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A functional soup. (Articles).

These days, it seems a 50th birthday is nearly always followed quickly by a prescription for cholesterol-lowering drugs. Thanks to research into phytosterols, the pills are being tossed aside to make room for functional foods that do the same.

During the past decade, consumers have become more aware to the importance of nutraceuticals and functional foods. Although many countries are still in the process of developing regulations for this new type of foods, Japan, the U.S., and, to some extent, Europe, have in place a regulatory system to deal with this issue. In Canada, functional food regulation is still under development. However, in 1996, Health Canada did define functional foods as foods that contain bioactive component/components that provide health benefits beyond basic nutritional value. Therefore, food enriched with nutrient constituents such as vitamins and minerals should not be considered functional foods, while foods with chemical compounds known to lower blood cholesterol fit the definition. Nutraceuticals may be considered as health bioactives that may be used in functional foods or medical dose formats such as tablets, pills, capsules or other dietary supplements. One of the most researched groups of nutraceuticals in the area of ca rdiovascular diseases (CVD) is phytosterols. With nearly 100 million Americans experiencing elevated cholesterol levels, phytosterols containing functional foods may offer preventive solutions that are safe and effective.

Phytosterols are found in vegetable oil, seeds, nuts and coniferous trees and are essential for stabilizing cell membranes in plants. A similar role is shared by cholesterol in animals. More than 40 plant sterols have been identified, of which [beta]-sitosterol, stigmasterol and campesterol are the most abundant (11). These particular sterols represent 4-desmethyl sterols that share an identical ring structure with cholesterol, but differ only in respective side chains (Figure 1). For example, the presence of a side chain substitution of a methyl-(campesterol) or an ethyl (sitosterol) group on carbon 24 distinguishes different sterols. Moreover, the additional double bond at position 22 is unique for stigmasterol (2).

Phytostanols are a less abundant class of sterols that are found in oil seeds and wood pulp alternatives and contain fully saturated ring structure as evidenced by the lack of the carbon-carbon double bond found in both cholesterol and phytosterols. The hydrogenation of plant sterols results in the formation of plant stanols; thus the saturation of the 5[alpha] position of campesterol produces campestanol and a similar positional saturation of [beta]-sitosterol will yield sitostanol.

In the Western diet, the average daily consumption of phytosterols is almost equivalent to that of cholesterols. This represents approximately 250 mg and 300mg, respectively. In contrast, vegetarian and Japanese diets produce a daily consumption of phytosterols that approximates 450 mg/day (3). The absorption of plant sterols is relatively low and the total serum phytosterol concentration has been shown to range from 0.3 to 1.7 mg/dL in adult men (4).

There are numerous studies that have shown that both phytosterols and phytostanols are effective at lowering serum cholesterol and LDL-cholesterol [5-10]. This is especially true in hypercholesterolemic individuals. A brief summary of the different findings from a number of studies that have reported LDL cholesterol-lowering power from plant sterol-containing food systems is given in Table 1. Similar to the unsaturated counterparts, plant stanols also have cholesterol-lowering properties when administered to individuals as a component of foods, yet they are relatively poorly absorbed or not absorbed at all (11).

The main mechanism underlying the hypercholesterolemic effect involves in part the competition between phytosterols and cholesterol for micellar solubilization based on similarities in the chemical structures (12, 13). As a result, phytosterols interfere with cholesterol absorption in the intestine, blocking some of the dietary and biliary cholesterol typically absorbed by the body (Figure 2).

There is no doubt that the selection of natural food sources of plant sterols will represent a low intake of sterols that is not sufficient to provide the substantial impact required to effectively lower blood cholesterol concentrations. Thus, the development of plant sterol-enriched supplements and functional foods has enabled a critical level of intake of phytosterol, which is required to display efficacy from the standpoint of lowering both total and LDL cholesterol. Studies conducted with hyperlipidemic subjects with familial hypercholesterolemia caused by the FH-North Karelia genetic mutation (FH-NK) have further demonstrated a LDL-cholesterol lowering potential for plant stanol esters (14). This study was aimed at incorporating dietary plant stanol-esters in margarine as an effective hyperlipidemic treatment in heterozygous adult patients, which if left untreated has a 30% greater chance of premature coronary heart disease.

