flaxseed as a functional food

ABSTRACT: The use of flaxseed as a dietary supplement is increasing in parallel with the research on its multitudinous effects on human health. Water-binding capacity of flaxseed insoluble fiber increases the intestinal bulk which is useful in the treatment of constipation, irritable bowel syndrome and diverticular disease. Soluble fiber from flaxseed mucilage delays gastric emptying, improves glycemic control, alleviates constipation and reduces serum cholesterol. Epidemiological studies show that the intake of dietary fiber and colorectal cancer correlate inversely. Flaxseed lignans and fatty acids have been investigated in several cohort studies for their effects on breast cancer risk and there is an association between elevated serum enterolactone and decreased incidence of breast cancer. The flaxseed diet has been shown to be beneficial on prostate cancer and benign prostate hyperplasia when defined by cell proliferation indexes and other cancer biomarkers. Alpha-linolenic acid seems to have an antiproliferative effect on prostate cancer cells. Elevated serum enterolactone level associates with a lower incidence of acute coronary heart disease. Respectively, low serum enterolactone enhances the risk for coronary deaths. Alpha-linolenic acid has been shown protective against cerebrovascular stroke and atherogenic carotid plaque formation. This article reviews health aspects of dietary flaxseed in light of current scientific research.

KEY WORDS: Alpha-linolenic acid, Dietary fiber, Flaxseed, Flaxseed toxicity, Lignans

INTRODUCTIONThe traditional use of flaxseed in human health has been

for constipation. Further discoveries of flaxseed fiber effects have been on blood glucose metabolism and hyperlipidemia. Other flaxseed constituents, oil and phyto-estrogens have been widely investigated in connection with cardiovascular diseases and cancer.

The fact that fiber, oil of vegetable origin and phyto-estrogens are present in a wide range, if not all of fruit, vegetables, seeds and grains obliges us to discuss their health effects also more generally. We aim however; to cover the main effects of these components in flaxseed focusing on the fact that flaxseed is a good source of them all. Flaxseed can be an especially important part of nutrition in areas not using soy products as a source of phyto-estrogens and among populations with low vegetable oil consumption. THE FUNCTIONAL ELEMENTS OF FLAXSEED

Flax typically has a small seed 3-6 mm in length and 2-3.5 mm in diameter. It is unique among cultivated seed plants with its contents of specific carbohydrates, proteins and lipids. By far the most human nutritional interest in this seed has focused on the carbohydrates, in the form of fibers, and on the lipids, especially the essential alpha-linolenic acid (ALA). The nutritional elements of flaxseed are presented in Table 1.

Flaxseed contains a seed coat or true hull, an embryo or the germ, a thin endosperm and two cotyledons. The seed coat, together with endosperm form five layers and contributes 36 % of the total weight of the seed. From outside to inside, there is the epidermis or the mucilage cells, round cells, fibers, cross-cells, and pigment cells that give seeds their color. A thick, shiny cuticle covers the seed coat.

The epidermal cells are filled with mucilage, which can expand rapidly to many times of its original dimension upon hydration. The cellular layer composed of fibers is lignified, porous and can be extremely thick. Two large cotyledons form 55 % of the total weight of the seed and constitute the bulk of the straight embryo. Cotyledons are the major oil storage tissues, containing 75 % of the seed oil. The oil is present as triacylglycerols in intracellular oil bodies of 1.3 µm in diameter (Freeman, 1995; Bhatty, 1995).

Flaxseed contains 35-45 % of fiber of which two-thirds is insoluble and one-third soluble. Insoluble fiber consists of cellulose, hemicellulose and lignin. Soluble fiber is in the form of mucilaginous material composed of polysaccharides. The majority of these polysaccharides are of non-starch type, similar to for instance guar gum, with major relative composition of gel forming carbohydrates (rhamnose + fucose, xylose, galactose

FLAXSEED AS A FUNCTIONAL FOOD

Anneli Tarpila1 , Tero Wennberg1 and Simo Tarpila2

1University of Helsinki, Faculty of Pharmacy, Division of Pharmaceutical Biology, P.O.Box 56 (Viikinkaari 5E), FIN-00014 University of Helsinki, 2Neomed Ltd., Somero, Finland

[Received September 14, 2004; Accepted May 6, 2005]

Current Topics in Nutraceutical Research Vol. 3, No. 3, pp. 167-188, 2005ISSN 1540-7535 print, Copyright © 2005 by New Century Health Publishers, LLC

www.newcenturyhealthpublishers.comAll rights of reproduction in any form reserved

Corresponding Author: : Professor Simo Tarpila, Kolavantie 26, FIN-17200 Vääksy, Finland.E-mail: [email protected]

and uronic acids). The optimal pH range for viscosity of flaxseed mucilage is 6-8, the pH environment in human intestines.

