Lorenza Burzi
Ina Gerlica
Introduction
Soy is a herbaceous annual plant that can reach 80-100 cm in height. It is covered with bristly hairs, hence the original name of soybean stubble. It has trifoliate compound leaves, small flowers, the color of which varies from white to red to purple depending on the variety and the fruit is a violet pod containing 1 to 5 seeds yellowish light or dark depending on the variety.
The part used are the seeds, which contain a high amount of proteins, lipids and polyunsaturated glucosides which include isoflavones and saponins.
The introduction of soy with food can occur through consumption of many products like milk, tofu, miso, oil, flour and flakes, soy lecithin, soy bread, meat, tamari and shoyu.
The interest in the beneficial properties of soy began when some epidemiological studies of Asian populations emphasize a lower incidence of certain cancers such as breast cancer, colon and prostate cancer. It is further noted that the oriental women had a more serene menopause than Western women and the risk of osteoporosis and cardiovascular disease was reduced. It was therefore predicted the existence of a relationship between soy consumption and reduced incidence of these diseases and conditions.
Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies (2011).
The health benefits of soy are related to the presence of phytoestrogens (naturally occurring substances in plants with estrogen-like action) and isoflavones (substances that are very effective against menopause symptoms). To be absorbed isoflavones must be converted into aglycones (daidzein and genistein) by the intestinal bacterial flora. Once absorbed these substances are reworked by the liver that metabolizes them producing derivatives with oestrogenic activity.
Nutritional value and composition
Soy is a legume such as beans, chickpeas or lentils, and like all legumes are rich in B vitamins, iron and potassium. Unlike other legumes soybeans, however, is more digestible and high in protein and fat (monounsaturated, polyunsaturated, and phospholipids such as lecithin). Soy proteins have a discrete amino acid profile with a biological value less than 75, and a protein efficiency ratio of 2.1.
Soybeans differs markedly in macronutrient content from other legumes, being much higher in fat and protein and lower in carbohydrates.
A complete display of the composition of the product, the amount and type of minerals, vitamines, lipids and aminoacids contained, is presented in the chart nutritional value of aliments.
Organic chemistry and biosynthesis
Isoflavones of nutritional interest are substituted derivatives of isoflavone, being related to the parent by the replacement of two or three hydrogen atoms with hydroxyl groups. The parent isoflavone is of no nutritional interest. The most important isoflavones are daidzein and genistein.
Isoflavones are produced via a branch of the general phenylpropanoid pathway that produces flavonoid compounds in higher plants. Soybeans are the most common source of isoflavones in human food; the major isoflavones in soybean are genistein and daidzein. The phenylpropanoid pathway begins from the amino acid phenylalanine, and an intermediate of the pathway, naringenin, is sequentially converted in to the isoflavone genistein by two legume-specific enzymes, isoflavone synthase, and a dehydratase.
Isoflavones acts as SERMs
Selective estrogen receptor modulators are a class of compounds that act on the estrogen receptor . A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.
Genistein is a relatively potent agonist for the recently characterized beta isoform of the estrogen receptor (ERbeta).The low nanomolar serum concentrations of unconjugated free genistein achieved with high-nutritional intakes of soy isoflavones are near the binding affinity of genistein for this receptor, but are about an order of magnitude lower than genistein's affinity for the "classical" alpha isoform of the estrogen receptor (ERalpha).
Estrogens play a role in almost all cells and tissues in the body. Many of these roles have been observed in women who have a decrease in estrogens due to menopause or gonadectomy. Other effects have been observed due to differences in gender, such as autoimmune disease prevalence in either men or women. These are some of the specific estrogen receptor-mediated effects on tissues:
- breast : cells express both ERalpha and ERbeta; the first promotes proliferation, while the other has a restraining influence on the regard
- osteoblasts : positive effects on bone metabolism were combined with vit D3
- vascular endothelium : cells express both ERalpha and ERbeta; isoflavones have the potential to induce and activate nitric oxide synthase ; this may account for he favorable influence of soy isoflavones on endothelial function
- kidney : agonist actions of tgfbeta-signalling on the mesangial cells, thus having a potential neprhoprotective activity
- hypothalamus : genistein increased ER beta mRNA expression in the paraventricular nucleus of the hypothalamus by 24%, while it has no action on ERalpha pathways.
