汉黄芩素和汉黄芩苷对UGT1A1体外抑制活性的比较研究  

Comparative Study on Inhibition Effects of Wogonin and Wogonoside against UDP-glucuronosyltransferase 1A1(UGT1A1)in Vitro

作　　者：白荣[1,2] 白洪越 孔水仙 陈晔 吕侠 BAI Rong;BAI Hongyue;KONG Shuixian;CHEN Ye;LV Xia(Department of Pharmacy,Shanghai East Hospital,Tongji University,Shanghai 200120;College of Integrative Medicine,Dalian Medical University,Dalian,Liaoning 116044;Key Laboratory of Biotechnology and Bioresources Utilization,Ministry of Education,College of Life Science,Dalian Minzu University,Dalian,Liaoning 116600;Sanlinkangde Community Health Service Center,Pudong New Area,Shanghai 200120)

机构地区：[1]同济大学附属东方医院药学部,上海200120 [2]大连医科大学中西医结合研究院,辽宁大连116044 [3]大连民族大学生命科学学院,生物技术与资源利用教育部重点实验室,辽宁大连116600 [4]上海市浦东新区三林康德社区卫生服务中心,上海200124

出　　处：《中国中医药科技》2020年第5期707-711,共5页Chinese Journal of Traditional Medical Science and Technology

基　　金：国家自然科学基金项目(81703606);上海市“医苑新星”青年医学人才临床药师项目。

摘　　要：目的:考察人体尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)的活性受汉黄芩素和汉黄芩苷抑制作用的强弱,并通过体内-体外外推(IV-IVE)方法对汉黄芩素在人体内引发草物-药物相互作用(HDI)的风险进行预测。方法:以混合人肝微粒体(HLMs)及重组表达UGT1A1作为酶源,UGT1A1酶的特异性荧光探针N-3-羧丙基-4-羟基-1,8-萘酰亚胺(NCHN)为底物,对人体UGT1A1酶受汉黄芩素和汉黄芩苷的抑制作用进行评估。通过非线性拟合优度R 2判断出抑制类型,求出半数最大抑制浓度IC 50和抑制动力学常数K i,并对汉黄芩素在人体内引发HDI的风险进行预测。结果:汉黄芩素对UGT1A1催化NCHN-O-葡萄糖醛酸化的抑制作用较为强烈,抑制类型为非竞争性抑制,求得的IC 50和K i值分别为2.53μmol·L^-1和1.60μmol·L^-1,而汉黄芩苷对UGT1A1活性的抑制能力较弱。此外,体外-体内外推(IV-IVE)方法的预测结果表明口服汉黄芩素可引起UGT1A1底物血浆药时曲线下面积增加6.6%~59.6%。结论:汉黄芩素有可能通过抑制UGT1A1的活性引发临床不良HDI的发生,为合理使用含汉黄芩素和汉黄芩苷的中草药与临床药物提供了理论指导。Objective:To investigate the inhibitory effects of Wogonin and Wogonoside on the activity of human UGT1A1,and to predict the risk of human herb-drug interaction(HDI)induced by Wogonin by in vitro-in vivo extrapolation(IV-IVE)method.Methods:Recombinant human UGT1A1 and human liver microsome(HLMs)as well as N-3-carboxypropyl-4-hydroxy-1,8-naphthalimide(NCHN)(UGT1A1 specific fluorescent probe substrate)were used to characterize the inhibitory effects of Wogonin and Wogonoside on human UGT1A1 in vitro.The inhibition type was determined by nonlinear goodness of fit(R 2),the IC50 and the inhibition kinetic constant(K i)were calculated,and the risk of human HDI induced by Wogonin was predicted.Results:The inhibitory effect of Wogonin on UGT1A1 catalyzed NCHN-O-glucuronidation was stronger than that of Wogonoside.The IC 50 and K i values were 2.53μmol·L^-1 and 1.60μmol·L^-1,respectively.The inhibitory effect of Wogonoside on UGT1A1 was weaker than that of Wogonin.In Addition,the prediction results of IV-IVE method showed that oral administration of Wogonin could increase the plasma area under the time curve of UGT1A1 substrate by 6.6%~59.6%.Conclusion:Wogonin might induce clinical adverse HDI by inhibiting the activity of UGT1A1,It provides theoretical guidance for the rational use of Chinese herbal medicine and clinical drugs containing Wogonin and Wogonoside.

关 键 词：汉黄芩素 汉黄芩苷 尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1) 抑制作用 体内外推 草药-药物相互作用(HDI) 

分 类 号：R285[医药卫生—中药学]