Soy and Human Health

The Astonishing Functional Food: Soy Protein and Soy Constituents
Soy Protein and Coronary Heart Disease
Soy and Digestive Tract Health
Soy Protein In Renal Disease
How Can Soy Help Diabetes?
Soy Protein Enhances Energy, Stamina and Sport Performance
Soy and Cancers
Soy and Breast Cancer
Soy and Menopausal Symptoms
Soy and Pre-Menstrual Syndromes
Soy and Bone Health
Losing Weight Healthily with Soy
Soy and Urological Cancer
Soy Lecithin and Human Health
Clinical Abstracts on Soy
Soy Clinical Reviews in Reputable Medical Journals: 1995 -2002

External Link
Soy uses based on scientific evidence by National Institute of Health (USA)

Introduction

Recent interest in the constituents of soybeans, particularly the isoflavones, has been explored to the status of a promising nutraceutical with potentially significant health benefits. The back bones of isoflavones in soy are genistein (4',5,7-trihydroxyisoflavone), daidzein (4',7-dihydroxyisoflavone) (See Figure 1) and their metabolites. In addition, soy products are a source of lignans, coumestans, saponins, plant sterols, phytates (inositol hexaphosphate), and protease inhibitors, all of which are also garnering attention for their health-promoting benefits.1 Soy constituents have been shown to have estrogenic, anti-estrogenic, antiviral,2 anticarcinogenic,3-5 bacteriocidal, and antifungal6 effects. Isoflavones are antimutagenic,4 antioxidant,7,8 mild anti-inflammatory,9 antihypertensive,9 and antiproliferative effects.3,10

Classification of Isoflavones

Flavonoids are a subgroup of plant constituents, the polypenols of which are further differentiated into isoflavonoids, with isoflavones a subcategory of isoflavonoids. (See Figure 2). Isoflavones are the most abundant of the subclasses of isoflavonoids of which comprises of two important isoflavones, genistein and daidzein. Figure 1 shows the chemical structures of genistein and daidzein in which genistein is a more hydrophobic molecule than daidzein.

Absorption, Metabolism and Excretion of Soy Isoflavones

Isoflavones is metabolized in the intestinal tract prior to absorption. After absorption, the isoflavones are transported to the liver where they are removed from the portal blood are then eliminated, primarily via the kidneys, similar to endogenous estrogens.14

The bioavailability of soy isoflavones is influenced by an intact, healthy gut, with microflora capable of converting these isoflavones to their active forms.15 Wheat fiber appears to decrease the bioavailability of genistein. A small cross-over study of seven healthy women found a more fiber-rich diet resulted in 55 percent less plasma genistein 24 hours after soy intake and a 20 percent reduction in total urinary genistein and was postulated that a fairly insoluble wheat fiber reduced the absorption of genistein by its bulking effect and hydrophobic binding.16

Isoflavone Content of Soy Products

Alcohol extraction, a process used in the production of many soy protein concentrates and isolates (used in soy protein powders), results in the removal of up to 90 percent of the isoflavones.21 The isoflavone content of soybeans varies considerably depending on over 10,000 varieties of soybeans, the year harvested, geographic location, and the plant.22

Other Soy Constituents

Protease Inhibitors: Researchers have looked with interest at. Two prominent protease inhibitors from soybeans are Bowman-Birk inhibitor (BBI) and Kunitz-Trypsin inhibitor (KTI) and their potential anti-cancer and anti-inflammatory effects. Interestingly, BBI has been found to inhibit expression of certain oncogenes in irradiated animal models,25 as well as inhibiting chemically induced carcinogenesis.26,27 Both in vitro and in vivo animal models have demonstrated that BBI appears to exert its effects directly on the target organ rather than by a non-specific effect on metabolism.28,29 Some researchers have theorized the dietary intake of exogenous PIs indirectly increases endogenous PI formation.30 And, to the fact that both raw and cooked soy products are equally effective in reducing cancer incidence, even though heating virtually destroys all protease activity.31

Lignans: Lignans are capable of exerting a phytoestrogenic effect in humans via anti-tumor and antiviral activity.11

Phytosterols: Phytosterols, such as ß-sitosterol, are found in high concentrations in soy products help to lower cholesterol via by binding cholesterol in the gut.31 The typical Western diet contains about 80 mg/day as compared to the traditional Japanese diet contains approximately 400 mg/day.35,36

Coumestans: The phytoestrogen, coumesterol, as well as other coumestan isoflavonoids, have been found by some researchers in significant quantities in soy foods of all types, including soybeans, soy flour, soy flakes, isolated soy protein, tofu, soy drinks, and soy sprouts.37

