The Journal of Nutrition Vol. 128 No. 10 October 1998, pp. 1589-1592

Soy Protein, Isoflavones and Cardiovascular Disease Risk^1,2

Alice H. Lichtenstein

Lipid Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111

	ABSTRACT

Abstract Introduction References

Since the early 1940s, scientists have examined the effect of soy protein on blood cholesterol concentrations. Although studies in animals have suggested that soy protein lowers blood cholesterol concentrations, similar studies in humans have yielded less consistent results. The presence or absence of the soybean isoflavone fraction may be a confounding factor. This fraction, consisting primarily of genistein, daidzein and glycetein, has been shown to have a hypocholesterolemic effect in animals and humans. Potential mechanisms by which soy protein and/or isoflavones induce lowering of blood cholesterol concentrations include thyroid status, bile acid balance and the estrogenic effects of genistein and daidzein. Some studies have suggested that isoflavones exhibit antioxidant properties and have favorable effects on arterial compliance. In addition to the aforementioned potential beneficial effects, the increased consumption of products containing soy protein may displace foods relatively high in saturated fat and cholesterol from the diet and hence have an indirect blood cholesterol-lowering effect.

	INTRODUCTION

Abstract Introduction References

The majority of work assessing the effect of diet on coronary heart disease (CHD) risk has focused on the fat and cholesterol content of the diet. Support for this relationship has been gleaned from both epidemiology and laboratory-based research. Despite tremendous efforts during the greater part of this century directed at clarifying the specific issues associated with the diet/CHD and diet/blood cholesterol level relationships, controversy remains (Conner and Conner 1997, Katan et al. 1997). One potential explanation for the lack of resolution may be related to dietary factors, other than fat, that play a role in regulating blood lipid concentrations. A recent meta-analysis of the available data has suggested a hypocholesterolemic effect of soy protein (Anderson et al. 1995). However, some outstanding issues remain, limiting the extent to which these findings can be extrapolated to make public health recommendations.

	SOY PROTEIN AND BLOOD CHOLESTEROL CONCENTRATIONS

The effect of dietary soy protein on blood cholesterol concentrations in the rabbit was first reported in the 1940s by Meeker and Kesten (see review by Kristchevsky 1995). Subsequent studies in a variety of animal species including rats, hamsters, guinea pigs, pigs, cynomolgus monkeys and baboons, but not dogs (Campbell et al. 1995), are consistent with the original research (see review by Carroll and Kurowska 1995; Anthony et al. 1996). Of note was the observation by Huff et al. (1977) that soy protein or an enzymatic hydrolysate of soy protein compared with casein lowered blood cholesterol concentrations in rabbits, but a mixture of L-amino acids equivalent to that of soy protein was not as effective. This observation has been subsequently confirmed (Tasker and Potter 1993).

After conducting an investigation focused on the effects of dietary carbohydrate on blood lipid concentrations in humans, Hodges et al. (1967) noted that the substitution of vegetable protein (soy) for animal protein resulted in a decrease in serum cholesterol concentrations. Over the next 20 years, a number of investigators reported similar hypocholesterolemic effects of soy protein (see reviews by Carroll and Kurowska 1995 and Sirtori et al. 1995). More recently, the results of work by Potter et al. (1993), Wong et al. (1995) and Teixeira et al. (1998) have suggested that isolated soy protein significantly lowered total and LDL cholesterol and in some cases maintained HDL cholesterol concentrations in mildly hypercholesterolemic males. Wang et al. (1995) reported a significant decrease in LDL cholesterol and a significant increase in HDL cholesterol concentrations in young females after supplementation with a high molecular fraction of soy protein compared with casein. However, not all observations have been positive (Gooderham et al. 1996, Grundy and Abrams 1983, Holmes et al. 1980, Jacques et al. 1992, Shorey et al. 1981, see review by Anderson et al. 1995).

Clearly, the effects of soy protein on blood cholesterol concentrations in humans have been variable, and the explanation for this remain elusive. Variations in the age and genetics of human study subjects (normocholesterolemic, familial hypercholesterolemic), study design (free-living, metabolic ward), fatty acid profile and cholesterol content of the soy protein-based diet, nonprotein constituents in the diet (e.g., fiber or plant sterols), length of study period, amount of soy protein consumed (in absolute terms and relative to animal protein) and type of soy preparation likely all contribute to the range of responses reported. Additionally, as suggested by Potter et al. (1996) and supported by the recent work of Anthony et al. (1996 and 1997), some of these discrepancies may be attributed to the presence of variable amounts of biologically active components in soy protein preparations, such as isoflavones, which have an independent effect on blood cholesterol concentrations.

