title: C5-hydroxylation of liquiritigenin is catalyzed selectively by CYP1A2.
abstract: Liquiritigenin (7,4'-dihydroxyflavone), the primary active component of a traditional Chinese medicine Glycyrrhizae radix, has a wide range of pharmacological activities. Six oxidative metabolites of liquiritigenin (7,3',4'-trihydroxyflavone, a hydroxyl quinine metabolite, two A-ring dihydroxymetabolites, 7,4'-dihydroxyflavone, and 7-hydroxychromone) have been detected in rat liver microsomes (RLMs), and one CYP3A4-catalyzed metabolite (7,4'-dihydroxyflavone) has been identified in human liver microsomes (HLMs) recently. In this study, a novel mono-hydroxylated metabolite was detected in reaction catalyzed by HLMs, and was identified as 4',5,7-trihydroxyflavanone by comparing the tandem mass spectra and the chromatographic retention time with that of the standard compound. Significant difference in CL(int) (9-fold) was found between these two oxidative pathways of liquiritigenin, and C5-hydroxylation pathway was identified as the major oxidative metabolism of liquiritigenin. The study with chemical selective inhibitor, cDNA-expressed human CYPs, correlation assay, and kinetic study demonstrated that CYP1A2 was the specific isozyme responsible for the C5-hydroxylation metabolism of liquiritigenin in HLMs.
authors.affiliation: The Second Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Ao-Xue
authors.initials: AX
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Hui-Xin
authors.initials: HX
authors.lastname: Liu
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Qi
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Cai-Xia
authors.initials: CX
authors.lastname: Tu
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D000328:Adult; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D002244:Carbon / Q000378:metabolism*; D002853:Chromatography, Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044950:Flavanones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D007700:Kinetics; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D044950:Flavanones; D011994:Recombinant Proteins; D002244:Carbon; D019388:Cytochrome P-450 CYP1A2; C083152:liquiritigenin