Saponins: Saponins are distributed widely in the plant kingdom, including in soybeans and appear to have anti-cancer properties by virtue of their antioxidant and anti-mutagenic properties.38 They also bind cholesterol and bile acids in the gut.31 An in vitro study demonstrated saponins isolated from soybeans exhibited potent antiviral effects on the HIV virus. Saponin B1 completely inhibited HIV-induced cytopathic changes and virus-specific antigen expression within six days after infection. Saponin B2 exhibited similar, although less potent, effects.39

Phytates: Although phytic acid (inositol hexaphosphate) has been implicated in blocking the absorption of minerals, the phytate content of plants, including soy, seems to be responsible for some of the anti-cancer properties through its highly charged antioxidant that is capable of scavenging hydroxyl radicals and chelating metal ions such as the pro-oxidant, iron may be more important than the fiber in dietary colon cancer prevention.40 Phytates also appear to enhance natural killer cell activity42 and helps protect against cardiac ischemia and reperfusion injury in animal models.43 Table 2 provides the summary of the functionality of soy constitutuents.

The Hormonal Effects of Phytoestrogens in Adults

Lu et al found the consumption of soy products by premenopausal women resulted in decreased circulating ovarian steroids and adrenal androgens, as well as increased length of the menstrual cycle.48 Six healthy females, age 22-29, were given 12 oz soy milk three times daily with meals for one month. Daily isoflavone intake was approximately 100 mg each of daidzein and genistein (in the form of their glycosides, daidzin and genistin). The estradiol levels decreased by 31 percent on days 5-7 of the cycle, 81 percent on days 12-14, and 49 percent on days 20-22. Luteal phase progesterone levels decreased by 35 percent, and DHEA sulfate levels decreased progressively during the month by 14-30 percent. The length of the menstrual cycle increased during the soy-feeding month from 28.3 +/- 1.9 days to 31.8 +/- 5.1 days.

The effects of phytoestrogens vary greatly depending on the species of animal, the particular phytoestrogen compound being tested, the age of the animal, the length of time of ingestion, the presence or absence of exogenous estrogen, the target tissue in question, and the dosage used. Historically, the consumption of soy products in Asian cultures, from a very young age, has not resulted in any apparent negative effects related to hormone imbalances.

It appears phyto- estrogens exert mild agonistic and antagonistic effects on estrogen, depending on the level of endogenous estrogen present and on the tissue being tested. In vitro studies demonstrate an estrogenic effect in the absence of endogenous estrogen, and an anti-estrogenic effect in the presence of estrogen. Much of the effect of phytoestrogens might be due to enzyme inhibitions. It appears phytoestrogens have an inhibitory effect on many enzymes involved in the biosynthesis and metabolism of steroid hormones. The effect on enzymes is further discussed below.

Mechanism of Action of Soy Isoflavones

There are many proposed mechanisms for the therapeutic effects of isoflavones. The mechanisms include inhibition of protein tyrosine kinase (PTK), binding of estrogen receptors (although soy's inhibition of cancer cell growth does not seem to be entirely estrogen dependent),58 inhibition of production of reactive oxygen species,59 induction of DNA strand breakage resulting in apoptosis or cell death,58 inhibition of angiogenesis,60 modulation of sex steroid binding protein,61 inhibition of 5 alpha-reductase,62 inhibition of P-form phenolsulfotransferase (PST) -mediated sulfation,63 inhibition of thrombin formation and platelet activation,64 and increased LDL receptor activity.65 The therapeutic implications of each of these mechanisms is elaborated below.

Therapeutic Applications

Cancer: Epidemiological studies showed that soy might be cancer protective, in which people from Asian cultures eating a diet high in soy foods, such as tofu, demonstrated lower rates of several types of cancers, including types not typically considered to be hormone- or diet-related. Based on 21 epidemiological studies, which evaluated the effect of soy diets on 26 different cancer sites found that 10 showed decreased risks for rectal, stomach, breast, prostate, colon, and lung cancers, while 15 showed no significant effect. Only one, in which fried bean curd was evaluated, showed an increased risk for esophageal cancer. On the other hand, the effects of fermented soy products miso soup and soybean paste were much less consistent.

Twenty-one studies, involving 25 cancer sites, evaluating fermented soy products, found an increased cancer risk in four studies, mixed results in four, no significant effects in 14, and a decreased risk in three. The increased risks of cancer from consumption of fermented soy products appear to involve primarily the gastrointestinal tract esophageal, stomach, colorectal, and pancreatic cancers.66 Please refer Table 3 for a summary of these studies.

