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Paula Gaynor, Ph.D.
Muhammed Majeed, Ph.D.,
 
Sabinsa Corporation
New Jersey, U.S.A.
 
 
Paper presented at the 36th National Pharmacy Week Celebration under the auspices of Indian Pharmaceutical Forum,
U.A.E.
1997
 

 
Introduction
 

Epidemiological data has unequivocally demonstrated that a diet rich in plant-based foods is closely linked with lower incidence of many of the major diseases that are so prevalent in today’s Western population. Although several classes of bioactive non-nutrients with weak estrogenic activity are considered to potentially play a role in disease prevention, much of the current interest has focused on a group of compounds belonging to the isoflavone class1. While isoflavones are widely distributed in the plant kingdom, the concentrations of these compounds are relatively high in legumes and in particular in the soybean2. The principal isoflavones present in soybeans and soyfoods are genistein, daidzein and glycitein and, for the most part, these aglycones usually exist in soy as various forms of glycosidic conjugates1, i.e., genistin, daidzin and glycitin.

There has been a veritable explosion of interest in genistein (4¢ ,5,7-trihydroxyisoflavone3) in the last ten years. Numerous studies have focused on the mechanisms by which genistein functions as an anticarcinogen. In addition, genistein may have a role to play in the prevention of osteoporosis and cardiovascular disorders - conditions which frequently accompany menopause in women.
 
   
 
Biological Properties of Genistein
 
1. Genistein and Cancer.  
 

Epidemiological evidence suggests that the low incidence of breast cancer in oriental women is related to the consumption of a flavonoid-rich diet4. Additionally, pre-clinical and clinical studies provide substantial evidence that genistein may function as an effective anti-carcinogenic agent. There are several mechanisms by which genistein is thought to exert its anti-carcinogenic properties.

1(a). Estrogenic/antiestrogenic activity:
Genistein has been shown to exhibit anti-estrogenic5 as well as estrogenic6 activity and both mechanisms could contribute to the protective effect of genistein in the development of breast cancer. A decrease in estrogen receptor number, as induced by the anti-estrogenic effect of genistein would lead to a decreased responsiveness to endogenous estrogens5, thereby playing a role in breast cancer prevention. The direct estrogenic activity of genistein resulted in a more differentiated, mature mammary gland7 consequently leading to greater protection against chemically induced mammary tumors8,9.

Isoflavones may help to prevent breast cancer by virtue of their intrinsic estrogenic activity - when ingested they may serve to downregulate the hypothalamus and pituitary and thereby reduce the ovarian synthesis of estrogens6. In pre-menopausal women, an isoflavone rich diet (45 mg/day for one month) was potentially beneficial in the prevention of breast cancer because it increased the length of the follicular phase and delayed menstruation10. Another clinical study showed that one month of soymilk ingestion (100mg genistein/day and 100mg daidzein/day) reduced the levels of 17b-estradiol and progesterone in six healthy premenopausal females6. Lower levels of ovarian hormones decrease the risk of breast cancer11.

1(b). Antioxidant Effects:
Genistein’s ability to function as an antioxidant may also be responsible for the anticarcinogenic effect of this isoflavone. Genistein has been shown to be a more potent antioxidant than other isoflavones and is also capable of inhibiting free radical oxygen species (O2.-) generation by xanthine oxidase. Reactive oxygen species are known to play an important role in mutagenesis and carcinogenesis12.

1(c). Inhibition of Tyrosine Kinase and Topoisomerase II Activity:
Tyrosine kinases and receptor tyrosine kinases are critical components of the biological control networks that govern cellular growth and differentiation13. Enhanced activity of tyrosine kinases has been implicated in many cancers14. In vitro trials have consistently shown that genistein is capable of inhibiting the activity of tyrosine kinase15-18. This further implicates the use of genistein as an anti-carcinogen since tyrosine kinase-specific inhibitors may be potentially employed as anti-cancer agents15.

Some of the most potent anti-tumor agents currently used in cancer chemotherapy inhibit DNA Topoisomerase (Topo) I or II. These enzymes are involved in the processes of DNA replication, transcription and recombination and play a key role during cell proliferation and differentiation19. A number of in vitro studies have demonstrated that genistein is capable of inhibiting TopoII20-22.

1(d). Induction of Apoptosis and Differentiation of Tumor Cells:
Apoptosis (programmed cell death) is a significant event in the physiological and pathological situations that control the development, differentiation and regression of tumor cells. On the basis of in vitro results, it has been proposed that genistein antagonizes tumor cell growth through both cell cycle arrest and induction of apoptosis23.

Most normal tissues are differentiated; that is, they have developed a specialized function and appearance. One of the major strategies currently being used in the fight against cancer is the use of noncytotoxic concentrations of agents that promote terminal differentiation (and hence inhibit proliferation) of human tumor cells24. In vitro studies have shown that genistein is capable of inducing differentiation of both human and animal cancer cells21, 24, 25.

1(e). Inhibition of Angiogenesis:
Possibly the most clinically important manifestation of pathological angiogenesis (the generation of new capillaries) is that induced by solid tumors. It has been demonstrated that genistein is the most potent amongst several plant diet derived inhibitors in preventing angiogenesis. The fact that epidemiological studies have revealed that people consuming the traditional soy rich Japanese diets are less prone to breast and prostate cancers, supports the speculation that genistein may prevent the development of solid tumor growth by inhibiting neovascularization26.