- hepatocyte : no expression of ERbeta, thus isoflavones differs from oral estrogens, neither modify serum lipids nor provoke prothrombotic effects associated with the increase risk for thromboemolitic disorders
- uterus : lack of uterotropic activity.
Tissue-Specific Effects of loss of estrogen during menopause and aging (2012).
Therapeutic use:
Breast cancer
Breast cancer is the most common cancer in women and a significant cause of death. Mutations of the oncosuppressor genes BRCA1 and BRCA2 are associated with a hereditary risk of breast cancer, and dysregulation of their expression has been observed in sporadic cases.
Soya isoflavones have been shown to inhibit breast cancer , but associations between the consumption of isoflavone-containing foods and breast cancer risk have varied in epidemiological studies.
Soya is a unique source of the phytoestrogens daidzein (4',7-dihydroxyisoflavone) and genistein (4',5,7-trihydroxyisoflavone), two molecules that are able to inhibit the proliferation of human breast cancer cells in vitro.
Mechanism of action:
Daidzein
It induces antiproliferative effects in a concentration- and time-dependent manner. Daidzein-induced apoptosis in MCF-7 cells was initiated by the generation of reactive oxygen species (ROS). Furthermore, this was accompanied by disruption of mitochondrial transmembrane potential, down-regulation of bcl-2, and up-regulation of bax, which led to the release of cytochrome C from the mitochondria into the cytosol, which, in turn, resulted in the activation of caspase-9 and caspase-7, and ultimately in cell death.
Daidzein induces MCF-7 breast cancer cell apoptosis via the mitochondrial pathway (2010).
Genistein
1) GE significantly inhibited cell growth in a dose-dependent manner in precancerous breast cells and breast cancer cells, whereas it exhibited little effect on normal human mammary epithelial cells. Furthermore, GE treatment increased expression of two crucial tumor suppressor genes, p21 and p16, although it decreased expression of two tumor promoting genes, BMI1 and c-MYC. GE treatment led to alterations of histone modifications in the promoters of p21 and p16 as well as the binding ability of the c-MYC-BMI1 complex to the p16 promoter contributing to GE-induced epigenetic activation of these tumor suppressor genes.
Epigenetic regulation of multiple tumor-related genes leads to suppression of breast tumorigenesis by dietary genistein (2013).
2) The mechanisms that might mediate the effects of an early life exposure to genistein on the mammary gland focuses on changes in gene expression, such as those involving BRCA1 and PTEN
Dietary exposure to the soy isoflavone genistein induced PTEN expression in mammary epithelial cells in vivo and in vitro, consistent with the breast cancer preventive effects of soy food consumption. PTEN and p53 functional interactions in the nuclear compartment of mammary epithelial cells is a mechanism for mammary tumor protection by genistein, increasing PTEN expression and nuclear localization. It leads to an autoregulatory loop involving PTEN-dependent increases in p53 nuclear localization, PTEN/p53 physical association, PTEN/p53 co-recruitment to the PTEN promoter region, and p53 transactivation of PTEN promoter activity. The PTEN/p53 cross-talk induced by genistein resulted in increased cell cycle arrest; decreased pro-proliferative cyclin D1 and pleiotrophin gene expression.
PTEN and p53 cross-regulation induced by soy isoflavone genistein promotes mammary epithelial cell cycle arrest and lobuloalveolar differentiation (2010).
