Soy Isoflavones—Phytoestrogens and What Else?

Abstract

The weak estrogen-like properties of isoflavonoids were discovered over 50 y ago. In recent years, the overall effects of the isoflavones in soy on human health have been the subject of lively debate largely based on their presumed estrogenic properties. Missing from our knowledge base is the systematic identification of the cellular and biochemical targets of isoflavones and the mechanisms that they influence. Because of the benign effects of isoflavones on cellular integrity, a concentration of the isoflavones can be reached in cell culture models where almost any process can be modulated. Modern systems biology approaches and high dimensional analysis techniques offer new ways to better understand the function of how cells and integrated biological mechanisms respond to compounds such as isoflavones. Data from experiments using DNA microarray analysis for examining the effects of genistein in the developing rat uterus indicate that genistein alters the expression of 6-8 times as many genes as does a physiological estrogen such as 17 beta-estradiol. Although these new approaches are exciting, their incipient high dimensionality places considerable strain on the quality of experimental design and meaningful statistical interpretation of the resulting data. In another approach using affinity chromatography methods, DING, a novel genistein-binding protein of yet unknown function, was isolated from human breast cancer MCF-7 cells. Its function remains to be established.

Nutritional flavonoids impact on nuclear and extranuclear estrogen receptor activities

“…The binding site (i.e., LBD) is composed of amino acid residues belonging to α-helices 3, 4, 5, and 12. When, ERα-LBD forms complexes with E2, the binding site is capped by the H12 helical domain, thus preventing, the easy departure of the estrogen ligand and accounting for the very low K d (100 pmol/L) of the E2:ER (Jordan, 2003;Barnes, 2004). Furthermore, the α-helix 12 positioned over the ligand-binding pocket forms an interaction surface for the recruitment of coactivators (Jordan, 2003;Brzozowski et al, 1997).…”

“…These distinctive estrogenic properties of 8-prenylnaringenin will foster new research on its potential as an ER modulator. E2 displacement by flavonoids could be equally well explained by flavonoids binding to a secondary site on the ER, thereby altering the K d value of E2, rather than there being competitive binding between these compounds (Barnes, 2004). Verification that genistein binds to the active site of an estrogen receptor had to wait until 1999, when an X-ray diffraction crystal structure was reported for the ERα: genistein complex (Jordan, 2003).…”

“…Surprisingly, humans may have only about 24,000 genes (Pennisi, 2003). Levels of control of the use of gene information are expected to go beyond simple expression of the genes and their protein partners (Barnes, 2004). The benefit of sequencing the genome has been the engineering of DNA microarrays that essentially encompass the entire set of genes that are expressed in a given model.…”

“…Such discrepancies are partially due to the analysis of gene array data which suffers from having many factors and few replicates, this leads to poor statistical power and most observed changes may be false (Barnes, 2004). Moreover, gene expression levels do not represent a whole cellular effect.…”

“…Among the most TABLE 1 TABLE 1 TABLE 1 TABLE 1 TABLE 1: Chemical structures of certain commonly occurring plant flavonoid aglycones Flavonoids, and especially isoflavones, have a long history in science. Often referred to as weak estrogens, they were chemically synthesized before the ring structure of the mammalian steroids was determined in the 1920's and 1930's (Barnes, 2004). They re-emerged from obscurity in the 1940's as the anti-estrogenic principle in red clover that caused infertility in sheep in Western Australia (Bennetts et al, 1946).…”