Wang Liping, Chen Qingwei, Zhu Lijun, Li Qiang, Zeng Xuejun, Lu Linlin, Hu Ming, Wang Xinchun, Liu Zhongqiu
First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, PR China (L.W., Q.C., X.Z., X.W.); International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China (L.W., L.Z., L.L., M.H., Z.L.); Department of Pharmacy, Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China (Q.L.); and College of Pharmacy, University of Houston, Houston, Texas (M.H.).
First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, PR China (L.W., Q.C., X.Z., X.W.); International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China (L.W., L.Z., L.L., M.H., Z.L.); Department of Pharmacy, Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China (Q.L.); and College of Pharmacy, University of Houston, Houston, Texas (M.H.)
Drug Metab Dispos. 2017 Mar;45(3):306-315. doi: 10.1124/dmd.116.073619. Epub 2016 Dec 28.
Luteolin partially exerts its biologic effects via its metabolites catalyzed by UDP-glucuronosyltransferases (UGTs) and catechol-O-methyltransferases (COMTs). However, the interplay of UGTs and COMTs in mediating luteolin disposition has not been well clarified. In this study, we investigated the glucuronidation and methylation pathways of luteolin mediated by the interplay of UGTs and COMTs in vivo and in vitro. A total of nine luteolin metabolites was detected in rat plasma and bile by liquid chromatography-tandem mass spectrometry, namely, three glucuronides, two methylated metabolites, and four methylated glucuronides. Luteolin-3'-glucuronide (Lut-3'-G) exhibited the highest systemic exposure among these metabolites. Kinetics studies in rat liver S9 fractions suggested two pathways, as follows: 1) Luteolin was glucuronidated to luteolin-7-glucuronide, luteolin-4'-glucuronide, and Lut-3'-G by UGTs, and then Lut-7-G was methylated to chrysoeriol-7-glucuronide and diosmetin-7-glucuronide by COMTs. 2) Alternatively, luteolin was methylated to chrysoeriol and diosmetin by COMTs, and then chrysoeriol and diosmetin were glucuronidated by UGTs to their respective glucuronides. The methylation rate of luteolin was significantly increased by the absence of glucuronidation, whereas the glucuronidation rate was increased by the absence of methylation, but to a lesser extent. In conclusion, two pathways mediated by the interplay of UGTs and COMTs are probably involved in the metabolic disposition of luteolin. The glucuronidation and methylation of luteolin compensate for each other, although glucuronidation is the predominant pathway.
木犀草素部分通过由尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）和儿茶酚-O-甲基转移酶（COMTs）催化产生的代谢产物发挥其生物学效应。然而，UGTs和COMTs在介导木犀草素代谢过程中的相互作用尚未得到充分阐明。在本研究中，我们在体内和体外研究了UGTs和COMTs相互作用介导的木犀草素的葡萄糖醛酸化和甲基化途径。通过液相色谱-串联质谱法在大鼠血浆和胆汁中总共检测到9种木犀草素代谢产物，即3种葡萄糖醛酸苷、2种甲基化代谢产物和4种甲基化葡萄糖醛酸苷。在这些代谢产物中，木犀草素-3'-葡萄糖醛酸苷（Lut-3'-G）表现出最高的全身暴露量。在大鼠肝脏S9组分中的动力学研究表明存在两条途径，如下：1）木犀草素被UGTs葡萄糖醛酸化生成木犀草素-7-葡萄糖醛酸苷、木犀草素-4'-葡萄糖醛酸苷和Lut-3'-G，然后Lut-7-G被COMTs甲基化生成芹菜素-7-葡萄糖醛酸苷和香叶木素-7-葡萄糖醛酸苷。2）或者，木犀草素被COMTs甲基化生成芹菜素和香叶木素，然后芹菜素和香叶木素被UGTs葡萄糖醛酸化生成它们各自的葡萄糖醛酸苷。木犀草素的甲基化率在没有葡萄糖醛酸化时显著增加，而葡萄糖醛酸化率在没有甲基化时增加，但程度较小。总之，UGTs和COMTs相互作用介导的两条途径可能参与了木犀草素的代谢过程。木犀草素的葡萄糖醛酸化和甲基化相互补偿，尽管葡萄糖醛酸化是主要途径。
