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LE Magazine February 1997

The Role of Soy In Medicine, Part 1

Palais des Congress - Sept. 15-17, 1996
By Candy Ostman

Brussels, Belgium was the site of the 2nd International Symposium on the Role of Soy in Preventing and Treating Chronic Disease. The turn out was huge. Over a thousand people from every corner of the globe in the "Palais des Congress"-a beautiful building with a water fountain out front and a spacious, modern theater inside, where the lectures were held. Downstairs, in the "Leopold 11 Room", were the exhibits and poster sessions.

image SEPT. 15, 1996

Phytochemicals and Cancer Prevention

The first topic of discussion on Sunday, September 15 was Cancer Prevention:Food and Phytochemicals by John Potter, M.D., Ph.D. of the Fred Hutchinson Cancer Research Center and University of Washington in Seattle, Washington.

Dr. Potter began by stating that the consumption of certain vegetables and fruits has long been believed to be useful in the prevention and treatment of disease. In 1981, Doll and Peto estimated that 10-to-70% of all cancers are attributable to diet. There appears to be much increased risk in associated with foods of animal origin. The evidence strongly suggests that it is not the consumption of one or two varieties of vegetables and fruit that confer benefit, but rather the intake of many kinds of plants can lower the incidence of cancer.

Dr. Potter pointed out that the fact that individuals who consume higher intakes of plant foods also have other healthy habits, such as a lower likelihood of smoking, does not necessarily account for the differences seen.

One reason the consumption of vegetables and fruits deters the development of cancer is that there are chemical compounds in these foods that prevent cancer formation. These include flavonoids, carotenoids, such as carotene, Vitamin-C, vitamin E, selenium, dietary fiber, as well as other chemicals such as dithiolthiones, isothiocyanates, indoles, phenols, and phytoestrogens. In scientific studies, these compounds have been shown to be anti-carcinogenic. Grouped as a whole, these chemicals are known as "phytochemicals" or "bioactive compounds".

Altering Carcinogenesis

Cancer progresses from exposure to carcinogens or their precursors through the actual appearance of a cancer. At almost every stage, phytochemicals have been shown to alter the likelihood of carcinogenesis. For example, the phytochemicals, lucosinolates, indoles, isothiocyanates and thiocyanates (all found in certain types of vegetables) can stimulate organs in the body to produce enzymes that inactivate carcinogens. Vitamin-C and phenols (present in wine and vegetables) block the formation of carcinogens such as nitrosamines. Flavonoids and carotenoids (widespread in vegetables and fruits) can act as antioxidants, actually disabling the carcinogenic potential of toxic compounds and free radicals.

Phytoestrogens (found in soybeans and also made from dietary fiber by bacteria in the colon) may be able to reduce the risk of hormone-related cancers, as well as combat other chronic diseases. Dietary fiber, upon fermentation in the colon, produces volatile fatty acids which may cause cancer cells to undergo programmed cell death.

Dr. Potter stated that, at present, it is not clear what quantity of fruit and vegetables we should eat every day to produce these anticarcinogenic effects, but he believes it should be at least 400 grams a day. He said he does not think you can get the same benefits from supplements alone, unless you consume a wide variety of fruits and vegetables on a regular basis.

Biotechnology and The Soybean

The next talk scheduled was on Biotechnology and the Soybean by Stephen Rogers, Ph.D. from the Monsanto Technical Center in Louvain-la-Neuve, Belgium.

Dr. Rogers explained that plant biotechnology enables researchers to transfer specific genes into crop plants to allow the expression of desirable traits such as disease prevention. He pointed out that there is a "glyphosate-tolerant soybean" (GTS) with a non-allergenic protein induced by genetic engineering, which has been shown to degrade readily in simulated gastric and intestinal fluids. This achievement indicates that, in the future, genetically-modified soybeans (and other plants) will enhance their ability to prevent and combat chronic disease.

Estrogenic Isoflavones

Next was an overview of Isoflavone Structure, Metabolism and Pharmacokinetics by Kenneth D. Setchell, Ph.D. of Children's Hospital and Medical Center in Cincinnati, Ohio.

