Potential Importance of Phytoestrogens to Human Health Molecular Mechanisms of Action

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The probable beneficial effects of phytoestrogens against breast cancer are likely to be mediated via numerous mechanisms. However, it has not been fully established whether the protective effects of soya and cereals result from their phytoestrogen content or from some other effect.

Many studies utilising breast cells in culture such as the oestrogen-sensitive MCF-7 cell line show that phytoestrogens (genistein was used in most of studies) stimulate tumor growth at low concentrations while inhibiting growth at higher concentrations. Genistein is a potent and specific in vitro inhibitor of tyrosine kinase action in the autophosphorylation of the epidermal growth factor (EGF) receptor and is thus frequently used as a pharmacological tool. The EGF receptor is overexpressed in many cancers, particularly those with the greatest ability for metastasis, and it has therefore often been assumed that some of the anticancer effects of genistein are mediated via inhibition of tyrosine kinase activity. However, this is likely to be an oversimplification of the true in vivo situation.

Although genistein is a much better ligand for oestrogen receptor fl (ERfl) than for the ERa (20-fold higher binding affinity), it can also act as an oestrogen agonist via both ERa and ERfl in some test systems. Mechanisms other than those involving oestrogen receptors are likely to be involved in the inhibition of cell proliferation by genistein because genistein inhibits both the EGF-stimulated and the 17fl-oestradiol-stimulated growth of MCF-7 cells. Although studies have shown that exposure to genistein can reduce the tyrosine phosphorylation of cell proteins in whole cell lysates, studies using cultured human breast and prostate cancer cells have not confirmed that genistein has a direct effect on the autop-hosphorylation of the EGF receptor. Many other mechanisms of anticancer action for isoflavones and genistein in particular have been suggested, including inhibition of DNA topoisomerases, cell cycle progression, angiogenesis, tumor invasiveness, and enzymes involved in oestrogen biosynthesis. They also include effects on the expression of DNA transcription factors c-fos and c-jun, on reactive oxygen species, on oxidative membrane damage and oxidative damage in vivo, and on the negative growth factor, transforming growth factor-fl (TGF-fl).

Although cholesterol lowering is probably the best documented cardioprotective effect of soya, vascular protection is also likely to contribute and may be mediated via a number of mechanisms. Soya isofla-vones are likely to contribute to the cardioprotective benefits of soya.

ERfl is the predominant ER isoform expressed in the rat, mouse, and human vascular wall. In the rat carotid injury model, following endothelial denudation of rat carotid artery, ERa is expressed at a low level, whereas the expression of ERfl increases by greater that 40-fold and treatment of ovariectomized female rats with genistein provides a similar dose-dependent vasculoprotective effect in this model to that observed with 17fl-oestradiol. However, studies in ERfl knockout mice have shown that ERfl is not required for oestrogen-mediated inhibition of the response to vascular injury and suggest that either of the two known oestrogen receptors (or another unidentified one) is sufficient to protect against vascular injury.

Vascular protection could also be conferred by the ability of genistein to inhibit proliferation of vascular endothelial cells and smooth muscle cells and to increase levels of TGF-fl. TGF-fl helps maintain normal vessel wall structure and promotes smooth muscle cell differentiation while preventing their migration and proliferation. Genistein has been shown to increase TGF-fl secretion by cells in culture, and increased TGF-fl production may be a mediator of some of the cardioprotective effects of soya isoflavones.

Antioxidant action is one of the mechanisms that may contribute to the vascular protective effects of soya isoflavones. Antioxidant properties have been reported for isoflavones both in vitro and in vivo. In a randomized crossover study of young healthy male and female subjects consuming diets that were rich in soy that was high (56 mg total isoflavones/day: 35 mg genistein and 21 mg daidzein) or low in isoflavones (2mg total isoflavones/day), each for 2 weeks, plasma F2-isoprostane concentrations were significantly lower after the high-isoflavone dietary treatment than after the low-isoflavone dietary treatment. The lag time for copper-ion-induced LDL oxidation was significantly longer.

Increased resistance to LDL oxidation has also been reported in a 12-week single open-group dietary intervention with soy foods (60 mg total isofla-vones/day) in normal postmenopausal women. A randomized crossover study in hyperlipidemic male and female subjects consuming soya-based breakfast cereals (168 mg total isoflavones/day) and control breakfast cereals, each for 3 weeks, reported decreased oxidized LDL (total conjugated diene content) following consumption of the soy-based breakfast cereal compared to the control.

