Estrogenic and genotoxic potential of equol and two hydroxylated metabolites of Daidzein in cultured human Ishikawa cells.
The soy isoflavone daidzein (DAI) is known to undergo metabolism to equol (EQO) and to 3'-hydroxy-DAI (3'-HO-DAI) and 6-hydroxy-DAI (6-HO-DAI) in humans. In order to better understand the implications of soy diets for human health, the hormonal and genotoxic activities of these DAI metabolites were studied in cultured human endometrial carcinoma cells. When the estrogenicity was tested by cell-free binding to recombinant human estrogen receptor (ER) alpha and beta as well as by the induction of enzyme activity and gene expression of alkaline phosphatase (ALP) in Ishikawa cells, the ranking order was EQO>DAI>3'-HO-DAI>6-HO-DAI. All compounds had a higher affinity to ERbeta than to ERalpha. No significant anti-estrogenic effects of the DAI metabolites were observed in the cells at non-cytotoxic concentrations. The in vitro genotoxicity was assessed by analyzing effects on cell cycle distribution and cell morphology as well as the induction of micronuclei (MN). EQO caused a slight increase in G1 and decrease in S phase of the cell cycle, and slightly but significantly induced kinetochore-positive as well as kinetochore-negative MN and an elevated proportion of abnormal mitotic spindles. 3'-HO-DAI, but not 6-HO-DAI, induced kinetochore-negative MN. The observation that major human metabolites of DAI exhibit estrogenic and genotoxic potential may be of relevance for the safety evaluation of diets containing soy isoflavones.
Institute of Applied Biosciences, Section of Food Chemistry and Toxicology, Kaiserstrasse 12, University of Karlsruhe, P.O. Box 6980, D-76128 Karlsruhe, Germany. leane.lehmann@chemie.uni-karlsruhe.de
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D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004790:Enzyme Induction; D060754:Equol; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007529:Isoflavones / Q000378:metabolism / Q000633:toxicity*; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D015162:Micronucleus Tests; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D048789:Phytoestrogens / Q000378:metabolism / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects
C007610:4',7-dihydroxy-3,4-dihydroisoflavone; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007529:Isoflavones; D009153:Mutagens; D048789:Phytoestrogens; D012333:RNA, Messenger; D060754:Equol; C004742:daidzein; D000469:Alkaline Phosphatase