Phytoestrogens

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Thousands of chemical structures have been identified in plant foods. Given the wide range of botanical species and plant parts from which phytochemicals are derived, they can contribute a significant variety and complexity to the human diet (27). In the past, the medicinal uses of spices and herbs were often indistinguishable from their culinary uses, and for good reason: people have recognized for centuries both the inherent value, as well as the potential toxicity, of phytochemicals in relation to human health. Plants have the capacity to synthesize a diverse array of chemicals, and understanding how phytochemicals function in plants may further increase our understanding of the mechanisms by which they benefit humans. In plants, these compounds function to attract beneficial and repel harmful organisms, serve as photoprotectants, and to respond to environmental changes. In humans, they can have complementary and overlapping actions, including antioxidant effects, modulation of detoxification enzymes, reduction of inflammation, modulation of steroid metabolism, and antibacterial and antiviral effects. Embracing a cuisine rich in spice, as well as in fruit and vegetables, may further enhance the chemopreventive capacity of one's diet (12,20,22,27-30).

It has been well established that cancer rates differ strikingly in various populations. Hormone-related cancers of breast, ovary, endometrium, and prostate have been reported to vary by as much as 5- to 20-fold between populations, and migrant studies indicate that the difference is largely attributed to environmental factors rather than genetics (31-33). The highest incidences of these cancers are typically observed in populations with Western lifestyles that include relatively high fat, meat-based, and low-fiber diets, whereas the lowest rates are typically observed in Asian populations with Eastern lifestyles that include plant-based diets with a high content of phytoestrogens (34-39). Migrants from Asian to Western countries, who maintain their traditional diet, do not show increased risk for these diseases, whereas an increased risk accompanies a change towards a Westernized diet (31,40). Much of the evidence is based on the differences in consumption of soy products as the major source of isoflavones in different areas of the world. The consumption of soy products is estimated to be highest in particular Japanese populations, with levels in the diet up to 200mg/day. Throughout Asia, the consumption of legumes is estimated to supply 25-45 mg total isoflavones in the diet each day, compared with Western countries with a consumption of less than 5 mg/day (41).

During the last years, there has been a growing interest in dietary natural plant estrogens (phytoestrogens), particularly those found in soy products, as a potential alternative to the synthetic estrogens in HRT (24,36,42,43). Together with lig-nans, coumestans, flavones, and flavanones, isoflavones belong to the larger group of nonsteroidal phytoestrogens. Interest in phytoestrogens has been fueled by observational studies showing a lower incidence of menopausal symptoms, osteoporosis, cardiovascular disease, and breast and endometrial cancers in Asian women who have a diet rich in soy products. Consistent with epidemiological studies are the findings that soy phy-toestrogens prevent mammary tumors and bone loss in rodents and atherosclerosis of coronary arteries in monkeys. Soy protein relieves hot flashes in postmenopausal women and attenuates bone loss in the lumbar spine of perimenopausal women. Furthermore, a high intake of dietary phytoestrogens is associated with a lower incidence of cancers of the colon, breast, and prostate. Isoflavones and other phytoestrogens have been considered to exert anticarcinogenic actions, mainly through antiestrogenic, antiaromatase, or antiproliferative mechanisms (33,44,45). Soy seems to protect against breast cancer if consumed throughout life, particularly before and during adolescence. Whether the phytoestrogens are responsible for the protection is not known; it is more likely that the soybean products or grain-fiber complexes are protective in their entirety. Many postmenopausal women are taking phytoestrogens in an effort to alleviate menopausal symptoms without increasing their risk of developing breast cancer. Moreover, many women with a history of breast cancer take phytoestrogens to control menopausal symptoms because estrogens are contraindicated.

