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SECOND INTERNATIONAL SYMPOSIUM
ON THE ROLE OF SOY
IN PREVENTING AND TREATING CHRONIC DISEASE
September 15-18, 1996
Soybean Isoflavones :
Levels in Foods and Pharmacokinetics
Metabolism of isoflavones in target cells
T.G. Peterson, G-P. Ji, M. Kirk, L. Coward, C.N. Falany and S. Barnes.
Department of Pharmacology & Toxicology, and Comprehensive Cancer Center Mass Spectrometry Shared Facility, University of Alabama at Birmingham, AL 35294, USA.
Although genistein (4',5,7-trihydroxyisoflavone) inhibits the proliferation of many human breast cancer cultured cell lines (e.g., MCF-7 cells), the IC50 values are in most cases at least one order of magnitude greater than the achievable blood concentration of genistein from soy-based diets. On the other hand, the growth of non-transformed human mammary epithelial (HME) cells is strongly inhibited by genistein. Biochanin A (4'-methoxygenistein) is a weak in vitro tyrosine kinase inhibitor, but is as effective as genistein in inhibiting MCF-7 cells. To provide a rationale for these differences, metabolism studies using 4-14C-labeled genistein and 4-14C-labeled biochanin A were carried out in MCF-7 and HME cells. These experiments showed that MCF-7 cells converted 50% of the added genistein to a more polar metabolite over a period of 2-4 days. After isolation of the metabolite, analysis using HPLC-mass spectrometry and protein NMR revealed that it was genistein-7-sulfate. Biochanin A was converted to two metabolites, genistein and genistein sulfate. In contrast to MCF-7 cells, HME cells produced no significant metabolites over the same time period. Immunoblot analysis of proteins separated by SDS-PAGE from MCF-7 and HME cell lysates revealed that the phenol sulfating form of phenol sulfotransferase was only expressed in MCF-7 cells. Subsequent experiments with other human breast cancer cell lines revealed that the greater the extent of genistein metabolism, the higher the IC50 value (and hence lower the sensitivity to genistein). In summary, metabolism of genistein and biochanin A in target cells can modify their growth inhibitory properties.
Supported by grants from AICR, NCI (CA-61668 & CA-13148), Nebraska Soybean Board and the United Soybean Board.
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