Flaxseed contains 35-45 % oil. Flaxseed oil has an exceptional fatty acid composition: depending on the strain 45-60 % of it is alpha-linolenic acid (ALA) and 15-18 % is linoleic acid (LA) (Figure 1). Soy, corn, cotton, sunflower or canola oils have a LA content of 35-37 %. These oils contain less than 2 % of ALA with an exception of soy oil of 3 % ALA. ALA and LA fatty acids are essential i.e. they must be included in the diet.

Plant lignans are phenolic compounds formed by the union of two cinnamic acid residues. Lignans are ubiquitous within the plant kingdom and are present in almost all plants. The biological role of plant lignans is not clear but the antifungal and insecticidal properties of these compounds indicate a possible role in plant host-defense systems, while in some plants they may function as growth regulators.

Flaxseed lignan precursors in the seeds are mainly secoisolariciresinol (SECO) but also matairesinol (MATA). They are, once eaten, converted by the microbial flora in colon to form enterodiol and further enterolactone. Since these compounds have structural similarities with estrogens they may have both estrogenic and antiestrogenic properties (they have been called phyto-estrogens (Adlercreutz, 1984)). Flaxseed is unique among grains with the main lignan precursors, SECO and MATA, content of SECO being over 500 000 µg/100 g which is hundredfold or even thousand fold higher than in any other plant source (Adlercreutz and Mazur, 1997; Table 2). The other phyto-estrogens, the isoflavonoids, are present mostly in soy. They undergo enterohepatic circulation and some are excreted in urine, mainly as glucuronide conjugates. Conjugation of these phenolic substances was thought to occur mainly in liver. It has been shown in in vitro study, however, that isoflavones genistein and daidzein are glucuronated and sulfated by enzymes of human adenocarcinoma cells (Murota et al., 2002), which may

168 Health effects of dietary flaxseed

Figure 1. Main fatty acids in flaxseed oil with their metabolites and average %contents in serum and leukocytes.

Table 1. The composition of ground flaxseed (partly defatted, cold-pressed with 20% of oil left).

Compound/Property Amount/100g of flaxseed

Water insoluble fiber 33.2 g

Water soluble fiber 11.0 g

Total pentosanes 8.1 g

Water soluble pentosanes 1.2 g

Beta-glucan 0.38 g

Total phosphatides 1.3 g

Lecithin 0.8 g

Protein 26 g

Fatty acids- α-linolenic acid- linoleic acid- oleic acid

20 g13.2 g2.8 g2.0 g

Water binding capacity 8.3 ml/g

Source: Report of analysis. Technical Research Center of Finland, Biotechnology, 1995

indicate this to happen in healthy cells as well. Recent evidence from study with human colon epithelial cell lines suggests that similar metabolism of enterolactone and enterodiol may take place during uptake in the colon and that colon epithelial cells may be responsible for this (Jansen et al., 2005). This may mean that free enterolactone and enterodiol are only present in colon and appear as conjugates elsewhere in tissues.

Dietary intake of lignans is positively associated with the serum enterolactone concentration. Main sources of dietary lignans are whole grain, vegetables and fruits. Mean daily intake of lignans of Finnish men and women was less than 0.2 mg (Kilkkinen et al., 2003a) and according to another survey of Finnish diets 0.4 mg (Valsta et al., 2003). A change of diet to low-fat, high-fiber type can cause a significantly elevated serum enterolactone within 12 weeks (Stumpf et al., 2000). It seems that even small amounts of added flaxseed in food can raise the lignan intake and thus the serum enterolactone significantly. We studied the effect of supplementation of flaxseed in processed foods (Tarpila et al., 2002). The mean flaxseed intake of 2 g/day and total lignan intake of 8 mg/day caused a significant increase in serum enterolactone concentration. In this study the flaxseed supplemented food portion was 20 % of the total daily food of the 80 healthy volunteers.

CONSTIPATION, GASTROINTESTINAL MOTILITY, IRRITABLE BOWEL SYNDROME AND DIVERTICULAR DISEASE OF COLON

Constipation and dietary fiber In Western societies, constipation remains a major health

problem mostly due to refined diet. It is well known that

a sufficient amount of dietary fiber is a cornerstone in the prevention and treatment of constipation.

Nordic Nutrition Recommendations (1996) suggests a daily fiber intake in the range of 25-30 g. Variation in the fiber intake between different countries and different populations is very large. The mean intake among several European countries is 22 g/d, ranging from 12 g/d to 34 g/d (Bingham et al., 2003), approximately 14.3 g/d in Japan and 21.9g/d in USA, ranging from 12 g/d to 36 g/d (Peters et al., 2003). It is commonly recommended dietary fiber intakes should be 30 g or more per day. This amount is expected to increase stool weight and frequency and normalize stool consistency (Devroede, 1988).

