Isoflavones And Other Soy Constituents In Human Health And Disease

In the past several years, soy and its constituents have garnered considerable attention, from both researchers and health practitioners. Epidemiological data which indicated people from Asian cultures have lower rates of certain cancers, including cancer of the breast, prostate and colon, sparked an interest in soy as a contributing factor. While soy constituents, including saponins, lignans, phytosterols, protease inhibitors, and phytates, have come under investigation, the constituents which seem to hold the most promise from a therapeutic standpoint are the two isoflavones, genistein and daidzein. Numerous epidemiological, human, animal, and in vitro studies have demonstrated that soy isoflavones are effective chemopreventive agents for certain types of cancer. Mechanisms involved include antiangiogenesis, estrogen receptor binding, modulation of sex hormone binding globulin (SHBG), anti-inflammatory and antioxidant effects, and inhibition of the enzymes protein tyrosine kinase (PTK) and 5 alpha-reductase. Interaction with many other enzymes has been suggested. Evidence also points to the beneficial effects of soy, particularly the isoflavones, in prevention of cardiovascular disease. Isoflavones appear to inhibit platelet activating factor and thrombin formation. They also increase HDL cholesterol and decrease triglycerides, LDL, VLDL, and total cholesterol. Other potential health benefits of soy include prevention of osteoporosis, via the phytoestrogen effects of isoflavones, and prevention of neovascularization in ocular conditions, via inhibition of angiogenesis. (Alt Med Rev 1997;2(6):433-450) Introduction Recent interest in the constituents of soybeans, particularly the isoflavones, has catapulted soy to the status of a promising nutraceutical with potentially significant health benefits. The principle isoflavones in soy are genistein (4',5,7-trihydroxyisoflavone), daidzein (4',7dihydroxyisoflavone) (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. Soy constituents have been shown to have estrogenic, anti-estrogenic, antiviral, anticarcinogenic, bacteriocidal, and antifungal effects. Isoflavones also have antimutagenic, antioxidant, mild anti-inflammatory, antihypertensive, and antiproliferative effects. This article will focus Kathi Head, N.D.—Technical Advisor, Thorne Research, Inc.; Associate Editor, Alternative Medicine Review. Correspondence address: P.O. Box 3200, Sandpoint, ID 83864, e-mail: [email protected] opyright 2001 horne esearch, Inc. ll ights eserved. o eprint ithout ritten Per ission Page 434 Alternative Medicine Review ◆ Volume 3, Number 1 ◆ 1998 Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission primarily on isoflavones as these are the constituents found in greatest quantity in soy products. Brief reference will be made to other beneficial constituents. Classification of Isoflavones Flavonoids are a subgroup of the larger group of plant constituents, the polypenols. Flavonoids are further differentiated into isoflavonoids, with isoflavones a subcategory of isoflavonoids. See Figure 2. Isoflavonoids differ from other classes of flavonoids by their greater structural variability, their frequent presence in plants in their free form, rather than as a glycoside, and by the greater frequency of isoprenoid substitution. They are not as ubiquitous in nature as some of the other flavonoids such as flavones and flavonols, being found primarily in one subfamily of Leguminosae, the Papilionoideae. Approximately 600 isoflavonoids have been identified. They are divided into subclasses depending on the oxidation level of the central pyran ring. Isoflavones are the most abundant of the subclasses of isoflavonoids. Genistein and daidzein are two important isoflavones. As can be seen in Figure 1, genistein has a hydroxy group in the 5 position, giving it three hydroxy groups, while daidzein has just two. Due to the fact that the 5 hydroxy group on the genistein binds to the 4 ketonic oxygen, genistein is a more hydrophobic molecule than daidzein. This affords genistein some of its unique therapeutic effects. Absorption, Metabolism and Excretion of Soy Isoflavones Isoflavones undergo extensive metabolism in the intestinal tract prior to absorption. Genistein is formed from biochanin A, and daidzein from formononetin. Genistein and daidzein also occur in soy products in the form of their glycosides, genistin and daidzin. In the case of the glycosides, intestinal bacterial glucosidases cleave the sugar moieties, releasing the biologically active isoflavones, genistein and daidzein. In adults, these are futher transformed by bacteria to specific metabolites: equol, O-desmethylangolensis, dihydrogenistein, and p-ethylphenol. Due to soy intake by livestock, isoflavone metabolites are also consumed directly in a diet high in dairy products and meat. In at least one study, genistein was well-absorbed in the small intestines by human subjects fed a soy beverage. After absorption, the isoflavones are transported to the liver where they are removed from the portal blood. However, a percentage of the isoflavones in the portal blood can escape uptake by the liver and enter the peripheral circulation. The effectiveness of this hepatic first-pass clearance influences the amount which reaches peripheral tissues. The isoflavones are then eliminated, primarily via the kidneys, similar to endogenous estrogens. After examining plasma, fecal and urinary concentrations of isoflavones in healthy volunteers, Xu et al concluded the bioavailability of soy isoflavones is influenced by an intact, healthy gut, with microflora capable of converting these isoflavones to their active forms. Wheat fiber appears to decrease the bioavailability of genistein. A small crossover study of seven healthy women found a O OH HO O Daidzein O OH HO O OH Genistein Figure 1. Structure of Genistein and Daidzein