Other challenges also exist for the blood cholesterol-reducing effect of plant sterols to be realized in individuals that wish to reduce the risk of cardiovascular disease by reducing blood cholesterol levels. For example, phytosterols had a long history of use since the 1950s as a supplement and a drug under the name of Cytellin in the U.S. and Positol in Canada. However, this drug had limited efficacy due to poor solubility.

The use of phytosterols in functional food formats to lower blood cholesterol levels began in the 1990s, when it was discovered that sterol and stanol fatty acyl ester derivatives could be efficiently incorporated into fatty foods, such as fat spreads and salad dressings. Margarines that are formulated from vegetable oil contain a range of fat (e.g. 34-80%) to carry the plant sterol esters and represent water in oil emulsions, whereby the water is emulsified into a continuous fat phase. Once consumed, intestinal lipases hydrolyze the fatty acid esters and yield the physiologically active free form of sterols.

Although most of the conducted clinical studies tested stanols and sterols in high fat-based matrices (margarine, oil, mayonnaise), a number of studies have recently shown that low-fat foods (yogurt, bread, milk) can be effective carriers of phytosterol and thus complement the goal of introducing diets low in saturated fat intake, both of which will help in the prevention of high LDL-cholesterol and reduced risk of CVD (10, 15, 16).

Stanol and sterol esters have been approved for use in margarine products such as Benecol[R] and Take Control[R] by the FDA under the GRAS (Generally Recognized As Safe) notification in 1999. Both spreads are products of a Finnish company, Raisio Oy Ltd., and an Anglo-Dutch food giant, Unilever, respectively. These spreads reached the American market in May of 1999. FDA clearance under the GRAS notification process for use in food products has also been approved for free coniferous sterols under the names of Phytrol[TM]/Reducol[R], Phytrol[TM] is the only Canadian mixture of sterols and stanols approved by the U.S. food authorities. The technology to produce Phytrol was invented in University of British Columbia, Vancouver, and it has been licensed to Forbes Medi-Tech Inc., a local biotechnology company.

Numerous clinical studies conducted with Phytrol[TM] in the U.S., Europe and Canada have produced consistent results demonstrating a significant cholesterol lowering effect. For example, a parallel, placebo-controlled study with 32 hypercholesterolemic men that were fed either a diet of prepared foods alone or diet containing 1.7 g Phytrol[TM]/day (6% sterols in margarine) for 30 days, showed that Phytrol[TM] intake lowered LDL-cholesterol levels by approximately 15% compared to the placebo (6). These findings were also confirmed using low-fat foods in clinical studies, where 120 hypercholesterolemic subjects consumed Phytrol[TM] containing milk drink at a dosage of 0, 0.9, 1.8, 3.6 g/d for four weeks (15). The results of clinical trails using free sterols containing food products are consistent with the results of trials conducted with stanol and sterol esters. Most of the trials show the reduction in the plasma LDL cholesterol levels between 8% and 16%. Generally, there is an agreement amongst scientists t hat there is no difference in efficacy between physical forms of sterols. Therefore, free and esterified sterols/stanols have similar efficacy on plasma cholesterol. The way of incorporation into the food matrix, however, may have a significant effect on plasma lipoproteins (17).

Although a number of clinical trials have been conducted using various dose ranges of sterols and stanols, it has been failed to observe additional lowering activity of plant sterols in patients consuming more than 2-2.5 grams sterols/day. Subsequently, the U.S. National Cholesterol Education Program (NCEP) recommends sterol/stanol consumption of 2 g/day as a part of the clinical primary prevention of coronary heart disease. The NCEP report indicates a reduced risk of 2% for every 1% reduction in serum cholesterol level (18). Thus, the findings above of marked reductions in serum cholesterol attributed to phytosterol consumption translate to a range of reduction of risk for CVD of 25-28%. A 14% reduction of risk for CVD has been identified for reduced intake of saturated fat without phytosterol consumption. Thus, the findings above strongly indicate that the daily intake of phytosterols from a functional food source will result in a reduction in risk of CVD that goes beyond reducing the consumption of satura ted fat. This conclusion can be taken further to suggest that intake of different phytosterol containing functional foods will have beneficial effects for those individuals who do not choose to alter their dietary fat intake from the approximate 7% of energy from saturated fats.

