紫草素对UGT1A1*1和UGT1A1*6催化SN-38葡萄糖醛酸化的抑制作用研究  

Inhibitory effect of shikonin on SN-38 glucuronidation catalyzed by UGT1A1*1 and UGT1A1*6

作　　者：陈银楠 刘勇[2] 陈悦悦 李巍 CHEN Yinnan;LIU Yong;CHEN Yueyue;LI Wei(Translational Medicine Research Institute,College of Medicine,Yangzhou University,Jiangsu Province,Yangzhou225009,China;School of Life and Pharmaceutical Sciences,Dalian University of Technology,Liaoning Province,Dalian124221,China)

机构地区：[1]扬州大学医学院转化医学研究院,江苏扬州225009 [2]大连理工大学生命科学与药学学院,辽宁大连124221

出　　处：《中国当代医药》2022年第27期20-24,共5页China Modern Medicine

基　　金：江苏省扬州市级计划社会发展项目(YZ2020084)。

摘　　要：目的比较紫草素对野生型UDP-葡萄糖苷酸转移酶1A1(UGT1A1*1)及其在亚洲人群中常见的单核苷酸突变UGT1A1*6催化SN-38葡萄糖醛酸化抑制作用的差异。方法采用超高效液相色谱-串联质谱(UPLC-MS/MS)法检测SN-38代谢产物SN-38葡萄糖醛酸酯(SN-38G)的生成速率,利用酶剩余活性的变化评价紫草素对UGT1A1*1和UGT1A1*6催化SN-38代谢的抑制作用。非线性回归计算获得紫草素在UGT1A1*1和UGT1A1*6体系中对SN-38G的半抑制浓度(IC50)。结果紫草素(1、10、100μmol/L)可使UGT1A1*1和UGT1A1*6催化SN-38葡萄糖醛酸化的反应速率均低于对照组(未加紫草素),差异有统计学意义(P<0.05)。其对UGT1A1*1和UGT1A1*6活性的IC50分别为4.357μmol/L和7.353μmol/L。结论紫草素可能通过抑制UGT1A1,进而降低前药伊立替康活性形式SN-38的代谢清除,从而造成草药-药物相互作用。因此,临床用药中应避免紫草素制剂与伊立替康的联合用药,以避免SN-38在体内积累引发临床不良发应。Objective To compare the inhibitory effects of shikonin on SN-38 glucuronidation catalyzed by wild-type UDP-glucuronosyltransferase 1A1(UGT1A1*1)and its common single nucleotide variant UGT1A1*6 in Asian population.Methods The production rate of SN-38 glucuronides(SN-38G),the metabolite of SN-38,was detected by ultra-performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS).The inhibitory effects of shikonin on the metabolism of SN-38 catalyzed by UGT1A1*1 and UGT1A1*6 were evaluated by the change of the residual activity of the enzymes.The half-maximal inhibitory concentration(IC50)of shikonin on SN-38G in UGT1A1*1 and UGT1A1*6 systems was calculated by nonlinear regression.Results The reaction rates of UGT1A1*1 and UGT1A1*6 catalyzed SN-38 glucuronidation by shikonin(1,10,100μmol/L)were lower than those of the control group,with statistical significances(P<0.05).The IC50 of shikonin on UGT1A1*1 and UGT1A1*6 were 4.357μmol/L and 7.353μmol/L,respectively.Conclusion Shikonin may cause herbal drug interaction by inhibiting UGT1A1,and thereby reduce the metabolic clearance SN-38,which is the active form of the prodrug irinotecan.Thus,the combination of shikonin and irinotecan should be avoided in clinical practices to prevent the accumulation of SN-38 in the body and the consequent adverse reactions.

关 键 词：SN-38 紫草素 UGT1A*1 UGT1A1*6 药物相互作用 

分 类 号：R555[医药卫生—血液循环系统疾病]