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S. BARNES¹, H. Kim¹, J. Xu¹, B. Boersma¹, R. Patel², M. Kirk³, M. Luo⁴, and V. M. Darley-Usmar². (1) Pharmacology & Toxicology, University of Alabama at Birmingham, 1670 University Blvd., Birmingham, AL 35294, (2) Pathology, University of Alabama at Birmingham, (3) Comprehensive Cancer Center Mass Spectrometry Shared Facility, University of Alabama at Birmingham, (4) Center for Macromolecular Crystallography, University of Alabama at Birmingham

Fruits and vegetables in the diet are important for our health. Soy foods, rich sources of protein, are associated with lowering the risk of several chronic diseases.

Soy is unique among fruits and vegetables in providing large quantities of the isoflavones daidzein (7,4'-dihydroxyisoflavone, DZN) and genistein (5,7,4'-trihydroxyisoflavone, GEN) as their glycosidic conjugates. Long known for its estrogenic properties, GEN has been recently shown to bind to estrogen receptor beta (ERb) with an affinity close to that of 17b estradiol. Since there is a differential distribution of ERb (the classical estrogen receptor) and ERb in tissues and individual cells, GEN may have preferential action (as an estrogen agonist or partial antagonist) at specific sites.

Its ability as a PTK inhibitor has also been widely investigated. However, in some cells GEN may not directly inhibit PTK enzyme activities, but rather downregulates their expression. Other potential mechanisms of action of GEN involve upregulation of TGF beta expression (controlling cell proliferation, particularly in the vascular system, and angiogenesis), effects on ion transport systems, and glucose transport. GEN and other bioflavonoids can interact with cellular and vascular space oxidants, thereby protecting critical biochemical targets such as LDL.

However, the production of oxidants may substantially exceed the capacity of the bioflavonoids to remove them in vivo. In a novel hypothesis, we have proposed that the products of the reactions between reactive oxygen species and bioflavonoids will have altered interaction with their receptor protein targets. In this way, GEN as one of its oxidant metabolites may have a higher affinity to ERa or ERb and other receptor targets than the unmodified isoflavone. Accordingly, the effect of GEN may be locally enhanced in tissues when oxidants are produced.

In summary, GEN and related bioflavonoids have several related mechanisms that may explain their widespread estrogen-like and non-estrogen-like responses in biological systems.