Supportive information generated from numerous clinical and safety evaluation studies, as well as the well recognized history of use phytosterol-enriched foods has lead to the conclusion that sterols and stanols are generally recognized as safe. One important concern is their potential interference with the absorption of fat-soluble nutrients such as vitamins and antioxidants. Clinical trials conducted with sterol and stanol esters have shown that [alpha]- and [beta]-carotene (pro-vitamins) levels were reduced 10-25% with no effect on serum retinol levels, vitamin D and vitamin K [7, 8, 19-21]. Moreover, it is known that dietary intake of carotenoids will greatly influence plasma carotenoid content. Therefore, decrease in carotenoid levels associated with the consumption of sterols imposes a low risk and can be prevented by the sufficient consumption of fruits and vegetable.

In conclusion, a number of human clinical and animal studies have shown that a daily intake of 1-2 grams of sterols can have beneficial effects on serum cholesterol and LOL-cholesterol levels without causing any adverse effects. Thus, functional foods-containing phytosterols are safe and beneficial for persons that seek to lower their blood cholesterol levels.
Table 1

Randomized double blind trials with margarines containing sterols [1].

Type of Sterols No. of Subjects Age Duration Daily dose
 (weeks) (g)

Stanols 510 33-50 2-52 1.0-4.0
Sterols 300 33-45 2-4 0.8-3.2

Type of Sterols Reduction in
 serum LDL (mmol/l)

Stanols 0.28-0.64
Sterols 0.20-0.44


References

(1.) Law, M., 'Plant Sterol and Stanol Margarines and Health', Brit. Med. J., 320:861-864, 2000.

(2.) Heinemann, T., Leiss, O., and K. von Bergmann, 'Effect of Low-dose Sitostanol on Serum cholesterol in Patients with Hypercholesterolemia', Atherosclerosis, 61:219-223, 1986.

(3.) Nair P., 'Diet, Nutrition Intake, and Metabolism in Populations at High and Low Risk for colon cancer: Dietary cholesterol, [beta]-sitosterol, and Stigmasterol'. Am. J. Clin. Nutr., 40:927-930, 1984.

(4.) Glueck, C.J., Speirs, J., Tracy, T., Stricher, P., Illig. E., and J. Vandegrift, 'Relationships of Serum Plant Sterols (Phytosterols) and cholesterol in 595 Hypercholesterolemic subjects, and Familial Aggregation of Phytosterols, Cholesterol, and Premature Heart Disease in Hyperphytosterolemic Probands and their First-degree Relatives', Metabolism. 40:842-848, 1991.

(5.) Jones, P.J.H., Howell, T., MaDougall, D.E., Feng, J.Y. and W. Parson, 'Short-term Administration of Tall Oil Phytosterols Improves Plasma Lipid Profiles in Subjects with Different Cholesterol Levels', Metabolism, 47:751-756, 1998.

(6.) Jones P.J.H., Ntanios F.Y., Raeini-Sarjaz M. and C.A. Vanstone, 'Cholesterol-lowering Efficacy of a Sitostanol-containing Phytosterol Mixture with a Prudent Diet in Hyperlipidemic Men', Am. J. Clin. Nutr. 69:1140-1150, 1999.

(7.) Gylling, H., Puska, P., Vartiainen, E. and T.A. Miettinen, 'Retinol, Vitamin D, Carotenes and [alpha]-Tocopherol in Serum of a Moderately Hypercholesterolemic Population consuming Sitostanol Ester Margarine', Atherosclerosis, 145:279-285, 1999.

(8.) Hendriks, H.F.J., Weststrate, J.A., van Vliet, T. and G.W. Meijer. 'spreads Enriched with Three Different Levels of Vegetable Oil Sterols and the Degree of Cholesterol Lowering in Normocholesterolemic and Mildly Hypercholesterolemic Subjects', Eur. J. Clin. Nutr., 53:319-327, 1999.

(9.) Hallikainen, M.A., Sarkkinen, E.S., Gylling, H. and M.I. Uusitupa, 'comparison of the Effects of Plant Sterol Ester and Plant Stanol Ester-enriched Margarines in Lowering Serum Cholesterol Concentrations in Hypercholesterotemic Subjects Fed a Low-fat Diet', Eur. J. Clin. Nutr., 54:715-725, 2000.

