Soy isoflavonoids and cancer -- metabolism at the target site.

Isoflavonoids are members of the broad class of plant polyphenols that have been shown in vivo to have benefit in the prevention of a wide variety of chronic diseases, including cancer. For genistein (5,7,4'-trihydroxyisoflavone) (GEN), the major isoflavone in soy, reported mechanisms for these biological activities are numerous and include regulation of estrogen-mediated events, inhibition of tyrosine kinase and DNA topoisomerase activities, synthesis and release of TGF beta, and modulation of apoptosis. However, the biochemical effects of GEN in cell culture occur at concentrations in the micromolar range, far above the circulating levels of the unconjugated GEN. This may point to the limitations of cell culture for the evaluation of the activity and mechanisms of potential anti-carcinogens. GEN is extensively metabolized in vivo, with only about 14-16% excreted in an unmodified form. Metabolism may also occur because of interaction between GEN (as well as other polyphenols) and oxidants produced by inflammatory cells (HOCl, HOBr and ONOO(-)). These react with GEN to form brominated, chlorinated and/or nitrated GEN. Emerging evidence indicates that these modifications may substantially increase the biological activities of the parent compound. Future investigations of GEN and other polyphenols must, therefore, take into account metabolism at the tissue site.