Messina et al examined 26 animal studies and reported that 17 (65%) of them demonstrated a protective effect of soy from experimental carcinogensis.66

There are many proposed mechanisms for the anti-cancer benefits of soy-based foods. Inhibition of PTK activity has been proposed as a major mechanism in the prevention of carcinogenesis. While synthetic PTK inhibitors have been proposed for the treatment of cancer, expected toxicity has restricted their development. In 1987, it was discovered genistein is a natural PTK inhibitor.58 Tyrosine kinase inhibition results in the inhibition of leukotriene production, (products of inflammation which have been implicated in the stimulation of tumor growth). In vitro studies found pretreatment of cancer cell lines with genistein completely inhibited leukotriene production.68

Influence on a number of other enzymes has been suggested as a possible mechanism for the anti-cancer properties of isoflavones. Some of these enzymes include DNA topoisomerases,69,70 ribosomal S6 kinase activity,71 phospholipase C-gamma,72 phosphatidylinositol kinases,73 and mitogen-activated protein kinase.74 In addition, genistein demonstrated in vitro inhibition of phenolsulfotransferase, an enzyme involved in sulfation-induced carcinogensis.63

In vitro studies have found genistein to be a very potent inhibitor of neovascularization or angiogenesis, one of the proposed mechanisms for cancer growth inhibition.60 Isoflavone effects on hormone regulation, expression and metabolism have been elaborated above and are discussed further below in the sections on breast and prostate cancer.

At issue in the study of soy isoflavones in the treatment of cancer is whether the concentration achieved by dietary consumption of soy products is enough to influence tumor growth. Studies on human volunteers consuming soy beverages, which provided 42 mg genistein and 27 mg daidzein daily, resulted in peripheral blood concentrations of 0.5-1.0 microM, a concentration much lower than that necessary to inhibit growth of cultured cancer cells.75 However, these same researchers found non-transformed mammary epithelial cell cultures to be much more sensitive to genistein, with inhibition of growth stimulation occurring in the range of 1-2 microM. This suggests a role of isoflavones as chemopreventive rather than chemotherapeutic agents.

Breast Cancer: Case-controlled, epidemiological, in vitro, and animal studies point to effectiveness of soy isoflavones in the prevention of breast cancer. A case-controlled study, published in the October 4, 1997 issue of The Lancet, examined the effect of phytoestrogens on breast cancer risk in one hundred forty-four women with early diagnosed breast cancer were paired with age and area-of-residency-matched controls. Adjustments were made for age at menarche, parity, and alcohol and total fat intake. Increased ingestion of soy isoflavones was associated with a reduction of up to four-fold in the risk for development of breast cancer.

Two case-controlled studies, one in Singapore,77 and one in Japan,78 found significant protection from soy intake for pre- but not postmenopausal women.

Epidemiological studies demonstrate an inverse relationship between soy intake and incidence of breast cancer (see Table 3). Americans have two to three times the breast cancer rate of Asians eating a traditional diet.79 An epidemiological study of Asian-American women found tofu intake to correlate inversely with breast cancer incidence, after adjustment for other dietary, menstrual and reproductive factors.80 This effect was observed both in pre- and postmenopausal women.

In summary, all four of the human studies examined seemed to indicate a protective effect of soy against breast cancer in premenopausal women. The effect on post-menopausal women was significant in two of the four studies.

In vitro experiments with human breast cancer cells confirm genistein to be a potent inhibitor of cell growth, regardless of estrogen receptor status. Other isoflavones, daidzein and biochanin A, demonstrated weaker growth inhibition.81-83 Pagliacci et al reported the in vitro inhibition of MCF-7 human breast cancer cells occurred through blocks at critical points in cell cycle control as well as via induction of apoptosis.84 Wang et al found genistein produced a concentration-dependent effect on breast cancer cell cultures. At lower concentrations (10-8 to 10-6 M) genistein stimulated growth, while higher concentrations (>10-5) inhibited growth. They concluded the effect of genistein at the lower concentrations appeared to be estrogen receptor mediated, while effects at higher concentrations were independent of estrogen receptors.51 Barnes et al found soy in the form of raw soybeans as well as soy protein isolate inhibited mammary tumors in experimental models.87

Prostate Cancer: Epidemiological evidence points to the benefits of soy constituents in the prevention of prostate cancer. Japanese men who consume a low-fat, high soy diet have low mortality rates from prostate cancer. Isoflavones in the plasma of Japanese men were between 7 and 110 times higher than in Finnish men, with genistein present in the highest concentrations.88 Mechanisms suggested include genistein-induced prostate cancer cell adhesion, direct growth inhibition, and induction of apoptosis. Growth inhibition appears to be independent of genistein's estrogenic effects.89 An in vitro study indicated the isoflavones genistein, biochanin A, and equol were potent inhibitors of 5 alpha-reductase,62 the enzyme necessary for the conversion of testosterone to dihydrotestosterone (implicated in prostate cancer).