The metabolism of flaxseed fiber can be stated as with any dietary fiber. The article of Spiller (1994) reviews comprehensively the effects of dietary fiber, including gastrointestinal (GI)-motility, constipation, glucose tolerance, hypocholesterolemic effect and fermentation. Soluble nonstarch

dietary fibers like flaxseed mucilage, pectins and guar gums are multibranched hydrophilic substances, forming viscous solutions that delay gastric emptying and nutrient absorption from the small bowel. They delay gastric emptying and improve glycemic control in diabetes, as well as alleviate constipation. In the GI tract, viscous solutions show antimotility; they impair the propulsive and mixing effects of GI contraction (Spiller, 1994). The effect of soluble fiber is believed to be more or less local: they increase the viscosity of the small intestinal contents and delay the digestion and absorption of carbohydrates. For example the addition of viscous polysaccharides to solutions of glucose delays gastric emptying and may limit the absorption of glucose and other rapidly absorbed solutes by slowing their delivery to the absorptive site in the duodenum and jejunum (Blackburn et al., 1984a; Holt et al., 1979). Although soluble fiber reduces intestinal mixing, the effects of these viscous polysaccharides on enzyme activity in the gut lumen may be offset by a compensatory increase in pancreatic enzyme secretion or a reduction in the luminal degradation of enzymes (Schwartz and Levine, 1980; Scarpello et al., 1982).

Perfusion of loops of small intestine in vivo with glucose solutions has shown that viscous polysaccharides reduce glucose absorption in proportion to the viscosity of the solutions (Isaksson et al., 1983; Johnson and Gee, 1981; Elsenhans et al., 1981). These results have been explained on the basis of an increase in the thickness of the unstirred water layer across which solutes have to diffuse before reaching the epithelial cell membrane (Blackburn et al., 1984b). In general, the addition of soluble fiber to liquid meals delays mouth-to-cecum transit time of the head of a meal. This effect is only partly explained by the delay in gastric emptying; there is

Health effects of dietary flaxseed 169

Table 2. Mean (µg/100 g) lignan (SECO and matairesinol) and isoflavonoid (genistein and daidzein) contents in various foods.

Product SECO1 Matairesinol Genistein Daidzein

Flaxseed 369 900 1087 0 0

Flaxseed, crushed and defatted

546 000 1300 0 0

Pumpkin seeds 21 370 0 1.53 0.56

Soybean flour 130 0 96 900 67 400

Whole grain wheat 32.9 2.6 0 0

Rye meal 47.1 65.0 0 0

Japanese green tea 2460 186 Not determined Traces

Mung bean sprouts 468 0.87 1902 745

Red clover seeds 13.2 3.8 323 178

Broccoli 414 23.1 6.6 4.7

Cranberry 1510 0 0 0

Source: Modified from Adlercreutz, H., Mazur, W. (1997) Phyto-estrogens and Western diseases. Annals of Medicine 29:95-120.

1 secoisolariciresinol

evidence for an additional delay in small bowel transit (Spiller, 1994; Blackburn et al., 1984b; Bueno et al., 1981). Pectins, alginates, hemicellulose, and lignins can act as weak cation exchangers, but most mineral binding occurs to weak bases that are found in association with polysaccharides. These include phytate, which is found in cereals. Mineral binding to plant cell wall material is of little nutritional significance in healthy people (Brown et al., 1988). Long-term vegetarians do not suffer from micronutrient deficiency (James, 1980). Bile acids bind with phenolic and uronic residues on the polysaccharide matrix, particularly when the pH in the intestinal lumen is low (Freeland-Graves, 1988). This may then limit fat absorption by impairing micellization. High fiber diet increases the excretion of fecal bile acids reflecting a decrease in serum total cholesterol (Kesäniemi et al., 1990; Miettinen and Tarpila, 1989). Flaxseed mucilage is similar to the guar gum used in those studies and therefore, may be expected to produce the same result. However, there are no studies reported from flaxseed mucilage.

Insoluble fibers, including cellulose and lignins, have little effect on gastric lumen emptying and small bowel transit time. The mechanism by which fiber increases fecal bulk is twofold. The bacterial fermentation in the colon degrades fibers actively and thus increases the bacterial mass in the colon. Cereal grains have highly lignified components that are resistant to bacterial digestion; they are thought to increase fecal bulk by physicochemical means; that is, by acting as ”sponges” for water, increasing the weight and the water content of stools. The crucial factor seems to be the water-holding capacity after exposure to colonic bacteria (Bannister et al., 1987; McBurney et al., 1985). Ground flaxseed with a particle size of 2-4 mm shows good water-binding capacity in the colon compared to finely ground flaxseed meal or whole flaxseed (Report of analysis. Technical Research Center of Finland, Biotechnology, 1995).

