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Soy isoflavonoids and cancer -- metabolism at the target site
B J Boersma1, S Barnes, M Kirk
1Department of Pharmacology & Toxicology, University of Alabama at Birmingham, VH G009, 1670 University Boulevard, Birmingham, AL 35294, USA.
Abstract:
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.
Insights
Genistein (GEN), a soy isoflavone, shows anti-cancer benefits, but its effects in cell cultures may not reflect real-world activity due to extensive metabolism. Modified GEN forms may be more potent.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Isoflavonoids, like genistein (GEN), are plant polyphenols with potential anti-cancer properties.
- GEN exhibits various biological activities, including regulating estrogen, inhibiting kinases, and modulating apoptosis.
Purpose of the Study:
- To address the discrepancy between in vitro and in vivo genistein (GEN) activity.
- To investigate the role of GEN metabolism in its biological effects and anti-cancer potential.
Main Methods:
- Reviewed existing literature on genistein (GEN) biological activities and metabolism.
- Analyzed in vitro studies versus in vivo circulating levels of unconjugated GEN.
- Considered the impact of metabolic modifications on GEN's bioactivity.
Main Results:
- In vitro studies often use micromolar GEN concentrations, exceeding physiological levels.
- GEN undergoes extensive in vivo metabolism, with only a small fraction excreted unmodified.
- Metabolism, particularly through reactions with inflammatory oxidants, can create modified GEN forms (brominated, chlorinated, nitrated).
Conclusions:
- Cell culture studies may overestimate genistein's (GEN) efficacy due to high concentrations.
- Metabolites of GEN may possess significantly enhanced biological and anti-cancer activities.
- Future research must consider tissue-site metabolism for accurate evaluation of GEN and other polyphenols.