基于UGTIA1抑制作用考察大黄素肝毒性作用  

Study on the hepatotoxicity of emodin based on the inhibition of UGT1A1 enzyme

作　　者：汪祺[1] 杨建波[1] 刘越[1] 文海若 马双成[1] WANG Qi;YANG Jian-bo;LIU Yue;WEN;Hai-ruo;MA Shuang-cheng(National Institutes for Food and Drug Control,Beijing 100050,China)

机构地区：[1]中国食品药品检定研究院

出　　处：《药物分析杂志》2019年第7期1177-1184,共8页Chinese Journal of Pharmaceutical Analysis

基　　金：国家自然科学基金(81503347,81773874)

摘　　要：目的:以胆红素代谢过程中UDP-葡萄糖醛酸转移酶1A1(UGT1A1)介导的胆红素葡萄糖醛酸结合环节为切入点,评价大黄素潜在肝毒性风险。方法:以胆红素为UCGT1A1底物,以表观抑制常数Ki为评价指标,采用体外肝微粒体孵育法,启动Ⅱ相代谢反应,考察大黄素原型成分的抑制作用,启动Ⅰ、Ⅱ相代谢反应,考察代谢产物及原型成分的综合抑制作用。结果:仅启动Ⅱ相反应时,大黄素以原型形式直接作用于UGT1A1,表现为中强抑制,抑制类型为竞争型抑制;同时启动Ⅰ、Ⅱ两相反应时,大黄素对UGTIA1的抑制作用转为弱抑制,提示大黄素存在Ⅰ相代谢过程,并且其Ⅰ相代谢产物对UGT1A1抑制作用较弱。结论:本实验初步证明大黄素原型对UGTIA1存在抑制作用,经由Ⅰ相代谢后抑制作用降低,肝毒性风险降低。Objective:To evaluate the potential hepatotoxicity of emodin on the basis of the bilirubin glucuronic acid binding mediated by UDP-glucuronosyltransferase 1 A1(UGT1 A1)during the process of bilirubin metabolism.Methods:The phase Ⅱ metabolic reaction was initiated by adopting bilirubin as the substrate of UGT1 A1 and the in vitro microsome incubation methods,while the apparent inhibition constant Ki was used as the evaluation index.The phase Ⅰ and Ⅱ metabolic reactions were simultaneously initiated to investigate the combined inhibition effects from metabolites and prototype components.Results:Emodin directly acted on UGT1 A1 in the form of a prototype and demonstrated a moderate competitive inhibition,when only the phase Ⅱ reaction was initiated;whereas the inhibitory effect of emodin was weaken when both phase Ⅰ and Ⅱ reactions were initiated,suggesting the participation of emodin in phase Ⅰ metab olic process,and the inhibitory effect of its phase Ⅰmetabolites on UGT1 A1 was weaker.Conclusion:This experiment preliminarily proves that the emodin prototype could inhibit UGT1 A1,which is reduced after phase Ⅰ metabolism,and the hepatotoxicity risk is decreased corespondingly.

关 键 词：大黄素 蒽醌 胆红素 内源性物质 UDP-葡萄糖醛酸转移酶1A1(UGT1A1) 大鼠肝微粒体(RLM) 肝代谢 代谢产物 

分 类 号：R917[医药卫生—药物分析学]