title: Metabolism of the isoflavones genistein and biochanin A in human breast cancer cell lines.
abstract: There is substantial variation in the growth inhibition of different human breast cancer cell lines by the isoflavones genistein and biochanin A. ZR-75-1 and BT-20 cells are > or = 2- to 4-fold less sensitive to these isoflavones than are MCF-7 cells, whereas T47D cells have a sensitivity similar to that of MCF-7 cells. To determine whether these differences are related to isoflavone metabolism by these cancer cells, each of the cell lines was incubated with [4-(14)C]genistein and [4-(14)C]biochanin A. Metabolites in the cell culture media were identified by radio-HPLC electrospray ionization mass spectrometry. One metabolite of genistein (genistein 7-sulfate) and 2 metabolites of biochanin A (genistein and genistein 7-sulfate) were detected by radio-HPLC. Further analysis by mass spectrometry identified 3 other metabolites, a hydroxylated methylated form of each isoflavone and a biochanin A sulfate. IC50 (the concentration at which the growth rate was halved) values of the breast cancer cell lines did not correlate well with production of genistein 7-sulfate from genistein or with biochanin A sulfate, genistein 7-sulfate, or genistein from biochanin A. However, IC50 values correlated with the production of the hydroxylated and methylated forms of the isoflavones. Only T47D cells produced these metabolites in this study, and only T47D cells had IC50 values similar to those of MCF-7 cells, which also produced the hydroxylated and methylated metabolites. These data suggest that the hydroxylated and methylated metabolites may be the active forms of genistein in human breast cancer cells and emphasize the importance of isoflavone metabolism in the mechanism of action of isoflavones.
authors.affiliation: Department of Pharmacology and Toxicology, and Comprehensive Cancer Center Mass Spectrometry Shared Facility, University of Alabama at Birmingham, 35294-0019, USA.
authors.forename: T G
authors.initials: TG
authors.lastname: Peterson
authors.forename: G P
authors.initials: GP
authors.lastname: Ji
authors.forename: M
authors.initials: M
authors.lastname: Kirk
authors.forename: L
authors.initials: L
authors.lastname: Coward
authors.forename: C N
authors.initials: CN
authors.lastname: Falany
authors.forename: S
authors.initials: S
authors.lastname: Barnes
mesh_terms: D016588:Anticarcinogenic Agents / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005260:Female; D019833:Genistein / Q000378:metabolism*; D006801:Humans; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D019833:Genistein; C004541:biochanin A