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The role of metabolism in mammary epithelial cell growth inhibition by the isoflavones genistein and biochanin A |
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| Authors: | Peterson, T.Greg Coward, Lori Kirk, Marion Falany, Charles N. Barnes, Stephen |
| Affiliation: | 1Departments of Pharmacology and Toxicology, University of Alabama at Birmingham Birmingham, AL 35294, USA 2Departments of Biochemistry and Molecular Genetics, University of Alabama at Birmingham Birmingham, AL 35294, USA 3Departments of Comprehensive Cancer Center Mass Spectrometry Shared Facility, University of Alabama at Birmingham Birmingham, AL 35294, USA |
| Abstract: | The basis for the differential sensitivity of cultured normalhuman mammary epithelial (HME) cells and a transformed humanbreast cancer MCF-7 cell line to growth inhibition by the isoflavonegenistein and its 4'-methyl ether derivative, biochanin A, wasexamined. In HME cells genistein is 5-fold more potent as agrowth inhibitor than biochanin A, whereas in MCF-7 cells biochaninA and genistein are equally potent as growth inhibitors. Basedon its properties as an in vitro protein tyrosine kinase (PTK)inhibitor, biochanin A would be expected to be a less potentgrowth inhibitor than genistein. To determine whether isoflavonemetabolism could account for the observed differences in growthinhibition, metabolism experiments were conducted with HME andMCF-7 cells using [4-14C]genistein and [4-14C]biochanin A. MCF-7cells extensively metabolized both isoflavones, producing twogenistein metabolites with molecular weights of 350 and 380and three biochanin A metabolites with molecular weights of270, 350 and 380. In contrast, significant genistein or biochaninA metabolism was not observed in HME cells. Using mass spectrometryand nuclear magnetic resonance analysis, metabolite 350 fromgenistein and biochanin A experiments was identified as genistein7-sulfate; biochanin A metabolite 270 was identified as genistein.Metabolite 380 was not unequivocally identified, but appearedto be a hydroxylated and methylated form of genistein sulfate.In MCF-7 cells, genistein 7-sulfate and metabolite 380 weredetected primarily in the cell media fraction, suggesting thatonce formed these polar metabolites were excreted from the cells.These data show that isoflavone metabolism by transformed breastepithelial cells modulates the growth inhibitory effects ofgenistein and biochanin A. In MCF-7 cells, genistein metabolismwas correlated with a decrease in growth inhibition, whereasbiochanin A metabolism was associated with an increase in growthinhibition. |
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