While many types of plant constituents have been found with weak estrogenic activity, much of the current interest in these phytochemicals has focused on the isoflavones, which are phenolic compounds that possess many biologic properties including estrogenic activity. While the isoflavones are widely distributed throughout the plant kingdom, they are found in relatively high concentrations in soybeans. The principal isoflavones found in soy are daidzein, genistein, and glycitein.

Dr. Setchell's talk dealt with the chemical structure and metabolism of the different components of the soybean. He pointed out that, on ingestion, dietary isoflavones are metabolized by intestinal bacteria, absorbed from the intestinal tract and transported via the portal venous system to the liver. His conclusion was that the data indicate that consuming modest amounts of soy protein results in relatively high circulating concentrations of phytoestrogens and that this could have a significant hormonal effect in many individuals.

Soy Protein Prevents Gallstones

The ability of soy protein to prevent cholesterol gallstones (cholelithiasis) was discussed by Dr. Catala of LEPSD, INRA, Jouy-en-Josas, France. Dr. Catala sought to determine what the effects of both soy and animal protein on gallstones. Diet is thought to be a large factor in the formation of gallstones. It was found that cholesterol crystallization was retarded and decreased by soy protein, but not by animal protein. Among the other findings was that the proportion of ursodeoxycholic acid (a bile acid used for gallstone dissolution) was shown to be doubled in subjects on the soy protein diet.

Soy Isoflavones and the Effects of Alcohol

The effects of the isoflavones in soy on alcohol pharmacokinetics was discussed by Dr. Renee C. Lin of the Dept. of Medicine and Biochemistry, Indiana University School of Medicine and VA Medical Center in Indianapolis. Dr. Lin studied an extract from an edible vine, Pueraria Lobata, which has been widely used in chinese medicine, and contains the isoflavones puerarin, daidzin, and daidzein, was tested for its anti-inebriation and antidipsotropic effects. Experiments in rats showed that both daidzin and daidzein shortened alcohol-induced sleep-time if the rats received ethanol (alcohol) intragastrically, but not intraperitoneally. None of the isoflavones tested showed any effect on the activity of the liver enzymes dehydrogenase and aldehyde dehydrogenase when administered orally and, as a result, could not accelerate clearance by the liver enzymes of the ethanol in circulation.

In another experiment using alcohol-preferring rats (P rats), all three isoflavones suppressed voluntary alcohol consumption. The isoflavones were shown to lessen alcohol intoxication but suppress the appetite for alcohol.

SEPT. 16, 1996

Effects of Soy On Kidney Function

The effects of soy on renal function in patients with nephrotic syndrome was discussed by M.G. Gentile, M.D. of the Dept. of Clinical Nutrition and Department of Nephrology, S. Carol Hospital in Milan, Italy. Dr. Gentile presented evidence that lipids contribute to glomerular and tubulo- interstitial injury, and that correction of lipid abnormalities associated with renal disease could slow the progression of chronic renal failure.

It is well documented that high dietary levels of animal protein and fat can cause or exacerbate kidney dysfunction and disease. Soy protein, however, has been shown to reduce proteinuria, renal histological damage, hyperlipidemia and glomerular hyperfiltration in rats whose kidneys have been removed. In these studies, a vegetarian soy diet caused significant reduction of urinary protein excretion (more than 30%) and total cholesterol (28%) , and LDL cholesterol (28%) It was found that urinary protein excretion was reduced dramatically the rats were on the vegan soy diet, but tended to return to baseline after the experimental period ended.

Effect of Soy on Renal Function in Diabetes

Dr. James W. Anderson of the VA hospital at the University of Kentucky in Lexington reported his findings on the effects of soy protein on renal function in type II diabetic men with kidney disease. Dr. Anderson pointed out that almost one-third of all diabetics develop impaired renal function of some kind. The subjects were given 42 grams of either soy or animal protein per day. It was found that soy protein improved renal function in Type II diabetics with nephropathy, but that animal protein did not.

In a private interview with Dr. Anderson, he mentioned that, in addition to the renal benefits in diabetics, it was discovered that the soy protein diet significantly reduced (up to 90%) the need for insulin in insulin-dependent type II diabetics, and that soy protein also increased insulin sensitivity in the same individuals.