Other components of fiber are susceptible to bacterial degradation; their availability to the fecal flora is thought to represent a major source of carbon for bacterial growth. In these instances, fecal bulk is largely accounted for by an increase in the excretion of bacteria. By whatever mechanism, and whether taken as dietary supplements or proprietary bulking agents, fiber increases stool bulk, and eases evacuation (Devroede, 1988; Phillips, 1985).

Although traditional medicine has used flaxseed for centuries to treat constipation, the controlled trials of flaxseed as a laxative are rare. Cunnane et al. (1995) studied the influence of consuming 50 g flaxseed per day for 4 weeks on several indexes of nutrition in 10 young healthy adults. Bowel movements per week increased by 30 % (p<0.05) while flaxseed was consumed. During flaxseed consumption, α-linolenic acid was increased significantly in adipose tissue, and n-3 polyunsaturates were increased in plasma lipids. Plasma LDL-cholesterol was also reduced by up to 8 %, and total urinary lignan excretion was increased more than five-fold (p<0.05). Muffins with 25 g flaxseed did not differ significantly from control muffins in their content of thiobarbituric acid-reactive substances, and

α-linolenic acid in the muffins was not significantly reduced by baking. Antioxidant vitamins and lipid hydroperoxides in plasma were not significantly affected by flaxseed consumption. The authors conclude that traditional flaxseed has modest beneficial effect on several indexes of nutritional status without compromising antioxidant status.

Irritable bowel syndrome Irritable bowel syndrome is a condition of variable etiology

and uncertain pathogenesis characterized by abdominal pain and discomfort, a disturbance in defecation and a range of symptoms and physiologic signs that suggest increased bowel sensitivity. Dietary fiber as a natural way to manage irritable bowel syndrome made it the first line treatment for this condition during 1970s and 1980s. Cann et al., (1984) showed that the addition seven grams of fiber in the form of wheat bran to the diet of such patients for six weeks resulted in significant improvement in symptoms. Analysis of individual symptoms in placebo-controlled trials showed that constipation was the only symptom that had a significantly greater response to bran than placebo (Prior and Whorwell, 1987).

Fifty-five patients with constipation pre-dominated irritable bowel syndrome were investigated for 3 months (Tarpila et al., 2004). The patients received 6-24 g (mean 17 g) of ground flaxseed or equivalent amount of psyllium daily, the dosage being changed depending on their response. After 3 months in the flaxseed group constipation and abdominal symptoms were decreased significantly. Psyllium with mostly water-soluble fiber showed faster effect on irritable bowel symptoms but the effect was not improved further after 2-3 months’ use.

Diverticular disease of colonIn Western societies diverticular disease is a most common

in elderly people. More than one third of people aged 60 and more than one half aged 90 are said to have diverticular disease. Dietary fiber is thought to protect against diverticular disease by making the colonic contents softer, bulkier, and easier to propel and reduce the pressures produced by the shortening colon. Especially the insoluble fiber, particularly cellulose, was found to be significantly associated with a decreased risk of diverticular disease in a large prospective cohort study with 43 881 US men (Aldoori et al., 1998).

Flaxseed oilTotal flaxseed contains 40-55 % flaxseed oil. Together with

fiber, it makes flaxseed a combination of bulk and lubricant laxative indicated for functional constipation and constipation predominant irritable bowel syndrome. Long-chain fatty acids together with bile acids induce colonic propulsion and secretion, both beneficial factors for constipation (Tomlin and Read, 1988).

BLOOD GLUCOSE METABOLISM, SERUM LIPIDS AND CARDIOVASCULAR DISEASE

Blood glucose and fiber



High-fat, low-fiber, low-nutrient diets combined with genetic susceptibility and low-level exercise may lead to symptoms associated with metabolic syndrome. These are insulin resistance, hyperlipidemia and hypertension. When progressing, metabolic syndrome may result in type 2 diabetes and coronary heart disease. Nutritional treatment, which means a change of diet and unhealthy life habits, gives long-term results and improvement of health.

The consensus of today claims the importance of lower postprandial plasma glucose and lower blood lipids through low-fat, high fiber diet. The latest recommendation for diabetic individuals and persons at risk (Andersson et al., 2004) is to maintain desirable body weight and to have a diet containing 55 % or more of carbohydrate, 12-15 % of protein, less than 30 % of fat including 12-15 % of monounsaturated fat. The diet provides 25-50 g/day of dietary fiber. This recommendation is supported by a study investigating the cross-sectional associations between carbohydrate-related dietary factors, insulin resistance and the prevalence of the metabolic syndrome in 2834 subjects (McKeown et al., 2004). The metabolic prevalence was significantly lower among those in the highest quintile of cereal fiber intakes. Investigators conclude that whole-grain intake may reduce the risk of developing the metabolic syndrome.