Studies have found that animals fed soy isolates high in the isoflavones, genistein and daidzein, demonstrated a reduced incidence of prostate cancer and a 27 percent longer disease-free period after exposure to chemical carcinogens than animals fed a soy isolate low in isoflavones.90 This not only points to the potential chemoprotective effects of soy, but seems to point to the importance of the isoflavones over other soy constituents. Peterson and Barnes found the isoflavones, genistein and biochanin A, but not daidzein, to inhibit several human prostate cancer cell lines.91

NIH Recommendations: The committee of the National Institutes of Health (NIH) studying chemoprevention from soy products made the following recommendations: "1. Future dietary studies involving soybeans should be carried out using soy products rather than isolated compounds, since soybeans appear to contain several potential anticarcinogens. 2. Standardized and improved analytical methods are needed so that the contents of all soy-based materials employed in soybean research, whether soybean fractions or soy products, can be accurately described. 3. Basic research in the absorption, metabolism, and physiology of potential anticarcinogens in humans should be conducted."

Cardiovascular Disease: A large meta-analysis of 38 controlled studies of the effects of soy diets, with animal protein diets serving as the controls, found a statistically significant decrease in serum lipids in the soy group. The changes were most significant in hypercholesterolemic subjects92. The intake of energy, fat, saturated fat, and cholesterol was similar between the two groups. Gooderham et al reported no effect on platelet aggregation or serum lipid levels in healthy, normocholesterolemic men fed soy protein compared to casein.93

One of the proposed mechanisms for the hypolipidemic effect involves an increase in LDL receptor activity in both humans and animals.65 Other metabolic changes which have been noted in animals and humans on soy diets include increased cholesterol and bile acid synthesis, increased apolipoprotein B and E receptor activity, and decreased hepatic secretion of lipoproteins (associated with increased clearance of cholesterol from the bloodstream).94 Proposals for the specific constituents involved include the amino acid profile, saponins, phytic acid, fiber, as well as the effects of isoflavones discussed below.94

Arterial thrombus formation is generally initiated by an injury to the endothelial cells lining the blood vessels. One of the first events after an injury is thrombin formation. This leads to a cascade of events including platelet activation, resulting in thrombus formation. Genistein has been found to inhibit thrombin formation and platelet activation.64 The pathogenesis of atherosclerotic plaque formation also involves, in addition to lipid accumulation, the infiltration of monocytes and T-lymphocytes into the artery wall, contributing to the thickening of the wall and occlusion of the vessel. Monocytes and lymphocytes are permitted to adhere to the endothelial cell surfaces via the expression of certain "adhesion molecules." The infiltration and proliferation appear to be controlled by peptide growth factors. Increased levels of isoflavones, genistein in particular, appear to alter the growth factor activity, and inhibit cell adhesion and proliferation, all activities necessary for lesion formation in the intima of the blood vessels95.

Animal studies with monkeys have confirmed the cardioprotective effects of soy. Soy protein diets, when compared to casein diets, resulted in significant improvements in lipid profiles, insulin sensitivity, and a decrease in arterial lipid peroxidation.96 Furthermore, animal studies also indicate the isoflavone content of the soy is an important factor. Monkeys were fed soy isolates high in isoflavones and compared in a cross-over trial with a soy isolate in which the isoflavones had been removed via alcohol extraction. LDL, VLDL, and total cholesterol:HDL ratios were significantly lowered, while HDL was significanly elevated in the group on the isoflavone-rich diet.21 No lipid lowering effect occured in the group on the casein diet.

Other Potential Therapeutic Benefits: While research on the health benefits of soy constituents has focused primarily on the chemopreventive effects for cancer and cardiovascular disease, there are a few other conditions which might benefit from the addition of soy isoflavones to the diet such as Osteoporosis, Eye disorders: (proliferative diabetic retinopathy).

Conclusion

Research indicates soy and its individual constituents have several potential health benefits. The primary isoflavones, genistein and daidzein, as well as their metabolites, exert a wide array of effects, which appear to offer protection against cancer, cardiovascular disease, osteoporosis, and ocular neovascularization. Many of the studies to date have been either epidemiological, animal, or in vitro. Further controlled human trials are needed to confirm the preliminary findings reported in these studies.

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