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Supplement: Fifth Internat'l Symposium on the Role of Soy in Preventing and Treating Chronic Disease

Soy Isoflavones—Phytoestrogens and What Else?^1,2

Department of Pharmacology & Toxicology, Center for Nutrient-Gene Interaction, University of Alabama at Birmingham, and Purdue University-University of Alabama at Birmingham Botanicals Center for Age-Related Disease, Birmingham, AL 35294

³To whom correspondence should be addressed. E-mail: sbarnes{at}uab.edu.

	ABSTRACT

TOP ABSTRACT LITERATURE CITED

 
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 17ß-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.

KEY WORDS: • isoflavones • mechanism of action • DNA microarray • high dimensional analysis

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 1920s and 1930s. Curiously, Wieland and Windaus were awarded the Nobel Prize for the latter discovery in 1927/28 despite it being the wrong structure (Fig. 1) (1). It was a portent of things to come when isoflavones re-emerged from obscurity in the 1940s as the estrogenic principle in red clover that caused infertility in sheep in Western Australia (2,3). This estrogenic action of isoflavones was viewed as a negative property. However, during the past 10–15 y, beneficial effects have been observed in humans and some animals. Confusion remains as to what isoflavones really are. This brief review attempts to address this latter issue from insights from recent data obtained using the rapidly emerging technologies of genomics and proteomics as well as from epidemiologic studies.

View larger version (13K): [in this window] [in a new window]   FIGURE 1 Structures of the steroid ring system at the time of the award of the Nobel Prize in Chemistry in 1927/28 (A) and the accepted structure (B) (3). Both molecules are representations of cholesterol according to each scheme.

The estrogenic action of isoflavones emerged from being an agricultural oddity to having a biochemical basis after the demonstration that it could apparently displace ³H-labeled 17ß-estradiol from the mammalian estrogen receptor (4). Because binding studies were not performed using ³H-labeled isoflavonoids, this displacement could have been equally well explained by the isoflavones binding to a secondary site on the estrogen receptor, thereby altering the K_d of 17ß-estradiol binding, rather than there being competitive binding between these compounds. Verification that genistein (5,7,4'-trihydroxyisoflavone) 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 genistein–estrogen receptor ß (ER-ß) complex (5). The binding site of the estrogen receptor can accommodate many ligands that are planar, aromatic, and with 2 oxygen atoms spaced 11.5 Å apart. The binding site is capped by the H12 helical domain (5), thus preventing the easy departure of the estrogen ligand and accounting for the very low (100 pmol/L) K_d of the estrogen–estrogen receptor complex. The antiestrogen raloxifene causes a shift in the position of the H12 helix away from the binding pocket and thereby increases the K_d for estrogen and reduces the latter’s effectiveness (5). Because genistein also causes a shift in the H12 helix, it may well also have antiestrogen properties in certain systems. However, even with a structure of this complex at a resolution of 1.8 Å, the precise role of genistein was still not clear.

A better test of estrogenicity is to measure the functional effect of isoflavones in cells expressing an estrogen response element–luciferase reporter gene construct. Several investigators reported that genistein increases the expression of luciferase in cells that coexpress ER- and ER-ß (6,7). However, even that observation clearly is not the whole story; indeed, it is dangerous to make any presumptive statement about isoflavones from cell-based studies or whether a single gene is turned on or off by genistein. Physiological estrogens are synthesized in both men and women. During gestation, estrogens levels are high in males but they fall after birth (8). They remain low in males during adult life. In athletes who supplement their use of anabolic steroids with testosterone to maintain their libido, substantial amounts of estrogens are formed. These interact with estrogen receptors and cause episodic breast growth (9). In women, estrogen levels rise at puberty and undergo a monthly cyclical variation for the next 3–4 decades. After menopause, estrogen levels are 3–4 times lower than at their peak but are not absent. Thus, the timing of exposure to a compound that may have estrogenic effects is crucial and for now poorly understood.