(10.) Judd, T.J., Baer, D.J., Chen, S.C., Clevidence, B.A., Muesing, R.A., Kramer, M and G.W. Meijer, 'Plant Sterol Esters Lower Plasma Lipids and Most Carotenoids in Mildly Hypercholesterolemic Adults', Lipids, 37:33-42, 2002.

(11.) Heinemann, T., Pietruck, B., Kullak-Ublick, G. and K. von Bergmann, 'comparison of Sitosterol and Sitostanol on Inhibition of Intestinal Cholesterol Absorption', Agents actions, 26:S117-S122. 1988.

(12.) Vanhanen, H.T. and T.A. Miettinen, 'Effects of unsaturated and Saturated Dietary Plant Sterols on their Serum Contents', Clin. Chim. Acta., 201:97-107, 1992.

(13.) Grundy, S. M. and M.A. Denke, 'Dietary Influences on Serum Lipids and Lipoproteins', J. Lipid Res., 31:1149-1172, 1990.

(14.) Vuorio. A.F., Gylling, H., Turtola, H., Kontula, K., Ketonen, P. and T.A. Miettinen, 'Stanol Ester Margarine Alone and with Simvastatin Lowers Serum Cholesterol in Families with Familial Hypercholesterolemia Caused by the FH-North Karelia Mutation', Atherosclerosis Thrombosis Vascular Biology, 20:500-506, 2000.

(15.) Beer, M.U., Pritchard, P.H., Olesen, M. and R. Black, 'Free Phytosterols from Tall Oil Delivered in Low Fat Food Matrix Successfully Lowers Plasma Cholesterol', IUNS Meeting, Vienna, Austria, August 2001.

(16.) Tikkanen, M., Hogstrom, P., Thomilehto, J., Keinanen-Kiukaanniemi, S., Sundvall, and H. Karppanen, 'Effect of a Diet Based on Low-fat Foods Enriched with Non-esterified Plant Sterols and Mineral Nutrients on Serum Cholesterol', Am. J. Cardiol., 88:1157-1162, 2001.

(17.) Anonymous, 'Plant based Products for Inhibition of Cholesteral Absorption: Efficacy, Safety and Future Research', Phytosterol workshop, Stresa, Italy, October 5-6, 2000

(18.) Anonymous, 'Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), J. Am. Med. Assoc., 285:2486-2497, 2001.

(19.) Gylling, H. and T.A. Miettinen, 'Cholesterol Reduction by Different Plant Stanol Mixtures and with variable Fat Intake', Metabolism, 48:575-580, 1999.

(20.) Plat. J. and R.P. Mensink, 'Vegetable Oil Based Versus wood Based Stanol Esters Mixtures: Effects on Serum Lipids and Homeostatic Factors in Non-Hypercholesterolemic Subjects', Atherosclerosis, 148:101-112, 2000.

(21.) Weststrate, J.A. and G.W. Meijer, 'Plant Sterolenriched Margarines and Reduction of Plasma Total- and LDL-Cholesterol Concentrations in Normocholesterolemic and Mildly Hypercholesterolemic Subjects', Eur. J. Clin. Nutr., 52:334-343, 1998.

Dr. Jerzy Zawistowski is vice-president of functional foods and nutraceuticals for Forbes Medi-Tech Inc. He is also chair of British Columbia Functional Foods and Nutraceutical Network and adjunct professor with University of British Columbia. His responsibilities include research and development in discovery of new natural health products as well as technology and product development in the field of functional foods and nutraceuticals.

Dr. David D. Kitts is a professor in the department of food, nutrition and health at the University of British Columbia. His main research areas are in the fields of food chemistry, toxicology and nutrition. He has investigated the physiological and safety of a number of known food constituents, including both naturally present as well as derived materials from food processing, for health potential.
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Title Annotation:phytosterols' cholesterol reducing benefits researched
Comment:A functional soup. (Articles).(phytosterols' cholesterol reducing benefits researched)
Author:Zawistowski, Jerzy; Kitts, David D.
Publication:Canadian Chemical News
Geographic Code:1CANA
Date:May 1, 2002
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