Role of metabolism in the effects of genistein and its phase II conjugates on the growth of human breast cell lines.

Genistein has been investigated for several decades for its potential role in breast cancer prevention. Previous researches have shown that glucuronide and sulfate conjugates are the major species circulating in the blood after genistein ingestion. It was hypothesized that enzymes (UDP-glucuronosyltransferases, sulphotransferases, β-glucuronidases, and sulphatases) present in breast tissues would catalyze the inter-conversion between the aglycone and the conjugates in situ. Therefore, our aim was to investigate how genistein, genistein-7-glucuronide (G-7-G), genistein-7-sulfate (G-7-S), and 4'-sulfate (G-4'-S) were metabolized in mammary cells and to determine the effects of metabolism on their proliferative actions using cultured breast cell lines. As expected, genistein stimulated the cell growth of breast cancer cells (MCF-7 and T47D) concentration-dependently at lower concentrations but inhibited their growth at higher concentration. It showed low activities in a non-tumorigenic cell line (MCF-10A) due to the absence of ERα. Genistein was extensively metabolized to glucuronides by MCF-7 and to sulfates by T47D, while it was poorly metabolized by MCF-10A. G-7-G displayed weak stimulation activity in breast cancer cells. G-7-G underwent extensive metabolism in T47D and MCF-10A but not in MCF-7. The proliferative effects of G-7-G on MCF-7 and T47D were associated with its hydrolysis to genistein in these cells. In contrast, G-7-S and G-4'-S were not metabolized by these three cells and had no effects on their growth. In conclusion, production of phase II metabolites did not affect the proliferation effect of genistein on MCF-7 and T47D. Deconjugation was correlated to the apparent proliferative effects of G-7-G in breast cancer cells.