Cunnane et al. (1993) carried out a study where muffins containing 25 g flaxseed each, two consumed daily for 4 weeks, resulted in 27 % lower postprandial glucose values than control muffins. Addition of 25 g of flaxseed mucilage to a 400 ml solution with 50 g glucose reduced the area under the blood glucose response curve by 27 % compared to oral glucose alone.

The effect of flaxseed protein on blood glucose has not been studied but may be comparable with other dietary plant proteins, i.e. suppression of postprandial blood glucose levels as seen after wheat albumin ingestion (Kodama et al., 2005).

Serum lipids and fiberHyperlipidemia is closely linked with impaired glycemic

response. The early studies of fiber effects on hyperlipidemia or blood lipids in general mostly failed to show any lipid lowering effect because the fiber under investigations was insoluble wheat bran. Studies with soluble dietary fiber such as pectin, guar gum, oat bran and psyllium started to emerge during 1960’s showing a clear reduction in blood lipids (Miettinen and Tarpila, 1989).

Flaxseed, which is a good source of soluble dietary fiber, has shown similar results in clinical studies. Cunnane et al. (1993) carried out a study where 50 g of ground raw flaxseed ingested daily by nine healthy volunteers for 4 weeks. They showed that total serum cholesterol reduced by 9 % and LDL cholesterol by 18 %. When flaxseed was baked in muffins both plasma total cholesterol levels and the ratio of LDL/HDL cholesterol had fallen by 6 % (Cunnane et al., 1995). In our study with 55 IBS patients receiving either ground flaxseed or psyllium 6-24 g/day for 3 months flaxseed reduced

the serum total cholesterol by 10 % and LDL cholesterol by 12 % (Tarpila et al., 2004). Several explanations have been suggested, such as enhanced gastric emptying, altered transit time, interference in bulk phase diffusion and sequestration of micellar components, including bile acids as well as the increased excretion of cholesterol into faeces.

Cardiovascular diseases and fiberDietary fibers may protect against coronary heart disease

by lowering blood cholesterol, attenuating blood triglyceride levels, decreasing hypertension and normalizing postprandial blood glucose levels. A pooled analysis of dietary fiber and its subtypes and risk of coronary heart disease has been conducted by Pereira et al. (2004). The original data from 10 prospective cohort studies from the United States and Europe was analyzed to estimate the association between dietary fiber intake and coronary heart disease. During 6 to 10 years of follow-up, 5249 incident total coronary cases and 2011 coronary deaths occurred among 91058 men and 245186 women. In the pooled data, each 10 g/day increment of total dietary fiber was associated with a 14 % decrease in risk of all coronary events and a 27 % decrease in risk of coronary death. Results showed an inverse association between the consumption of dietary fiber from cereals and fruits and the risk of coronary heart disease. Flaxseed supplement of 10-20 g/d increases the fiber intake by 5-10 g/d thus augmenting to reach the beneficial recommended amount of dietary fiber.

The effect of dietary fiber on hypertension has been investigated in two studies recently, unfortunately neither with flaxseed. In a randomized controlled study with 41 hypertensive patients (36 completed), subjects were normalized on low-protein, low-fiber diet for a period of four weeks (Burke et al., 2001). After that they were randomized to 4 groups either to 1) continue the low-protein, low-fiber diet or 2) a diet supplemented with soy protein, increasing the total protein intake to 25 %, 3) a diet supplemented with additional 12g of soluble fiber, or 4) supplemented with both protein and fiber. The 24-hour ambulatory blood pressure was compared from the end of the baseline period to the end of intervention of eight weeks. Relative to control subjects, the net reduction in 24-hour systolic blood pressure was 5.9 mmHg with fiber and with protein.

In another recent study 110 participants with elevated, untreated or stage 1 hypertension were randomized to receive 8 g/day of water-soluble fiber from oat bran or a placebo intervention (He et al., 2004). Nine blood pressure measurements were obtained during 12 weeks. Oat bran fiber caused an average decrease of systolic blood pressure of 2.0 mmHg.

Cardiovascular diseases, serum lipids and flaxseed oilFlaxseed oil is a good source of essential fatty acids, especially

of ∝-linolenic acid (ALA). According to large epidemiological studies, high ALA plasma concentration prevents cardiovascular diseases but this has not been consistent in clinical studies. ALA has certain anti-inflammatory properties that may act


independently of lipid metabolism. The recent recommendation for ALA intake is 2 g/day,

which can be obtained in 4-5 g of flaxseed oil. The major issue is the ratio of ALA: LA, which should be favoring ALA. For the European population the best sources of ALA are recommended to be canola oil, ground flaxseed and green leafy vegetables (DeLorgeril, 2004; DeLorgeril and Salen, 2004).

