title: Identification of key licorice constituents which interact with cytochrome P450: evaluation by LC/MS/MS cocktail assay and metabolic profiling.
abstract: Licorice has been shown to affect the activities of several cytochrome P450 enzymes. This study aims to identify the key constituents in licorice which may affect these activities. Bioactivity assay was combined with metabolic profiling to identify these compounds in several complex licorice extracts. Firstly, the inhibition potencies of 40 pure licorice compounds were tested using an liquid chromatography/tandem mass spectrometry cocktail method. Significant inhibitors of human P450 isozymes 1A2, 2C9, 2C19, 2D6, and 3A4 were then selected for examination of their structural features by molecular docking to determine their molecular interaction with several P450 isozymes. Based on the present in vitro inhibition findings, along with our previous in vivo metabolic studies and the prevalence of individual compounds in licorice extract, we identified several licorice constituents, viz., liquiritigenin, isoliquiritigenin, together with seven isoprenylated flavonoids and arylcoumarins, which could be key components responsible for the herb-drug interaction between cytochrome P450 and licorice. In addition, hydrophilic flavonoid glycosides and saponins may be converted into these P450 inhibitors in vivo. These studies represent a comprehensive examination of the potential effects of licorice components on the metabolic activities of P450 enzymes.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Qiao
authors.forename: Shuai
authors.initials: S
authors.lastname: Ji
authors.forename: Si-Wang
authors.initials: SW
authors.lastname: Yu
authors.forename: Xiong-Hao
authors.initials: XH
authors.lastname: Lin
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Jin
authors.forename: Yao-Kai
authors.initials: YK
authors.lastname: Duan
authors.forename: Liang-Ren
authors.initials: LR
authors.lastname: Zhang
authors.forename: De-An
authors.initials: DA
authors.lastname: Guo
authors.forename: Min
authors.initials: M
authors.lastname: Ye
mesh_terms: D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006035:Glycyrrhiza / Q000737:chemistry*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D062105:Molecular Docking Simulation; D010936:Plant Extracts / Q000737:chemistry; D053719:Tandem Mass Spectrometry
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D010936:Plant Extracts; D003577:Cytochrome P-450 Enzyme System