Cho Pil Joung, Kim Ju-Hyun, Lee Hye Suk, Kim Jeong Ah, Lee Sangkyu
BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
Biopharm Drug Dispos. 2019 Feb;40(2):94-98. doi: 10.1002/bdd.2169. Epub 2019 Feb 4.
Licoricidin is a major prenylated isoflavone of Glycyrrhiza uralensis Fisch. (Leguminosae), and its pharmacological effects have been reported frequently. Typically, flavonoids having multiple hydroxyl groups are unambiguous substrates for glucuronyl conjugation by UDP-glucuronosyltransferases (UGTs). The pharmacological effects of flavonoids are derived from the conjugation of glucuronide to yield the bioactive metabolite. Here, the metabolism of licoricidin in pooled human liver microsomes (HLMs) was investigated using high-resolution quadrupole-orbitrap mass spectrometry. One metabolite (M1) was identified in HLMs after incubation with licoricidin in the presence of uridine 5'-diphosphoglucuronic acid (UDPGA) and NADPH. The structure of M1 was determined as a monoglucuronyl licoricidin, which was selectively produced by UGT1A9. Licoricidin showed a higher metabolic ratio and rapid metabolism with the recombinant human UGT1A9 than mycophenolic acid, a well-known UGT1A9 substrate. In conclusion, the selective formation of 7-glucuronyl licoricidin by UGT1A9 in HLMs could serve as a new selective substrate to determine the activity of UGT1A9 in vitro.
甘草定是甘草（豆科）中一种主要的异戊烯基化异黄酮，其药理作用已有诸多报道。通常，具有多个羟基的黄酮类化合物是尿苷二磷酸葡萄糖醛酸转移酶（UGTs）进行葡萄糖醛酸结合反应的明确底物。黄酮类化合物的药理作用源于葡萄糖醛酸结合生成生物活性代谢物。在此，利用高分辨率四极杆-轨道阱质谱法研究了甘草定在人肝微粒体（HLMs）中的代谢情况。在尿苷5'-二磷酸葡萄糖醛酸（UDPGA）和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）存在的情况下，将甘草定与HLMs孵育后，鉴定出一种代谢物（M1）。M1的结构确定为单葡萄糖醛酸甘草定，它是由UGT1A9选择性产生的。与已知的UGT1A9底物霉酚酸相比，甘草定与重组人UGT1A9表现出更高的代谢率和更快的代谢速度。总之，HLMs中UGT1A9选择性形成7-葡萄糖醛酸甘草定可作为一种新的选择性底物，用于体外测定UGT1A9的活性。