	ISOFLAVONES AND BLOOD CHOLESTEROL CONCENTRATIONS

Soybeans are naturally high in a group of compounds collectively termed isoflavonic phytoestrogens or isoflavones (Dwyer et al. 1994). The three major isoflavones in soybeans are genistein, daidzein and glycetein (Fig. 1). Their relative abundance in soy protein varies widely and depends on the specific soy product of interest and the processing techniques used to produce it (Anderson and Wolf 1995). This group of compounds has been reported to have both estrogenic and antiestrogenic activity (Cassidy et al. 1995, Miksicek 1995).

View larger version (12K): [in this window] [in a new window]   Fig 1. Structure of the major soy protein isoflavones.

Traditional methods of isolating soy protein (dehulling, flaking and defatting soybeans) result in a relatively pure preparation of protein that is low in isoflavonoids (Adlercreutz 1990, Lusas and Riaz 1995), whereas methods used to produce textured soy protein result in a preparation that retains the isoflavonoids (Anderson and Wolf 1995). Isoflavonoid concentration ranges from 2.0-2.4 mg/g of total isoflavonoids (genistein, daidzein and glycetein) in textured soy protein, soy flour and soy granules to 0.62-0.99 mg/g of total isoflavonoids in isolated soy protein. In humans, incorporation of 45 g of soy flour has resulted in a 20- to 40-fold and 50- to 100-fold increase in blood and urinary phytoestrogens, respectively (Morton et al. 1994). Subsequent work has established a dose-dependent relationship of soy protein consumption and urinary isoflavonoid excretion at more moderate doses (Karr et al. 1997).

Evidence for an independent effect of isoflavonoids on blood cholesterol concentrations has been demonstrated in rats, hamsters, nonhuman primates and humans (Anthony et al. 1996, Balmir et al. 1996, Cassidy et al. 1995, Clarkson et al. 1998, Pelletier et al. 1995). In humans, Cassidy et al. (1995) have reported that 45 mg of isoflavonoids, but not 23 mg isoflavonoids, resulted in a significant reduction in total and LDL cholesterol concentrations in young females. Similar findings were reported by Potter et al. (1993) and Bakhit et al. (1994). In contrast, Nestel et al. (1997) reported no significant effect on blood lipid concentrations of 45 mg of genistein administered over a 5- to 10-wk period.

In an interesting study involving male cynomolgus monkeys, Anthony et al. (1997) reported that soy protein + phytoestrogens [soy(+)] resulted in lower total and LDL cholesterol and higher HDL cholesterol concentrations than either a casein and lactalbumin mixture or an alcohol-extracted soy protein low in phytoestrogens [soy()]. Additionally, the prevalence of atherosclerotic lesions was lowest in the monkeys fed the soy(+), intermediate in the monkeys fed the soy() and highest in the monkeys fed the casein and lactalbumin. The effects of the diets on lesion size and lipid content were similar in pattern to that of lesion prevalence, in both the coronary and peripheral arteries.

	BIOAVAILABILITY OF ISOFLAVONES

Heinrich and co-workers reported that a variety of factors influence the bioavailability of soybean isoflavones. Xu et al. (1994) assessed the bioavailability of soymilk daidzein, relative to genistein, and found the former to be more bioavailable than the latter in adult females. Xu et al. (1995) found that the efficiency of absorption of soymilk isoflavones varied from 13 to 35%, depending on individual gut microflora. Tew et al. (1996) further reported that wheat fiber fed to subjects with soy protein reduced plasma genistein by 55% but had no significant effect of daidzein concentrations. Lampe et al. (1998) suggested, in females, that dietary fiber or other components of a high fiber diet may promote the growth and/or the activity of bacterial populations favorable for the conversion of soy-derived daidzein to one of its catabolic products, equol, for subsequent absorption from the colon. The data in males were inconclusive. Fermentation decreases isoflavone content of food items but increases bioavailability (Hutchins et al. 1995).

In total, these and other studies, documenting a wide range of variability in metabolic response to dietary isoflavones, suggest that the area of isoflavone bioavailability is complex and requires further work to identify the putative factors and the relative importance of each.

	POTENTIAL MECHANISM(S) OF SOY PROTEIN IN LOWERING BLOOD CHOLESTEROL CONCENTRATIONS OR CHD RISK

Thyroid status.  Hypercholesterolemia, secondary to altered thyroid function, has been clearly documented in humans (Schaefer and Levy 1985). Forsythe (1995) summarized the animal data on the effect of soy protein on blood thyroxine concentrations and suggested that the elevation in blood thyroxine concentrations preceding the decline in blood cholesterol concentrations is consistent with a potential mechanism for cholesterol lowering. However, no relationship between the effect of soy protein and blood cholesterol concentrations via thyroid status has been observed in rats and hamsters (Balmir et al. 1996, Potter et al. 1996). No data on the effect of substituting soy for animal protein on thyroid function in humans are available.

