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In vitro metabolism of isoliquiritigenin by human liver microsomes. 2008

Jian Guo, and Dongting Liu, and Dejan Nikolic, and Dongwei Zhu, and John M Pezzuto, and Richard B van Breemen
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, 833 S. Wood St., Chicago, IL 60612-7231, USA.

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.

UI MeSH Term Description Entries
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D002853 Chromatography, Liquid Chromatographic techniques in which the mobile phase is a liquid. Liquid Chromatography
D003577 Cytochrome P-450 Enzyme System A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism. Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D047188 Chalcones Derivatives of CHALCONE that are important intermediates in the formation of FLAVONOIDS with anti-fungal, anti-bacterial, anti-inflammatory, and anti-tumor properties. 1,3-Diphenyl-propanediones,1,3-Diphenyl-propenones,1,3-Diphenylpropanediones,1,3-Diphenylpropenones,Chalconoids,1,3 Diphenyl propanediones,1,3 Diphenyl propenones,1,3 Diphenylpropanediones,1,3 Diphenylpropenones
D053719 Tandem Mass Spectrometry A mass spectrometry technique using two (MS/MS) or more mass analyzers. With two in tandem, the precursor ions are mass-selected by a first mass analyzer, and focused into a collision region where they are then fragmented into product ions which are then characterized by a second mass analyzer. A variety of techniques are used to separate the compounds, ionize them, and introduce them to the first mass analyzer. For example, for in GC-MS/MS, GAS CHROMATOGRAPHY-MASS SPECTROMETRY is involved in separating relatively small compounds by GAS CHROMATOGRAPHY prior to injecting them into an ionization chamber for the mass selection. Mass Spectrometry-Mass Spectrometry,Mass Spectrometry Mass Spectrometry,Mass Spectrometry, Tandem

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