Diuretic Effect of Soy Isoflavones

Octavio J. Alda, M.D. presented evidence that the soy isoflavones (equol and genistein) have an ion transport inhibitory pattern similar to the potent loop anti-diuretic drug furosemide, a smooth muscle vaso-relaxant, which increases the renal excretion of sodium, chloride, potassium, magnesium, and calcium. He then presented findings of the comparative effects on kidney tubular and hemodynamic parameters of the isoflavones equol and genistein and furosemide.

It was shown that both genistein and equol stimulated fluid and electrolyte excretion similar to furosemide, with genistein more potent than equol. All three substances increased the glomerular filtration rate and filtration fraction, thus improving hemodynamic values. Furosemide and equol did not produce significant hemodynamic changes. This may be due to the fact that the rat kidneys in the experiment were not preconstricted. However, genistein was able to vasodilate the kidney.

Dr. Alda concluded that the soy isoflavinoids genistein and equol have many benefits in the treatment of diseases such as heart and kidney disease, and as replacements for loop-diuretics.

Can Soy Prevent Post-Menopausal Bone Loss?

Bahram H. Arjmandi, Ph.D. from the Dept. of Human Nutrition and Dietetics of the University of Illinois at Chicago looked at the effects of a high soy protein diet on bone loss in rats due to ovarian hormone deficiency. Dr. Arjmandi first pointed out that a synthetic isoflavone called ipriflavone has been shown to prevent bone loss in rats due to depleted ovarian hormones. He then described a study in forty-eight 95-day-old rats who had either been either ovariectomized, or given a sham operation, who were fed soy protein isolate with or without isoflavones.

The results showed much better bone health in rats fed soy protein with isoflavones than in rats fed soy protein isolate without isoflavone. Dr. Arjmandi noted that the results of the study showed soy protein containing isoflavones similar to ipriflavone, is very effective in preventing bone loss, and that soy protein rich in soflavones may very well be an effective treatment for preventing post-menopausal bone loss in women.

John Anderson, Ph.D. of the Dept. Of Nutrition at the University of North Carolina presented evidence that genistein has estrogen-like action that enables it to enhance the retention of bone in ovariectomized lactating rats. In fact, Dr. Anderson's studies suggest that certain levels of genistein are as effective as the potent estrogen replacement drug Premarin. According to these studies, a optimal dose of genistein (smaller doses seem more effective than larger doses) results in an equivalent per cent retention of bone mineral mass as a physiologic dose of the most potent of the estrogens-estradiol. Genistein has also been shown to preserve trabecular bone tissue.

Dr. Anderson believes that genistein may act as an agonist of estrogen receptors in bone tissues, however the effects of genistein may not be limited to this mechanism. He believes it might also effect other enzymes in bone cells, and postulates that genistein and diazdein (another isoflavone) have actions similar to peptide hormones and effect receptors or signaling proteins in the cell membrane. Fortunately, genistein does not appear to have any adverse side effects when used at reasonable levels. However, it does have the potential for toxic side effects in high doses. The same is not true of daidzen, which may operate by different mechanisms and appears to have very low toxicity.

Stimulating Bone Formation

Dr. Paolo Fanti of the University of Kentucky in Lexington discussed the effects of genistein on bone loss in ovariectomized rats. He started by stating that his studies indicate that the mechanism of action of genistein (the most abundant and best characterized soybean phytoestrogen) appears to differ from that of estrogens.

The protective effect of estrogen on bone is characterized by suppression of bone turnover, whereas the effect of genistein seems to depend on stimulation of bone formation rather than suppression of bone resorption. Although both estrogen and genistein protect against bone loss after cessation of ovarian function, genistein reduces both trabecular and compact bone loss. The amount of genistein excreted by the rats used in this study was similar to that recovered in humans after oral intake of the compound, indicating that therapeutic results are possible with dietary amounts. Genistein does not appear to affect osteoclasts. Both Premarin (the most popular estrogen drug) and genistein suppress cytokine production.

Clinical Study of Soy in Post-Menopausal Women

As part of a study in which the hypocholesterolemic effects of soy and isoflavones on postmenopausal women, scientists at the University of Illinois at Urbana-Champaign also investigated changes in bone density and bone mineral content prior and following the six-month study. According to Dr. John W. Erdman, 66 postmenopausal women received 40 grams of protein on a daily basis.

