Abstract
The female flowers of hops (Humulus lupulus L.) are used in the brewing of beer and are under investigation for use in dietary supplements for the management of menopausal symptoms in women. Hop extracts contain the weakly estrogenic compound isoxanthohumol (IX), proestrogenic xanthohumol, and the potent estrogen 8-prenylnaringenin (8PN). Because IX can be metabolized in the human liver to form 8PN, the specific cytochrome P450 (P450) enzymes responsible for this O-demethylation reaction were identified. In addition, the enzymes that convert IX and 8PN to their most abundant metabolites were identified because these metabolic pathways might also affect the estrogenicity of hop preparations. Specifically, the P450 enzymes that catalyze the oxidation of the prenyl side chains of IX and 8PN into trans- or cis-alcohols were investigated. Human liver microsomes and monoclonal antibodies that inhibit specific P450 enzymes were used in combination with liquid chromatography/mass spectrometry to identify the enzymes responsible for these transformations. CYP2C19 was found to catalyze the formation of both cis- and trans-alcohols of the prenyl side chain of 8PN with Km values of 14.8 ± 3.2 and 16.6 ± 4.6 μM, respectively. CYP2C8 converted 8PN regioselectively to the trans-alcohol of the prenyl group with a Km of 3.7 ± 0.9 μM. Finally, CYP1A2 was found to catalyze the O-demethylation of IX to generate 8PN, with a Km value of 17.8 ± 3.7 μM. These results suggest that the estrogenicity of hop constituents in vivo will depend in part on metabolic conversion that may show individual variation.
Footnotes
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This work was supported by Grant P50 AT00155 provided jointly by the National Center for Complementary and Alternative Medicine (NCCAM), the Office of Dietary Supplements (ODS), the Office for Research on Women's Health (ORWH), and the National Institute of General Medicine (NIGMS) of the National Institutes of Health (NIH). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM, ODS, ORWH, NIGMS, or the NIH.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.008250.
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ABBREVIATIONS: IX, isoxanthohumol; 8PN, 8-prenylnaringenin; HLM, human liver microsome; 8PN-M2, 8-prenylnaringenin trans-prenyl alcohol; IX-M1, isoxanthohumol cis-prenyl alcohol; IX-M2, isoxanthohumol trans-prenyl alcohol; P450, cytochrome P450; mAb, monoclonal antibody; 8PN-M1, 8-prenylnaringenin cis-prenyl alcohol; HPLC, high-performance liquid chromatography; LC/MS, liquid chromatography/mass spectrometry; ANOVA, analysis of variance.
- Received November 9, 2005.
- Accepted April 5, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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In this issue
IDENTIFICATION OF HUMAN HEPATIC CYTOCHROME P450 ENZYMES INVOLVED IN THE METABOLISM OF 8-PRENYLNARINGENIN AND ISOXANTHOHUMOL FROM HOPS (HUMULUS LUPULUS L.)