1(f). Inhibition of Multidrug Resistance to Anticancer Drugs:
Multidrug resistance (MDR) is the simultaneous resistance to several types of commonly used anti-neoplastic agents and it leads to the failure of cancer chemotherapy due to decreased drug accumulation in resistant cells. In vitro studies have shown that genistein is capable of reversing decreased drug accumulation27 and decreasing the resistance of leukemia cells to a number of anti-cancer drugs28.

 
     
2. Genistein and Osteoporosis  
 

Osteoclasts are macrophage derivatives which mediate bone degradation and osteoporosis results when the rate of osteoclastic bone degradation (resorption) exceeds bone formation. A recent patent has shown that genistein can inhibit osteoclast acid secretion (acid secretion leads to bone degradation) and reduce bone resorption29. It has also been concluded that genistein suppresses osteoclastic function in vivo and in vitro at concentrations consistent with a tyrosine kinase mechanism and has low toxicity29. The results of a six month clinical study involving sixty six postmenopausal women also indicate the potential use of soy isoflavones in the maintenance of bone health30.

  
     
3. Genistein and Cardiovascular Disease  
 

Although dietary soy protein is well recognized for its beneficial effects in the promotion of cardiovascular wellness31, the role which isoflavones and genistein play is still largely under investigation. The effects of genistein on platelet aggregation, cholesterol levels and lipoprotein levels have been investigated.

3(a) Platelet Aggregation
In individuals with conditions such as atherosclerosis and heart disease, excessive platelet aggregation leads to clot formation and may increase the risk of heart attack and strokes. Consequently, any factor which inhibits excessive platelet aggregation is potentially beneficial. Genistein was shown to inhibit platelet aggregation in vitro32, 33. In a clinical study, it was shown that the consumption of a soy protein isolate beverage powder can increase plasma isoflavonoids to levels which are insufficient to significantly inhibit platelet aggregation ex vivo. It was suggested that future studies be conducted to evaluate whether a larger subject group or higher plasma isoflavone concentrations are required to reach a statistically significant inhibition of platelet aggregation in ex vivo studies34.

3(b). Cholesterol and Lipoproteins Levels:
Lipoproteins are responsible for the transport of the major blood lipids and are classified as high-density lipoproteins (HDL), low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL). A larger proportion of total serum cholesterol carried as HDL-cholesterol is associated with a reduced risk of atherosclerosis and cardiovascular disease while elevated LDL-cholesterol is associated with the development of atherosclerosis35. Peripubertal rhesus monkeys were fed a diet which contained either soy protein isolate with the isoflavones intact (Soy +) or extracted (Soy -). Administration of the Soy + diet caused a larger reduction in the LDL and VLDL cholesterol in males and females, increased HDL-cholesterol levels in females and decreased the total plasma cholesterol to HDL-cholesterol ratio by 20% for males and 50% for females. The beneficial effects of the Soy (+) diet were most likely due to the presence of the isoflavones36. In normocholesterolemic patients, plasma concentrations of total cholesterol and HDL-cholesterol were not significantly altered after 28 days of consuming 60 g/day of soy protein isolate beverage powder. It was considered that a lowering of total cholesterol levels may have occurred had the patients been hyperlipidemic upon entry into the study34.

  

 

 
 

Metabolism, Bioavailability and Toxicity of Genistein.

  
 

As mentioned above, in soy foods, the aglycones genistein and daidzin are mainly present in the glucoside forms genistin and daidzin, e.g. in soybean milk powder, only 4-5% of the isoflavones are in the form of aglycones37. Absorption of soybean isoflavones may begin in the proximal small intestine38. Lower down in the intestine, the gut bacterial deconjugating enzymes hydrolyze the isoflavone glycosides to produce genistein and daidzein. In addition, glucosidases of intestinal microflora in the lower bowel can liberate the aglycones, thereby promoting their absorption. The intestinal microflora, however, also extensively metabolize and degrade the isoflavones, thereby prohibiting their reabsorption from the lower bowel38. After absorption, isoflavones are extensively transformed by phase II enzymes thus making their retention in the human body unlikely39. Following transformation, isoflavones undergo urinary and biliary excretion38.

In a clinical study, genistein was shown to have relatively poor bioavailability39. The considerable variation in genistein bioavailability among seven female subjects in a similar study38 was attributed to the relative ability of gut microflora to degrade isoflavones. Despite the relatively low bioavailability of isoflavones, genistein may still be absorbed in sufficient quantities to exert potentially beneficial biological effects 38,39.

Since one-third of the world’s population consume substantial amounts of soy, and hence genistein, and have low rates of breast and prostate cancer and of cardiovascular disease, it can be concluded that in humans, genistein is not toxic and may indeed be the cause of the lower risk of these diseases40. The administration of upto 50 mg of genistein in the form of one or more tablets is reported to have no significant toxicity and no or few side effects29.

  
 
Conclusion  
 

On the basis of the numerous scientific studies published in peer-reviewed literature, it may be concluded that genistein is potentially beneficial in treating diseases such as cancer and osteoporosis. It’s role in the prevention of cardiovascular disease requires further investigation at this point in time. Epidemiological studies and the history of soy consumption in Asia offer sufficient evidence with regard to the safety and health benefits of genistein.

In view of the multi-faceted benefits of this soy isoflavone, it may seem prudent to shift towards soy-rich diets. However, soy foods contain the b-glucoside, genistin and conversion to the active aglycone form is dependent upon the activity of the gut microflora which in turn results in wide variations in the bioavailability of genistein from soy products38.

Consequently, the administration of genistein in the form of a standardized dietary supplement is a convenient means of ensuring improved absorption with the resulting potential health benefits.

  
 
References  
 
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