Effects of soya isoflavones on arterial function, including flow-mediated endothelium-dependent vasodilation (reflecting endothelial function) and systemic arterial compliance (reflecting arterial elasticity), may contribute to vascular protection and these have been measured in a number of studies. A randomized double-blind study administering either soy protein isolate (118 mg total isoflavones/ day) or cesin placebo for 3 months to healthy male and postmenopausal subjects (50-75 years of age) showed a significant improvement in peripheral pulse wave velocity (reflecting peripheral vascular resistance and one component, together with systemic arterial compliance, of vascular function) but worsened flow-mediated vasodilation in men and had no significant effect on the flow-mediated vasodilation in postmenopausal women.

Some beneficial effects following dietary intervention with soy isoflavones have been observed on bone health, and the mechanism is likely to be via an oestrogenic action, particularly because ERfl is highly expressed in bone, although this requires further investigation. Consumption by postmeno-pausal women (6-month parallel group design) of soy protein (40g/day providing either 56 mg isofla-vones/day or 90 mg isoflavones/day) compared to caesin and nonfat dry milk (40 g/day) produced significant increases in bone mineral content (BMC)

and bone mineral density (BMD) in the lumbar spine (but not in any other parts of the body) only in the higher isoflavone (90mg/day) group compared to the control group. In a long-term study, consumption by postmenopausal women (2-year parallel group design) of isoflavone-rich soy milk (500 ml/day providing 76 mg isoflavones/day) compared to isoflavone-poor soy milk control (providing 1 mg isoflavones/day) resulted in no decline in BMC and BMD in the treatment group compared to significant losses in the control group. The ability to produce equol was associated with a better response to the treatment.

Some beneficial effects following dietary intervention with soy isoflavones have been observed on the cognitive function aspect of brain health, and the mechanism is likely to be via an oestrogenic action, particularly because ER^, in addition to ERa, is expressed in brain. Although other mechanisms may contribute, they remain to be elucidated. Consumption by young healthy male and female subjects (parallel group design) of a high-soy diet (100 mg isoflavones/day for 10 weeks) compared to a low-soy diet (0.5 mg isoflavones/day) resulted in improved cognitive function, including significantly improved short-term and long-term memory and mental flexibility. These improvements were found in males and females. Consumption by post-menopausal women (parallel group design, placebo controlled) of a dietary supplement (soy extract containing 60 mg isoflavones/day for 12 weeks) resulted in improved cognitive function, particularly improved long-term memory.

Phytoestrogens can cause infertility in some animals and thus concerns have been raised over their consumption by human infants. The isoflavones found in a subterranean clover species (in Western Australia) have been identified as the agents responsible for an infertility syndrome in sheep. No reproductive abnormalities have been found in peripubertal rhesus monkeys or in people living in countries where soy consumption is high. Indeed, the finding that dietary isoflavones are excreted into breast milk by soy-consuming mothers suggests that in cultures in which consumption of soy products is the norm, breast-fed infants are exposed to high levels without any adverse effects. Isoflavone exposure soon after birth at a critical developmental period through breast feeding may protect against cancer and may be more important to the observation of lower cancer rates in populations in the Far East than adult dietary exposure to isoflavones. Although some controversy exists as to whether soy-based infant formulas containing isoflavones pose a health risk, a review of studies on the use of soy milk in infants suggests that there is no real basis for concern. Toxicity from isoflavones may arise from their action as alternative substrates for the enzyme thyroid peroxidase, and people in Southeast Asia would be protected by the dietary inclusion of iodine-rich seaweed products.

Potential Importance of Glucosinolate Derivatives and Related Compounds to Human Health: Molecular Mechanisms of Action

There may be some important health protective effects of glucosinolate derivatives and related compounds. The hydrolytic products of some glucosino-lates have been shown to display anticancer properties. Glucosinolates are hydrolyzed following exposure to the endogenous plant enzyme myrosi-nase (also found in the gut microflora) to form iso-thiocyanates. Isothiocyanates are biologically active compounds with anticancer properties and are more bioavailable than glucosinolates.

