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Study of Inhibitory Effects of Quercetin and its Major Metabolite Q3GA on Human UDP-glucuronosyltransferase 1A Isoforms by Liquid Chromatography-tandem Mass Spectrometry

Rui Zhang;Ye Wei;Tingyu Yang;Xixi Huang;Jinping Zhou;Chunxiao Yang;Jiani Zhou;Yani Liu;Shaojun Shi

  Quercetin is a flavonoid compound that is widely present in plant-derived food.Quercetin?3?O?β?D?glucoside(Q3 GA) is a predominant metabolite of quercetin in animal and human plasma. The inhibitory effect of UDP-glucuronosyltransferase enzymes(UGTs) by herbal components might be a key factor for clinical herb-drug interaction. In this paper, we aim at investigating the inhibition profile of quercetin and Q3 GA on recombinant UGT1 A isoforms in vitro through the use of nonspecific substrate 4-methylumbelliferone(4-MU) and liquid chromatography-tandem mass spectrometry(LC-MS/MS). Preliminary screening experiment showed that both quercetin and Q3 GA exhibited strong inhibition on UGT1 A1, UGT1 A3, UGT1 A6 and UGT1 A9 except for the weak inhibitory effect of Q3 GA on UGT1 A9. Kinetic experiments were also performed to characterize the inhibition of quercetin and Q3 GA towards these UGT isoforms. Quercetin exerted the noncompetitive inhibition towards UGT1 A1, UGT1 A6, with a half maximal inhibitory concentration(IC50) value of 7.47 and 7.07 μM, and an inhibition kinetic parameter(Ki) value of 2.18 and 28.87 μM, respectively. It also showed mixed inhibition towards UGT1 A3 with an IC50 value of 10.58 μM and a Ki value of 1.60 μM, and competitive inhibition towards UGT1 A9 with an IC50 value of 2.81 μM and a Ki value of 0.51 μM. While Q3 GA displayed negligible inhibition towards UGT1 A1, UGT1 A3 and UGT1 A6 with an IC50 value of 45.21, 106.5 and 51.37 μM, respectively. In this study, we found that the inhibitory ability of quercetin on UGT1 A1, 1 A3, 1 A6, 1 A9 were widely more potent than that of Q3 GA, and herb-drug interaction might occur when quercetin was co-administered with drugs that mainly are metabolized by UGT1 A1, UGT1 A3, UGT1 A6 and UGT1 A9.……