A, et al. Sesquiterpenes and flavonol glycosides from Zingiber aromaticum and their CYP3A4 and CYP2D6 inhibitory activities［J］. J. Nat. Prod., 2004, 67(7): 1079.
       
       ［55］Row E, Brown SA, Stachulski AV, et al. Development of novel furanocoumarin dimers as potent and selective inhibitors of CYP3A4［J］. Drug Metab. Dispos., 2006, 34(2): 324.
       
       ［56］Fukuda K, Ohta T, Oshima Y, et al. Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimers as components of drug interaction［J］. Pharmacogenetics, 1997, 7(5):391.
       
       ［57］Usia T, Watabe T, Kadota S, et al. Potent CYP3A4 inhibitory constituents of Piper cubeba ［J］. J. Nat. Prod., 2005, 68(1):64.
       
       ［58］Su CR, Ueng YF, Dung NX, et al. Cytochrome P3A4 inhibitors and other constituents of Fibraurea tinctoria［J］. J. Nat. Prod., 2007, 70(12): 1930.
       
       ［59］Liu Y, Zhang JW, Li W, et al. Ginsenoside metabolites, rather than naturally occurring ginsenosides, lead to inhibition of human cytochrome P450 enzymes［J］. Toxicol. Sci., 2006, 91(2): 356.
       
       ［60］Yoo HH, Lee SH, Jin C, et al. Mechanism-based inactivation of cytochrome P450 3A4 by methylenedioxyphenyl lignans from Acanthopanax chiisanensis［J］.Planta. Med., 2008, 74(8):822.
       
       ［61］Lichti-Kaiser K, Staudinger JL. The traditional Chinese herbal remedy tian xian activates pregnane X receptor and induces CYP3A gene expression in hepatocytes. Drug Metab. Dispos., 2008, 36(8):1538.