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Lookup NU author(s): Dr Kathryn Atherton,
Dr Elaine Mutch,
Professor Dianne Ford
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Metabolism of the isoflavones daidzein and genistein, which may protect against some cancers, was studied using human liver microsomes and recombinant CYP isoforms. The detection of three, more polar metabolites of each isoflavone by RP-HPLC required NADPH, consistent with CYP-mediated metabolism. For different liver preparations, metabolite generation from daidzein showed a significant linear correlation with metabolite generation from genistein, indicating metabolism by the same CYP(s). The lowest rate of metabolism of both isoflavones was by the preparation with the lowest CYP1A2 activity. Metabolite peak areas were substantially and significantly reduced by the CYP1A2 inhibitor furafylline and to a lesser extent by the CYP2E1 inhibitor 4-methylpyrazole. Recombinant CYP1A2, but not CYP2E1, generated the metabolites of daidzein and genistein and recombinant CYP1A1 and CYP1B1, expressed at sites including the breast and prostate, were also active. The effects of two CYP-derived metabolites of daidzein, 6,7,4′-trihydroxyisoflavone and 7,3′,4′-trihydroxyisoflavone, were studied in the MCF-7 human breast cancer cell line at a concentration (50 μM) at which daidzein induces an antiproliferative response. 7,3′,4′-Trihydroxyisoflavone reduced total cell numbers to a greater extent than 6,7,4′-trihydroxyisoflavone or daidzein and increased cell death. Together, these data demonstrate proof of principle that CYP-mediated metabolism of daidzein can be an activation pathway. We conclude that CYP1A2 makes the major contribution to the hepatic metabolism of both daidzein and genistein and along with metabolism at sites of hormone-dependent tumours may enhance a cancer-protective effect of daidzein if sufficiently high concentrations are reached in target tissues. © 2006 Elsevier Inc. All rights reserved.
Author(s): Atherton KM, Mutch E, Ford D
Publication type: Article
Publication status: Published
Journal: Biochemical Pharmacology
ISSN (print): 0006-2952
ISSN (electronic): 1873-2968
PubMed id: 16814747
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