Natural, synthetic, and environmental estrogens have numerous effects on the development and physiology of mammals. Estrogen is primarily known for its role in the development and functioning of the female reproductive system (20,46-48). However, roles for estrogen in male fertility, bone, the circulatory, cardiovascular, and immune system have been established by clinical observations regarding sex differences in pathologies, as well as observations following menopause or castration, or from ER knockout studies. Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. In recent years, it has become apparent through the use of ER agonists and antagonists that the biological actions of estrogens are multifaceted. Estrogens and antiestrogens mediate their effects through diverse molecular mechanisms (49). The predominant biological effects of estradiol are mediated through two distinct intracellular ERs, ERa and ER^, each encoded by a unique gene but possessing the hallmark modular structure of functional domains characteristic of the steroid/thyroid hormone superfamily of nuclear receptors (47-51). There is a hypervariable N-terminal domain that contributes to the transactivation function, a highly conserved central domain responsible for specific DNA binding, dimerization, and nuclear localization, and a C-terminal domain involved in ligand binding and ligand-dependent transactivation (47-49,52). Recent investigations have revealed cellular/molecular mechanisms of ER signaling at multiple levels: (1) classical ligand-dependent; (2) ligand-independent; (3) DNA binding-independent; and (4) cell-surface (nongenomic) signaling (typically, leading to rapid events, which are initiated at the plasma membrane and result in the activation of intracellular signaling pathways within seconds to minutes). Certain compounds that act via the ER, now referred to as SERMs, can demonstrate remarkable differences in activity in the various estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for understanding these tissue-selective actions (53-55).

Estrogens are used in HRT to prevent hot flashes, urogenital atrophy, and osteoporosis in postmenopausal women. Hormone replacement therapy also may prevent heart disease, Alzheimer's disease, and colon cancer. Unfortunately, HRT has not lived up to its potential to improve the health of women, because estrogens have been associated with an increased incidence of breast and endometrial cancer (18).

This relationship has hampered compliance with HRT severely and has sparked an intense pursuit for SERMs that have a safer profile. Recently, raloxifene has been approved for the prevention and treatment of osteoporosis. Raloxifene is classified as a SERM because it exhibits agonist activity in some tissues such as the bone, and acts as an antagonist in other tissues including the breast. Although these effects are extremely desirable, raloxifene also increases hot flashes, is weaker than estrogens at increasing bone mineral density, and does not improve cognitive function or prevent hip fracture. Thus, the quest for superior SERMs to be used in HRT continues to be intense (17). Isoflavones are widespread in the plant kingdom, as they are predominantly found in leguminous plants and are especially abundant in soy. Lignans exist as minor constituents of building blocks in the formation of lignin in plant cell walls. They are found widely in cereals, legumes, fruit, and vegetables, with exceptionally high concentrations in flaxseed.

The isoflavones, genistein, daidzein, and biochanin A, which are abundant in soybeans and widely available as herbal tablets, are especially popular among postmenopausal women (17). The structural similarities between these substances, endogenous mammalian estrogens, and potent synthetic estrogens have attracted a lot of attention (42,56). Numerous studies have revealed that the biological activity of 17^-estradiol greatly depends on the presence of at least two hydroxyl groups, one located in the A-ring of the steroid nucleus and the other at C (17) (see Fig. 1). Unlike 17^-estradiol, phytoestrogens are not steroids, but they possess hydroxyl groups (present or introduced by hydroxylation) that can be positioned in a stereochemical alignment resembling that of 17^-estradiol. The distances between two hydro-xyl groups in isoflavones, mammalian lignans, and 17^-estradiol are comparable. It appears that this feature is an essential factor for strong binding to the ER. Phytoestrogens are also structurally related to the antiestrogen tamoxifen, which is widely used in the treatment of breast cancer (57).

Another possibility deserving consideration is that some of the phytoestrogen actions may be attributable to properties

Coumestrol

17p-estradiol

Coumestrol

17p-estradiol

Figure 1 Different structures of (phyto)estrogens.

that do not involve hormone receptors such as antioxidative effects, interference with particular enzymes, protein synthesis, calcium transport, Na+/K+ adenosine triphosphatase, growth factor action, lipid oxidation. Besides its role in immune function, its activities may affect cell proliferation, angiogenesis, and cell differentiation, as well. In this respect, genistein is also known as a broad specificity tyrosine kinase inhibitor, blocks topoisomerase I and II activity and inhibits phosphodiesterases (30,42,58-65). Although preliminary results suggest phytoestrogens may inhibit the transcription factor NF-kB, which is strongly linked to inflammatory and immune responses and is associated with oncogenesis in certain models of cancer, the identification of molecular and cellular targets of chemopreventive phytochemicals is still incomplete (29).

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