The content of the protein was either soy with a moderate concentration of isoflavones, soy with a high concentration of isoflavones, or a milk-derived protein containing neither soy nor isoflavones. Results showed significant increases in bone density and bone mineral content for the lumbar spine in both soy protein diets compared to the control diet. Increases in other skeletal areas also were noted in the soy diets. Dr. Erdman concluded that soy isoflavones show real potential for maintaining bone health.

Soy Lowers Cholesterol Levels

The first clinical study reporting the cholesterol-lowering ability of soy protein was in 1967. Individuals who received a textured soybean product rather than animal protein experienced a 20% drop in cholesterol. Dr. Cesare R. Sirtori of the University of Milan in Italy, who spoke at the soy conference, had similar results in his first clinical study using soy protein (20 to 24% reduction in total cholesterol).

image Many such studies have been conducted since, including studies in renal patients and children. In all cases, soy protein lowered cholesterol levels. It has been effective both in borderline high hypercholesterolemia patients and those with extremely high cholesterol levels. In fact, patients with cholesterol levels greater than 250-280 mg/dl have been shown to be most responsive to the cholesterol-lowering benefits of soy.

The mechanism by which soy exerts such a profound cholesterol-lowering effect remains elusive. Since isoflavones have low bioavailability, it's been suggested that the focus of attention should be on the protein components of soy. Dietary changes from animal protein to soy protein have been followed by significant increases in LDL-receptor activity in the liver in animals and lympho-monocytes in man. Dr. Sirtori feels that more studies are needed to identify the mechanism responsible for the ability of soy protein to stimulate LDL-receptor activity.

Dr. Susan Potter of the University of Illinois reported on the effects of a 40-gram soybean protein diet (one with high amounts of isoflavones, the other with moderate amounts) given to 66 hypercholesteremic, postmenopausal women on a daily basis.

The results showed reductions in total cholesterol for all groups, however the reductions were much more significant in the soy groups, the largest reduction occurring in the soy protein containing the highest level of isoflavones. According to Dr. Potter, the results indicate that soy protein, at each isoflavone level, may decrease the risk of cardiovascular disease by having positive influences LDL cholesterol, as well as the ratio of total cholesterol to HDL cholesterol. Not affected were levels of TSH, T4, T3, nor were levels of cortisol, insulin or glucagon. Interestingly, the soy protein with lower levels of isoflavones produced the most rapid response.

Elzbieta M. Kurowska, Ph.D. of the University of Western Ontario in Canada suggested that cholesterol reduction would be even greater if whole soybean products (containing soy protein and soy oil) were substituted for animal products (containing both animal protein and animal fat). To investigate this hypothesis, 34 hypocholesterolemic men and women were placed on a diet of either 2% cow's milk; a combination of skim milk and soy oil; or a soybean product containing soy protein and 2% soy oil.

The results, after about 6 weeks, showed that the whole soybean product had significantly increased HDL cholesterol levels by 7% and had decreased the LDL/HDL cholesterol ratio by 14%. Similar, although not as dramatic results, were observed in the skim milk and soy oil diet group. However, all groups showed very little effect on fasting plasma total, LDL cholesterol and triglycerides. Therefore, Dr. Kurowska concluded that the intake of whole soybean products can improve plasma lipid profiles in individuals with moderate hypercholesterolemia even though the effect is not entirely due to soy protein. Individuals with higher initial LDL and lower HDL cholesterol levels showed the best response to whole soybean products.

Response to Soy in Men With Normal Lipid Levels

Dr. Karin Nilausen of the University of Copenhagen School of Medicine in Denmark remarked that, in previous studies where soy protein was compared to casein (animal protein), decreases in LDL cholesterol (LDL-C) and increases in HDL cholesterol (HDL-C) were observed in individuals with normal cholesterol levels.. In the study he was reporting on at the conference, nine normolipidemic males were given a liquid protein formula containing soy protein for one month followed by a liquid protein formula containing casein for a month. After a month on each diet, plasma levels of HDL-C were found to have increased, while plasma levels of LDL were found to have decreased in subjects receiving the soy protein formula.