Response to estrogens during puberty is believed to be crucial with regard to their effects on breast cancer. Treatment of rats given a combination of 17ß-estradiol and progesterone just before puberty led to a 90% reduction in mammary tumors induced by the carcinogen N-methyl-N-nitrosourea (10). Similarly, Lamartiniere’s group (11,12) showed that rats exposed to dietary levels of genistein during puberty have a lower incidence of mammary tumors when challenged by the carcinogen 7,12-dimethylbenz[a]anthracene. This result has been confirmed by other investigators (13). Genistein only administered during adult life has no affect on mammary tumors in rats (11). Genistein may even promote tumor cell growth but only in immune-compromised, ovariectomized mice, a poor model of human disease (14). Interestingly, rats that had been treated with genistein during puberty had far fewer tumors when given genistein as adults (11,15). This indicates that important physiological and biochemical events that occur during puberty are affected by genistein and possibly other isoflavones. Epidemiologic data support this concept; Asian women who had consumed tofu during adolescence but not in adult life still had a lowered incidence of breast cancer compared with those who never consumed tofu or only did so in adult life (16,17). The importance of the timing can also been seen in the cases of identical twins. The first twin to menstruate (47% of the twins studied had at least a 1-y difference when this occurred) is 5 times as likely to get breast cancer than the twin who menstruates later (18). Thus, individual sensitivity to estrogens may play an important role in chronic diseases; this may be a product of both the genetic makeup of the individual and epigenetic events produced by dietary exposure to physiologically active agents such as isoflavones at critical times in development.

What is going on during this initial surge in estrogen levels? In the breast there is a large-scale proliferation of the mammary epithelial cells (19). Interestingly, only a few cells express estrogen receptor (20). The surrounding cells divide in response to growth factors from the estrogen receptor–positive cells. Key issues are therefore the proportion of cells that respond to estrogen and the extent of the response to a given amount of estrogen. Specific mechanisms whereby isoflavonoids control this process remain to be elucidated. However, it is clear that this is a multifactorial process and that research focused only on individual genes and proteins that they encode is unlikely to unravel the true story. Considerable interaction effects probably exist between individual genes that are not accounted for by the classical methods of experimentation that have been prevalent for the past 50 y.

Estrogens uncovered

During the past 20 y or so, molecular biology investigations have unraveled the genes that encode the proteins of life. Surprisingly, humans may have only 24,000 of these genes (21), not many more than the fruit fly (22), worm (23), or mustard plant (24,25). Levels of control of the use of gene information are expected to go beyond simple expression of the genes and their protein partners. Gene silencing through methylation of cytosines is 1 mechanism of an epigenetic process (26). Other mechanisms may be mediated through acetylation and methylation of critical lysine residues on the histones (27), proteins that are intimately associated with specific genes. Connections exist between polyphenols (the class of compounds to which isoflavonoids belong) and histone deacetylation. Resveratrol, a wine phytoestrogen, substantially increases the activity of SIRT1, a histone deacetylase. In a yeast model, it has the same effect as caloric restriction on increasing longevity (28).

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. This has enabled investigators to examine all the effects of a putative estrogen and not just the effects on their favorite gene or protein. Naciff et al. (29) applied this method to the effects of 3 estrogens (17-ethinyl estradiol, bisphenol A, and genistein) on the uterus of immature rats. In this model, genistein has been shown to be weakly uterotrophic (30). Analysis of gene array data suffers from having many factors (k > 10,000) and few replicates, which leads to poor statistical power and many false leads; most observed changes are false (31). However, the discovery of true results is quite efficient. Even with 3 replicates, 95% of the true changes should be detected. Naciff et al. (29), by using 3 different doses of the estrogens, not only provided 3 replicates but also showed that the responses observed varied according to the dose. This enabled the detection of 26 genes that were systematically affected by 17-ethinyl estradiol treatment. For bisphenol A, 35 genes were affected, many in common with 17-ethinyl estradiol. In contrast, genistein affected 227 genes, the majority of which were downregulated. Although genistein increased the expression of the progesterone receptor (an estrogenic effect), most of the remainder of its apparent effects in the developing uterus were not estrogenic. Several involve the homeostasis of calcium, consistent with genistein’s properties as an agent for the prevention of osteoporosis (32,33).