A metabolite of glucobrassicin (3-indoylmethyl-glucosinolate), indole-3-carbinol has been shown to inhibit the growth of human tumors of the breast and ovary. Furthermore, indole-3-carbinol may modulate the oestrogen hydroxylation pathway such that a less potent form of oestradiol is produced, thus conferring protection against oestrogen-related cancers.

Consumption of Brussels sprouts (300g/day of cooked sprouts) for 1 week has been shown to increase rectal glutathione S-transferase -a and -k isoenzyme levels. Enhanced levels of these detoxification enzymes may partly explain the epidemiological association between a high intake of glucosinolates in cruciferous vegetables and a decreased risk of colorectal cancer. It is likely that genetic polymorphisms and associated functional variations in biotransformation enzymes, particularly in glu-tathione S-transferases, will alter the cancer preven-tative effects of cruciferous vegetables.

Compounds including the isolated glucosinolate sinigrin and aqueous extracts of cooked and autolyzed Brussels sprouts (rich in glucosinolate degradation products) decreased hydrogen peroxide-induced DNA stand breaks in human lymphocytes and thus exerted a DNA-protective effect. Oral adminiatration of sinigrin has been shown to induce apoptosis and suppress aberant crypt foci in the colonic mucosa of rats treated with 1,2-dimethylhydrazine. Similar effects were observed with oral administration of freshly prepared Brussels sprout juice, rich in glucosi-nolate breakdown products including isothiocyanates.

Isothiocyanates can prevent the formation of chemical carcinogen-induced tumors of the liver, lung, mammary gland, stomach, and oesophagus in animal models. The anticarcinogenic effects of isothiocya-nates may be mediated by a combination of mechanisms, including inhibition of carcinogen activation by cytochromes P450: This could be achieved by both direct inhibition of enzyme catalytic activity and downregulation of enzyme levels and induction of phase 2 enzymes such as glutathione transferases and NAD(P)H:quinone reductase (these detoxify any remaining DNA-attacking electrophilic metabolites generated by phase 1 enzymes). Dietary glucosinolates and their breakdown products have been tested as anticarcinogens in terms of their ability to induce the anticarcinogenic phase 2 enzyme marker quinone reductase in murine Hep a1c1c7 cells, and the relative activities observed were found to be dependent on the nature of the side chain of the parent glucosinolate.

Phenethyl isothiocyanate protects mice against nitrosoamine-induced lung tumorigenesis. It also modulates the activity of phase 1 and phase 2 xeno-biotic-metabolizing enzymes, resulting in the inhibition of the oxidative activation of a number of chemical carcinogens.

The isothiocyanate sulforophane is a particularly potent inducer of detoxification enzymes. A novel isothiocyanate-enriched broccoli has been developed that has an enhanced ability to induce phase 2 detoxification enzymes in mammalian cells compared to standard commercial broccoli.

Undesirable goitrogenic effects have been identified for isothiocyanates and other hydrolytic products of glucosinolates. Furthermore, in contrast to the anticancer effects of brassica vegetables discussed previously, a number of genotoxic effects have also been demonstrated in bacterial and mammalian cells. In bacterial assays (induction of point mutations in Salmonella TA98 and TA100 and repairable DNA damage in Escherichia coli K-12), juices from eight brassica vegetables tested caused genotoxic effects in the absence of metabolic activation. The order of potency was Brussels sprouts > white cabbage > cauliflower > green cabbage > kohlrabi > broccoli > turnip > black raddish. In mammalian cells, structural chromosome aberrations were observed with some of the juices, with the most potent being Brussels sprouts and white cabbage, and genotoxic effects were accompanied by decreased cell viability. The isothiocyanate-containing fraction (and other breakdown products of glucosinolates) of these brassica juices was found to contain 70-80% of the total genotoxic activity of the juices. The flavonoid- and other phenolic-containing fraction had a much weaker effect. In related studies, the isothiocyanates, allyl isothiocyanate and phenethyl isothiocyanate, were found to be more than 1000-fold more cytotoxic in a Chinese hamster ovary cell line than their parent glucosinolates (sinigrin and gluconasturtiin, respectively). Phenethyl isothiocya-nate also induced genotoxic effects (chromosome aberrations and sister chromatid exchanges).

More data are required before an overall recommendation can be made regarding the likely beneficial or otherwise influences of glucosinolates (and their derivatives) on human health.

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