Dr. William W. Wong talked about how soy protein lowers plasma lipid levels in humans. Thirteen hypocholesterolemic men and 13 hypercholesterolemic men were placed on a soy protein or animal protein diet for 36 days, followed by a 70-to-107-day interim period. They were then placed on the alternative protein for an additional 36 days. At the end of this period, cholesterol absorption and bile acid kinetics were measured. The results showed that the soy protein diet lowered LDL cholesterol levels in both hypocholesterolemic and hypercholesterolemic individuals. Fractional cholesterol absorption and cholic acid kinetics were not affected by either diet.

Dietary Soy Prevents Atherosclerosis

Mary S. Anthony, M.S. of the Bowman Gray School of Medicine at Wake Forest University in Winston-Salem, North Carolina discussed the effects of soy isoflavones on atherosclerosis. She started her talk by stating that deaths from cardiovascular disease are much lower in countries like Japan where a great deal of soy is consumed.. "It is a well-known fact", she said, "that diets rich in soy reduce atherosclerosis, which seems due to soy protein's ability to reduce plasma lipoproteins.". In some studies, she noted, it has been shown that the addition of an alcohol extract of soy protein to a casein-based diet resulted in lower LDL cholesterol in rats.

Her studies in monkeys have shown that soy protein diets lower total plasma cholesterol and LDL cholesterol, and increase HDL cholesterol compared to a casein-based diet. In fact the casein-based diet had the highest risk for atherosclerosis, while soy-based diets showed the lowest risk. The soy diet also improved coronary artery reactivity, which has additional implications for the reduction of coronary heart disease. She concluded by saying that it appears that the alcohol-extractable components of soy protein, most likely genistein, are responsible for much of soy protein's cardiovascular benefits.

Phytoestrogens For The Menopause

Dr. Sulistiyani of the Primate Research Center at Bogor Agricultural University in Indonesia stated that, in his opinion, one of the reasons estrogen replacement therapy is so effective in helping to reduce the risk of coronary heartdisease in post-menopausal women may be due in part to its antioxidant properties. However, there is an increased risk of breast cancer and uterine cancer in those women using estrogen.

One alternative is to take phytoestrogens, such as genistein, which has been shown to protect the heart against cardiovascular disease. In studies using Cynomolgus female monkeys who had their ovaries removed to simulate post-menopausal women, it was shown that, in vivo genistein inhibited LDL oxidation by 48%. When used in combination with vitamin E this effect was even more pronounced.

SEPT. 17, 1996

Soy Fights Lipid Peroxidation

Dr. Takemichi Kanazaw of Hirosake University School of Medicine in Japan explored the molecular constituents contained in the soybean that are responsible for its ability to protect LDL cholesterol from peroxidation, as well as its anti-platelet ability, and other cholesterol-reducing effects. Dr. Kanazawa concluded that he believes soybeans can be very useful in the prevention of vascular disease.

Dr. Mary Astuti of Gadjah Mada University in Togyakarta, Indonesia discussed the role of the traditional food, tempe, a product of soybean fermentation, which is a good source of vitamin B-12 and iron, in lipid peroxidation. Tempe contains the antioxidant enzyme SOD (superoxide dismutase). In her studies in rats, Dr. Astuti found that tempe also has the ability to inhibit lipid peroxidation. She concluded that tempe may contain substances that have the ability to inhibit lipid peroxidation as well as having a positive effect on hyperlipidemia.

Dr. Alan Chart of the University of Washington in Seattle found that both genistein and daidzein (another soy isoflavone) inhibits LDL oxidation. He found that genistein is slightly more effective, although daidzein may not be as toxic in larger amounts. He also observed that the two isoflavones may exert their antioxidant effects in a manner similar to Vitamin-C, which quenches free radicals in the aqueous environments. He concluded that genistein and daidzein may be useful in the prevention of atherosclerosis.

Dr. Norberta Schoene of the Beltsville Human Nutrition Research Center in Beltsville, Maryland reported that isoflavones in soy may have a positive effect on cardiovascular disease because of the ability to decrease clot formation in platelets that cause vascular obstruction. The potential, she concluded, for soy to exhibit anti-thrombotic action deserves further study.