Dietary ALA has little, if any effect on blood lipid or lipoprotein levels (Nelson and Chamberlain, 1995). When flaxseed oil is fed to humans, there is a rise of serum ALA content and, with a delay, a rise also in the EPA (eicosapentaenic acid), DPA (docosapentaenic acid) and DHA (docosahexaenic acid) contents of plasma (Emken et al., 1994). The ingestion of EPA and DHA from fish or fish oil has been reported to lead to decreased production of prostaglandin E2 metabolites, thromboxane A2, and leukotriene B4, as well as increased concentrations of thromboxane A3, prostacyclin PG13 and leukotriene B5. These changes indicate less inflammatory reactions, less platelet aggregation and less blood vessel vasoconstriction (Simopoulos, 1999). Flaxseed ALA is metabolized to EPA, which is a precursor for less inflammatory cytokines and compensatorily inhibits the metabolization

of arachidonic acid (AA) to more inflammatory cytokines (Fig.2).

In our study (Tarpila et al., 2002) no significant changes in serum total cholesterol, HDL-cholesterol or LDL-cholesterol were observed during 4 weeks’ intervention period continued with a 4 months’ open follow-up period, when 5 g of flaxseed oil was added to 100g of a variety of 11 different processed foods. Serum ALA percentage of total fatty acids increased during 4 weeks from 0.95 to 1.72 (reference values 0.4-1.2) and during the open flaxseed period from 1.0 to 1.9. Significant increases were found also in EPA and DPA but not in DHA. No change was noted in arachidonic acid concentration during intervention. Serum linoleic acid tended to increase but the change was not significant. All fatty acids were determined as total fatty acids.

The ability of ALA in rapeseed oil in a daily amount of 50 g to compensate for the effects of a restriction in fish intake on fatty acid composition has been studied with 40 healthy volunteers in a cross-over manner (Valsta et al., 1996). It was shown that ALA was metabolized to EPA to a significant extent and would resemble the effect of a weekly portion of 50-100 g of fatty fish in diet. This finding proves the plant source of

Figure 2. Effect of ALA, LA and oleic acid on the production of lipid and peptide inflammatory mediators.Source: James, M.J., Gibson, R.A., Cleland, L.G. (2000).


essential fatty acid ALA to be able to provide some long-chain n-3 fatty acids with important health promoting factors.

The original study by DeLorgeril et al. (1994) showed that Mediterranean ALA-rich diet was significantly more effective in secondary prevention of coronary events and death after 5 years’ follow-up. In this study 605 patients who survived a myocardial infarction within 6 months of enrolment were randomized to either an unmodified diet or the diet modified with higher intake of vegetables, fruits, bread, fish and margarine and lower intake of butter, meat, sweets and cakes.

A large prospective cohort study with 76283 women without previous cardiovascular disease was completed with a follow-up time of 10 years (Hu et al., 1999). During that time 232 cases of fatal myocardial infarctions and 597 cases of nonfatal myocardial infarctions were documented. Although the assessment of dietary ALA intake was perhaps not accurate, it was calculated reasonably enough to give a conclusion of the protective effect of ALA in diet against fatal myocardial infarctions. In a recent meta-analysis from 5 prospective cohort studies high ALA intake was found to be associated with reduced risk of fatal heart disease (Brouwer et al., 2004). Previously, similar conclusions were made in a Finnish study with 285 men and 130 women with established coronary artery disease (Erkkilä et al., 2003). In this study the patients were followed for 5 years with recordings of dietary fatty acids and their composition of serum cholesteryl esters. During the follow-up, 36 patients died, 26 had a myocardial infarction and 12 had a stroke. The association between high proportions of n-3 fatty acids (ALA, EPA, DHA) and a lower risk of coronary artery disease death was found.

The possible association between serum fatty acids and the risk of stroke has been studied with a group of 96 US men who suffered a stroke during a follow-up time of 6.9 years compared with 96 matched controls (Simon et al., 1995). After adjusting for known risk factors for cerebrovascular disease it was found that only serum ALA remained significantly associated with the risk of stroke with lower ALA observed in stroke subjects. In this study serum ALA concentrations, measured as fatty acids in the cholesterol esters and the phospholipids of serum lipoproteins showed percentages of 0.47 (stroke cases) and 0.54 (controls) that are considered low.

