8种五味子木脂素类化合物对羧酸酯酶2的抑制作用  

Inhibitiory effect of eight lignan compounds of Fructus Schisandrae chinensis on carboxylesterase 2

作　　者：李洁[1,2] 舒恒[3] 姜永珊[3] 吴敬敬[4] 金强[4] 胡晋红[1] 

机构地区：[1]第二军医大学附属长海医院药学部,上海200433 [2]上海中医药大学附属第七人民医院药学部,上海200137 [3]大连医科大学中西医结合系,辽宁大连116044 [4]中国科学院大连化学物理研究所药用资源开发研究组,辽宁大连116023

出　　处：《中国药理学与毒理学杂志》2017年第4期340-345,共6页Chinese Journal of Pharmacology and Toxicology

基　　金：国家自然科学基金(81672961);上海市第七人民医院人才培养计划(XX2015-04)~~

摘　　要：目的考察8种五味子木脂素类化合物体外对羧酸酯酶2(CES2)活性的抑制作用,并对CES2强抑制剂进行草药-药物相互作用(HDI)风险预估。方法采用荧光素二乙酸酯(FD)作为CES2的特异性荧光探针底物,加入人肝微粒体(HLM),将8种五味子来源的化合物单体五味子甲素、五味子酚、五味子酯戊、五味子醇甲、五味子醇乙、戈米辛J、戈米辛G和戈米辛O,分别与FD在37℃条件下共同孵育10 min,以DMSO作为对照,荧光酶标仪测定孵育液中FD代谢产物荧光素的生成量,计算残余活性及半数抑制浓度(IC_(50)),进一步进行体内的HDI风险预估。结果五味子甲素和五味子酚在100μmol·L^(-1)浓度下可使CES2残余活性分别降至DMSO对照组的14.5%和15.3%(P<0.01),其IC_(50)为8.06和8.91μmol·L^(-1),其余6种木脂素对CES2抑制作用较弱;HDI风险预测结果表明,五味子甲素或五味子酚与CES2底物共用时,引起药物暴露水平分别增加11.24倍和0.40倍。结论五味子甲素和五味子酚对CES2具有强抑制作用,联合使用五味子相关中药制剂时,需要警惕HDI风险的发生,防止出现血药浓度大幅增加而诱发药物不良反应。OBJECTIVE To investigate the inhibitory effect of eight lignan compounds of Fructus Schisandrae chinensis in vitro on carboxylesterase 2 （CES2） and to estimate the herb-drug interaction （HDI） risks of strong CES2 inhibitors selected from the above compounds. METHODS Fluorescein diacetate （FD） was employed as a specific fluorescent probe of CES2. The residual activity of CES2 was detected in human liver microsomes after the intervention with deoxyschizandrin, schisanhenol, schisantherin E, schisandrol A, schisandrol B, gomisin J, gomisin G, and gomisin O at 37℃ for 10 rain, respectively. 1% DMSO served as control. Residual activity of CES2 was assessed with metabolite production of FD detected by fluorescent intensity, combined with IC50 values of the above compounds to predict HDI risks between lignans and CES2-metabolizing drugs. RESULTS Compared with control group, the activity of CES2 was significantly inhibited by deoxyschizandrin and schisanhenol （P〈0.01）, with ICso values of 8.06 μmol·L-1 and 8.91μmol. L1, respectively. The other six lignans compounds exhibited mild inhibitory effect on CES2. HDI risk prediction of deoxyschizandrin or schisanhenol indicated that exposure of CES2-metabolizing drugs might increase 11.24 and 0.40 times, respectively. CONCLUSION Deoxyschizandrin and schisanhenol exhibit strong inhibitory effects against CES2 in vitro so that potential HDI risks should be taken into account during administration of drugs containing Fructus Schisandrae chinensis.

关 键 词：五味子木脂素 羧酸酯酶2 草药-药物相互作用 减毒增效 

分 类 号：R285[医药卫生—中药学]