3) Genistein's chief method of activity is as a tyrosine kinase inhibitor . Tyrosine kinases are less widespread than their ser/thr counterparts but implicated in almost all cell growth and proliferation signal cascades. Genistein inhibits protein tyrosine kinase (PTK), which is involved in phosphorylation of tyrosyl residues of membrane-bound receptors leading to signal transduction, and it inhibits topoisomerase II, which participates in DNA replication, transcription and repair. Inhibition of DNA topoisomerase II also plays an important role in the cytotoxic activity of genistein.
Anticancer therapeutic potential of soy isoflavones, genistein (2004).
Moreover, recent experiments in vivo on rats proved that dietary glycine soya (GS), which is rich in phytoestrogens, can enhance the anti breast cancer efficacy of the SERM tamoxifen (TAM). Exposure to both TAM and dietary GS enhanced the anti tumor efficacy of TAM via a combination of tumor cell apoptosis and inhibition of tumor cell proliferation.
Glycine soya diet synergistically enhances the suppressive effect of tamoxifen and inhibits tamoxifen-promoted hepatocarcinogenesis in 7,12-dimethylbenz[α]anthracene-induced rat mammary tumor model (2011).
Menopausal symptoms
Menopause is a transitional time for women. Hormone replacement therapy has been the mainstay of therapy for menopausal symptoms. With recent research findings, women and their physicians are seeking alternatives that do not carry the risks associated with HRT. Exercise has been shown to help some women with symptoms of hot flashes, as have relaxation techniques and deep breathing. Dietary changes to incorporate whole foods and soy are thought by some to help with menopausal symptoms.
Efficacy of soyfoods and soybean isoflavone supplements for alleviating menopausal symptoms is positively related to initial hot flush frequency (2003).
Osteoporosis
Following menopause, the ovaries stop producing estrogen, a hormone that helps prevent bone loss. The estrogen deficiency is known to cause significant alterations in bone metabolism. Some people may develop osteopenia, a condition characterized by low bone density. Osteopenia can eventually lead to osteoporosis, a more severe condition with lower bone density. Treatment with soy isoflavones might be an alternative to hormone replacement therapy in decreasing bone loss from postmenopausal estrogen deficiency.the beneficial effects of soy isoflavones on bone depend on the estrogen receptor number and endogenous hormone milieu .Thus perimenopausal and menopausal women are more receptive to therapeutic effects of isoflavones on bone rather than postmenopausal ones.
Preventive effects of phytoestrogens against postmenopausal osteoporosis as compared to the available therapautic choices (2011).
Side effects:
Thyroid : Soy effects on the thyroid involve the critical relationship between iodine status and thyroid function. Studies on rats demonstrate that genistein actions on thyroid involve the inactivation of thyroid peroxidase (TPO) in vitro, with a dose-dependent mechanism. Although these effects are clear and reproducible, other measures of thyroid function in vivo (serum levels of triiodothyronine, thyroxine, and thyroid-stimulating hormone; thyroid weight; and thyroid histopathology) were all normal. Additional factors appear necessary for soy to cause overt thyroid toxicity. These clearly include iodine deficiency but may also include additional soy components, other defects of hormone synthesis, or additional goitrogenic dietary factors.
Goitrogenic and estrogenic activity of soy isoflavones (2002).
Meanwhile a more recent study achieved to demonstrate there is no effect of thyroid by genistein, concluding that genistein aglycone intake does not significantly increased the risk of clinical or subclinical hypothyrodism at the dose of 54 mg/d.
Genistein aglycone does not effect thyroid function: resulkts from a three-year, randomised, double blind, placebo controlled trial (2010).
Neural disorders : Consumption of dietary phytoestrogens resulting in very high plasma isoflavone levels (in many cases over a relatively short interval of consumption in adulthood) can significantly alter sexually dimorphic brain regions (influencing the brain androgen-metabolizing enzime, aromatase), anxiety, learning and memory. The biological actions of phytoestrogens, specifically isoflavones and their metabolites, found in animal soy-containing diets on brain and behavior implicate the importance of phytoestrogens in brain and neural disorders, such as Alzheimer's disease, especially in women.
Neurobehavioral effects of dietary soy phytoestrogens (2002).