Carotid atherosclerosis is a known risk factor for stroke. The association between dietary ALA and the presence of atherosclerotic plaques and the intima media thickness of the carotid arteries were studied with 1575 healthy participants (Djousse et al., 2003). After the assessments with high-resolution ultrasound method it was found that higher dietary ALA consumption was inversely related to thickness of the internal and bifurcation segments of the carotid arteries but not to the common artery. LA, fish long chain fatty acids or fish consumption had no association with carotid artery disease.

The protective effect of omega-3 fatty acids of marine (EPA, DHA) or plant origin (ALA) against coronary heart disease is highly associated to antiarrhythmic and antiaggregation effects of these fatty acids but it is still not known whether ALA is

cardioprotective by itself only or also through its conversion into EPA and DHA and further to the corresponding eicosanoids and prostaglandins.

Certain hemostatic effects of flaxseed oil or fish oil diets were studied with 30 healthy volunteers (Freese and Mutanen, 1997). Total supplemented amount of oil was 1 g/200 kcal of the calculated energy expenditure. The peaking time or extend of F VII: C (Factor VII affecting coagulant activity) in the postprandial state was reported to be parallel with the test groups. Flaxseed oil diet seemed to flatten the postprandial platelet response to ADP (adenosinediphosphate, a common platelet aggregation inducer).

Human studies of fatty acids or flaxseed oil as such on hypertension are lacking. Omega-3 fatty acids can increase endothelium-derived relaxing factor as shown with animals fed with cod liver oil or fish oils (Simopoulos, 1999). The released relaxing factor is presumably nitric oxide. Relaxing factor contributes to antithrombotic and antiatherosclerotic effects of omega-3 fatty acids by relaxing vascular smooth muscle and inhibiting blood platelet aggregation. Supporting results are reported in a study where high flaxseed diet had no effect on blood pressure in spontaneously hypertensive rats or in normotensive rats (Talom et al., 1999). Instead, vasorelaxant responses of mesenteric arterial bed to acetylcholine or bradykinin were greater in spontaneous rats fed with high-flaxseed diet suggesting the improving effect of high-flaxseed diet on endothelial vasorelaxant function through a pressure-independent mechanism.

Cardiovascular diseases and lignansLow serum enterolactone has been associated with acute

coronary events in a prospective population-based study with 167 men who had an average of 7.7 years of follow-up to an acute coronary event (Vanharanta et al., 1999). Compared to matched controls the serum enterolactone was 25.1 % lower among the coronary cases. It was estimated that the risk of acute coronary event was 52 % lower with men with high serum enterolactone, which was determined to be above median value of 15.11 nmol/l. One of the suggested mechanisms is that enterolactone is an antioxidant preventing lipid peroxidation. This factor, determined as increased plasma F2-isoprostones, was later shown to be enhanced in men with low serum enterolactone (Vanharanta et al., 2002). Further, it was suggested that a high serum enterolactone level is associated with reduced coronary heart disease related and cardiovascular disease related mortality in middle-aged Finnish men (Vanharanta et al., 2003). These findings are of extreme importance among the western populations with high incidence and mortality of coronary heart disease. There was no consistent association between the dietary fiber intake and the risk of acute coronary events in the original study that may indicate the importance of fiber types in diet, i.e. lignified fibers.

CANCER Dietary fiber and colorectal cancer


The dietary fiber research has come full circle not only for the effect on constipation but also for the prevention of colorectal cancer. It faces the original constitution introduced during 1970’s with report of very high daily fiber intake among African populations (Burkitt et al., 1977). After those days there has been numerous studies with variable results published. Flaxseed is a good source of dietary fiber: only 10 g of flaxseed in the daily diet increases the daily fiber intake by 1 g of soluble fiber and by 3 g of insoluble fiber. Recently, three large studies have raised considerable discussion about the correlation of dietary fiber and incidence of colorectal cancer.

A prospective, 16-year follow-up study with over 88 000 US nurses were studied for the association between dietary fiber intake and the risk of colorectal adenoma (Fuchs et al., 1999). Results showed no protection. Categorically, it seems that the total fiber intake, and not only fiber from cereals, was too low (under 25 g/day) to show any protective effect. This study was followed by two large studies, one with a US population and another with populations of ten European countries. The US study (Peters et al., 2003) was performed by the Prostate, Lung, Colorectal, and Ovarian Cancer Screening project team (PLCO) and compared the dietary fiber intake of 33 971 people who on sigmoidoscopy showed no polyps with 3591 people who had at least one histologically-verified adenoma in the distal large bowel. In this study the range of total fiber intake was 12.6 – 36.4 g/day and among these people the risk for colon adenoma decreased with increasing fiber intake. The association with reduced risk for rectal adenoma was not so clear.