Gene arrays and other broad approaches in proteomics, metabonomics, and metabolomics will be used increasingly to address the question of what an estrogen is. This will lead to a totally new picture of what isoflavones are. The story may well go beyond these methods. Eight years ago we took the approach of building a molecular fishing hook to isolate the proteins that genistein bound to in human breast cancer MCF-7 cells (34). 2-Carboxygenistein was coupled to aminohexylagarose, the matrix used to affinity-absorb genistein-binding proteins in the cytosol of these cells. After careful washing to remove nonspecifically bound proteins, 2-carboxygenistein (1 mmol/L) was used to elute the proteins that were absorbed by the matrix. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis of the eluted fraction revealed a single protein. Edman degradation produced an amino-terminal amino acid sequence that at the time had no counterpart in any of the protein or genome databases. In 1996 a protein with a similar amino-terminal sequence was discovered in synovial fluid (35). Later another member of what is now known as the DING protein family was located in human fibroblasts (36). Similarly, mouse brain yielded another DING family member (37). Attempts to isolate cDNAs encoding the DING proteins have failed despite the genomes of their host (man, mouse, and the mustard plant) being almost fully sequenced. One clue as to what is happening was the discovery (Fig. 2) of an internal sequence of human fibroblast DING (38) that perfectly corresponds to dvl-3, the homolog of the disheveled gene in the fruit fly. This gene is a member of the wnt-1 signaling pathway (Fig. 3), which is associated with breast cancer in mice (39). This suggests that DING may play a role in regulating tumor cell growth independently of the estrogen receptor.

View larger version (16K): [in this window] [in a new window]   FIGURE 2 Partial sequencing of a human fibroblast DING protein. This procedure was developed by Adams et al. (34). They obtained several tryptic peptides and used the sequences of 2 of them to create degenerate oligonucleotides. These were used for a polymerase chain reaction. The resulting nucleotide product was not helpful in cloning a cDNA from the human fibroblast cDNA library; however, when it was sequenced and translated, it was found to contain the sequence of another tryptic peptide. Intriguingly, there was a 240-bp sequence that was a perfect match to disheveled, a Drosophila gene that is analogous to dvl-3, part of the Wnt signaling pathway.

View larger version (92K): [in this window] [in a new window]   FIGURE 3 Wnt signaling pathway in the breast. Wnt is a glycoprotein that binds to frizzled (Fzl), a membrane receptor. This in turn signals disheveled (Dvl) and turns off the kinase activity of glycogen synthetase kinase-3ß (GSK-3ß) in the axin/adenomatous polyposis coli (APC) complex. As a result, ß-catenin (ß-cat) is not phosphorylated and associates with the DNA transcription factor T-cell factor/lymphoid enhancer-binding factor (Tcf/Lef). This permits Tcf/Lef to enter the nucleus. If Dvl does not turn off GSK-3ß, then ß-catenin is phosphorylated and instead of binding to Tcf/Lef, it is targeted to the proteasome and degraded.

	FOOTNOTES

 
¹ Published in a supplement to The Journal of Nutrition. Presented as part of the Fifth International Symposium on the Role of Soy in Preventing and Treating Chronic Disease held in Orlando, FL, September 21–24, 2003. This conference was supported by The Solae Company; United Soybean Board; Archer Daniels Midland Company; Cargill Health and Food Technologies; Cargill Soy Protein Solutions; Dr. Chung’s Food Co., Ltd.; Illinois Soybean Association/Illinois Soybean Checkoff Board; Indiana Soybean Board; Nichimo International Inc.; Solbar Plant Extracts Ltd.; Soyatech, Inc.; Wyeth Consumer Healthcare; AOCS; DrSoy Nutrition; and Soyfoods Association of North America. Guest editors for this symposium were Mark Messina, John Erdman, and Kenneth D.R. Setchell.

² Support for the work on isoflavonoids, polyphenols and their biological effects comes in part from National Institutes of Health Grants to the Purdue-UAB Botanicals Center for Age-related Disease from the NIH Office of Dietary Supplements and the National Center for Complementary and Alternative Medicine (P50 AT-00477), and the UAB Center for Nutrient-Gene Interaction in Cancer Prevention from the National Cancer Institute (U54 CA-100949).

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