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Nutrition and Cancer

Daidzein-Sulfate Metabolites Affect Transcriptional and Antiproliferative Activities of Estrogen Receptor-ß in Cultured Human Cancer Cells¹

Pierangela Totta, Filippo Acconcia, Fabio Virgili^*, Aedin Cassidy, Peter D. Weinberg^**, Gerald Rimbach and Maria Marino²

Department of Biology, University "Roma Tre," I-00146 Rome, Italy; ^* National Institute for Food and Nutrition Research (INRAN), I-00178 Rome, Italy; School of Medicine, Health Policy & Practice, University of East Anglia, Norwich, NR4 7TJ, UK; ^** Department of Bioengineering, Imperial College, London SW7 2AZ, UK; and Institute of Human Nutrition and Food Science, Christian Albrechts University, D-4111 Kiel, Germany

²To whom correspondence should be addressed. E-mail: m.marino{at}uniroma3.it.

Daidzein (D), a soy isoflavone, is almost completely metabolized in the gut and liver. This biotransformation converts D to more water-soluble products and may affect its biological activity. The ability of daidzein metabolites to modulate 17ß-estradiol (E2)-sensitive gene transcription, cell growth, and a proapoptotic cascade was determined in human cancer cells devoid of any estrogen receptor (ER) and rendered E2 sensitive after transfection with ERß. The data show that D and some but not all of its metabolites 1) induce promoter activity, 2) reduce proliferation, 3) promote p38/mitogen-activated protein kinase (MAPK) phosphorylation, and 4) activate a proapoptotic cascade involving the cleavage of caspase-3 and its substrate poly(ADP-ribose)polymerase (PARP) in human cancer cells in an ERß-dependent manner. Pretreatment of cells with ICI 182,780, a pure antiestrogen, completely prevented the actions of D and its metabolites. These findings highlight the important and complex influence of metabolic transformation on key physiological effects of isoflavones and demonstrate the need to take biotransformation into account when assessing the potential health benefits of consuming soy isoflavones.

KEY WORDS: • daidzein metabolites • 17ß-estradiol • estrogen receptor • gene transcription • apoptotic cascade

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