In vitro metabolism of isoliquiritigenin by human liver microsomes.
Isoliquiritigenin (2',4',4-trihydroxychalcone), a chalcone found in licorice root and other plants, has shown potent antitumor, antioxidant, and phytoestrogenic activity in vitro. In preparation for in vivo studies, the metabolism of isoliquiritigenin by human liver microsomes was investigated, and seven phase 1 metabolites were identified. In addition to aromatic hydroxylation that occurred on the A or B ring to form 2',4,4',5'-tetrahydroxychalcone or butein, respectively, reduction of the carbon-carbon double bond of an alpha,beta-unsaturated ketone and cyclization occurred to form 2',4,4'-trihydroxydihydrochalcone and (Z/E)-6,4'-dihydroxyaurone. All metabolites were characterized and identified by using liquid chromatography-tandem mass spectrometry with comparison to authenticated compounds. Finally, monoclonal antibody inhibitors of specific human cytochrome P450 (P450) enzymes and recombinant human P450 enzymes were used to identify the enzymes responsible for the formation of the major mono-oxygenated metabolites, and P450 2C19 was found to be a significant enzyme in the formation of butein from isoliquiritigenin, which also has anticancer activity. Cytochromes P450, reactive oxygen species, and peroxidases can all contribute to the formation of (Z/E)-6,4'-dihydroxyaurone in human liver microsomes.
Guo
Jian
J
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, 833 S. Wood St., Chicago, IL 60612-7231, USA.
Liu
Dongting
D
Nikolic
Dejan
D
Zhu
Dongwei
D
Pezzuto
John M
JM
van Breemen
Richard B
RB
D000970:Antineoplastic Agents / Q000378:metabolism*; D047188:Chalcones / Q000378:metabolism*; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D053719:Tandem Mass Spectrometry
D000970:Antineoplastic Agents; D047188:Chalcones; D003577:Cytochrome P-450 Enzyme System; C040920:isoliquiritigenin