The European Prospective Investigation into Cancer and Nutrition (EPIC) consortium examined prospectively dietary fiber intakes and incidence of colon cancer in 519978 people from ten European countries (Bingham et al., 2003). The study findings showed total dietary fiber consumption to associate inversely with colorectal cancer risk and lead to the statement that doubling of total fiber intake from foods could reduce the risk of colorectal cancer by 40 %. This study also concludes that no food source of fiber was significantly more protective than others. Fiber type may matter, however. Dietary fiber is mainly composed of plant cell walls, which vary in composition and properties according cell type and plant species. It has been shown that different types of cell walls adsorb a range of carcinogens to different extents (Ferguson and Harris, 1996). Especially lignin, which is an important component in flaxseed cell walls in its fiber cell layer, or suberin were good adsorbers and furthermore made the plant cell walls resistant to degradation in the colon.

Flaxseed oil and cancerIt is generally considered that the high content of ALA in

flaxseed oil plays a protective role in carcinogenesis. However, controversial results reporting the antiproliferative effects of ALA do exist. It is worth keeping in mind that flaxseed oil is also composed of other fatty acids that may be of importance. Furthermore, the whole composition of dietary fat and its profiles in different adipose compartments in humans is the

background for the individual significance. The onset of carcinogenesis is a multifactorial phenomenon and therefore cannot be explained with a deficiency of one nutrient. There is a need for studies where the dietary ALA intake is clearly above the recommended 2 g/d.

There is some early data that dietary ALA can retard tumor growth in rodent mammary-tumor models (Johnston, 1995). The effect of supplementation of flaxseed, flaxseed lignan secoisolaricirecinol-diglycoside (SD) or flaxseed oil on established rodent mammary tumors and appearance of new tumors has been studied by Thompson et al., (1996). Tumors were induced with a single 5-mg dose of 7,12-dimethylbenzanthrazene (DMBA) and diet supplementation started 13 weeks after the induction. The amount of flaxseed oil administered daily was 1.82 % (equivalent to 5 % flaxseed diet). After 7 weeks of treatment the established tumor volume was 50 % smaller compared to control basal diet. The fatty acid composition of the tumors in the oil group showed an increased incorporation of total n-3 acids, particularly ALA and its elongation product EPA resulting in significant rise in the ratio of n-3 to n-6. The authors present the possibility of an increase in peroxidation of these fatty acids in the membranes of tumor cells to have led to a decrease in the viability of the tumor cells. Alternatively, the significant rise in the EPA compared to arachidonic acid may have led to the reduction of tumor-promoting prostaglandins of the E2 series. In another study (Tou et al., 1999) flaxseed oil failed to produce structural changes in rodent developing mammary glands and was suggested to be protective against mammary cancer.

As the metabolism of tumors is highly changed compared to normal tissue and the fatty acids from blood may not be good indicators of the impaired metabolism it may be useful to determine the fatty acid contents of tumors, as done by Thompson et al., (1996). It is assumed that fatty acid contents of adipose tissue reflect the dietary fatty acid intake. Low ALA content of adipose breast tissue has been found in 123 breast cancer patients compared to 59 controls with benign breast tissue changes (Klein et al., 2000). These results support their earlier findings with inverse association between the level of ALA in breast fat and the development of metastasis subsequent to breast cancer treatment (Bougnoux et al., 1994). The low dietary intake of ALA might be the cause of depletion in the breast adipose tissue; therefore the recording of fatty acid intake for a longer period of time is necessary. There are also controversial results about the correlation of ALA intake and its content in adipose tissue (London et al., 1991). The authors discuss about the lack of good biomarkers to investigate the fate of ALA from ingested food to breast adipose tissue of breast cancer patients or to any other type of tumor. As it has been discussed generally about the changed metabolism of tumors and as it is known that cancerous tissue has an increased cell growth, it might be worth testing the levels of growth promoting eicosanoids.

The peroxidation theory mentioned earlier (Thompson et al., 1996) has been investigated (Cognault et al., 2000) in a


rodent model with N-nitroso-N-methylurea –induced late stage tumors in order to find out if the oxidative status of a PUFA-enriched (flaxseed oil) diet could modulate the growth of tumors. The diet was supplemented with antioxidant (vitamin E) or peroxidant (ferric citrate) system. Tumor growth increased in the presence of vitamin E compared with control and decreased when prooxidant was added. There was no difference if the diet was low in PUFA. The kinetic parametric analysis showed further that tumor growth resulted from variations in cell loss and not from changes in cell proliferation. The authors discuss the possibility of antioxidants to act as tumor promoting factors in late stage tumors although they are known to be protective at the early stages of carcinogenesis.

Recent experimental work gave proof of the protective effect of flaxseed oil on colon carcinogenesis. Diet supplemented with 15 % flaxseed oil prevented azoxymethane-induced colon tumor development in rats when compared to corn oil (Dwivedi et al., 2005). