何首乌中二蒽酮类成分肝毒性研究

目的：以胆红素代谢过程中UDP-葡萄糖醛酸转移酶1A1（UGT1A1酶）介导的胆红素葡萄糖醛酸结合环节为切入点，考察何首乌中二蒽酮及蒽酮糖苷成分的肝毒性。方法：以胆红素为UGT1A1酶底物，以表观抑制常数Ki为评价指标，采用体外大鼠肝微粒体孵育法测定待测单体成分肝毒性有无及大小，并寻找构效关系。结果：待测单体成分在大鼠肝微粒体（RLM）体系中对UGT1A1酶的抑制由强至弱的顺序为：顺式-大黄素-大黄素二蒽酮（强抑制），反式-大黄素-大黄素二蒽酮（强抑制），polygonumnolide C2（强抑制），polygonumnolide C3（中等强度抑制），polygonumnolide C4（弱抑制），且存在构效关系，推测6（6'）-羟基为活性必需基团，其空间暴露程度可影响其与UGT1A1酶的结合，导致不同程度的抑制作用。结论：本实验初步探讨了何首乌中二蒽酮类成分潜在肝毒性的作用机理，为研究毒性中药提供了新的思路。

Objective:To study the hepatotoxicity of dianthrones in Polygoni Multiflori Radix on the basis of the bilirubin metabolism mediated by glucuronidation of UDP-glucuronosyltransferases 1A1 (UGT1A1 enzyme).Methods:Using bilirubin as the UGT1A1 enzyme substrate and the apparent inhibition constant Ki as the evaluation index,the hepatotoxicity was tested by adding the monomers into the rat liver microsomes.And the structure-activity relationship (SAR) was investigated.Results:The order of the inhibition of UGT1A1 enzyme in the system of rat liver microsomes(RLM)was as follows:cis-emodin dianthrones(strong inhibition),trans-emodin dianthrones (strong inhibition),polygonumnolide C2(strong inhibition),polygonumnolide C3(moderate inhibition),polygonumnolide C4(weak inhibition).And structure-activity relationship was found.It was presumed that the 6 (6')-position hydroxyl group was an active and necessary group,whose spatial exposure directly affected the combination with UGT1A1 enzyme to induce different inhibition.Conclusion:The mechanism of potential hepatotoxicity of dianthrones in Polygoni Multiflori Radix was discussed in this study,thus providing a new idea for the study of toxic traditional Chinese medicine.