Bile acid balance.  Dietary soy protein has been reported to enhance bile acid excretion in rabbits and rats (see review by Potter 1996) and, via this mechanism, has been suggested to decrease blood cholesterol concentrations indirectly by increasing rates of excretion. Lack of change in fecal neutral steroid and bile acid excretion, despite significant decreases in blood cholesterol concentrations, was reported in humans by Fumagalli et al. (1982) and confirmed by Grundy and Abrams (1983). More recently, Nagaoka et al. (1997) reported that lower serum cholesterol concentrations in rats as a result of soy feeding were associated with increased fecal excretion of total steroids. In separate studies, they also reported that data derived from Caco-2 cells suggested a suppression of cholesterol absorption attributable to the soy preparation.

Estrogenic activity.  In females, estrogen replacement therapy results in a decrease in plasma cholesterol concentrations (Eaker et al. 1993). Estrogenically active isoflavones occur naturally in soybeans. However, these isoflavones are considerably less potent than synthetic estrogens (10³ to 10⁵) (Davis et al. 1998), and absolute concentrations in food products vary widely, depending on processing techniques. As yet undetermined is the potential contribution of the isoflavones to blood cholesterol lowering via an estrogen-like mechanism.

Arterial compliance.  Nestel et al. (1997) reported that administration of genistein (45 mg for 5-10 wk) to perimenopausal women resulted in a significant improvement in systemic arterial compliance (arterial elasticity). Plasma lipid concentrations were unaffected by the consumption of soy isoflavones in that study. Honore et al. (1997) assessed the effect of isoflavones on coronary vascular reactivity in atherosclerotic female macaques. They reported that in females fed a low isoflavone diet, arteries constricted in response to acetylcholine, whereas arteries from females fed a high isoflavone diet dilated. In addition, genistein administered intravenously to animals fed the low isoflavone diet resulted in dilation in previously constricted vessels.

Oxidative status.  The oxidation of LDL results in a lipoprotein particle that is generally thought to be more atherogenic than the native LDL (Esterbauer et al. 1997, Steinberg 1997). Isoflavonoids have been reported to inhibit the oxidative modification of LDL by macrophages (Kapiotis et al 1997), enhance the resistance of LDL to oxidation (de Whalley et al. 1990, Kanazawa et al. 1995) and exhibit antioxidant activities in an aqueous phase (Ruiz-Larrea et al. 1997, Wei et al. 1993). This antioxidative activity has been related to the ability of isoflavonoids to scavenge free radicals (Sekizaki et al. 1993). Feeding rats soy protein, compared with casein, has been reported to lower oxidative stress as measured by thiobarbituric acid-reactive substances.

Recent work by Kapiotis (1997) has documented the ability of genistein to inhibit LDL oxidation in vitro when challenged with copper ions or superoxide/nitric oxide radicals as measured by thiobarbituric acid-reactive substance formation, altered electrophoretic mobility and lipid hydroperoxides. Additionally, genistein inhibited bovine aortic endothelial cell-and human endothelial cell-mediated LDL oxidation and protected vascular cells from damage by oxidized LDL. The antioxidative effect of genistein was not observed by Nestel et al. (1997).

	SUMMARY

Although some of the data generated in humans are consistent with the data generated in animals, suggesting a relationship between dietary soy protein and decreased CHD risk (Table 1) primarily via decreased blood cholesterol concentrations, the area is clouded by the inability to rule out confounding factors that may also affect the outcome measures. Variability in study design and the characteristics of the study subjects further complicate interpretation of the data. Limited evidence suggests that the isoflavone fraction of soybeans may have an independent and favorable effect on blood cholesterol concentrations in nonhuman primates and humans, and enhance the resistance of LDL to oxidation, hence decreasing the atherogenicity of the particle. The bioavailability of isoflavones is variable and is affected by the composition of the gut microflora and the fiber content of the diet. Further work is required to assess the absolute magnitude of these effects and identify characteristics of individuals most likely to benefit from increased isoflavone intake. Additional mechanisms suggested to be related to the beneficial effects of soy protein and/or isoflavones with respect to decreasing CHD risk include thyroid status, bile acid balance and arterial compliance. It should be noted that in addition to the potentially beneficial effects of soy protein/isoflavones on CHD risk, the judicious substitution of soy for animal protein can result in lower saturated fat and cholesterol intakes, thereby indirectly resulting in a more favorable blood cholesterol level and potentially reducing CHD risk.

	FOOTNOTES

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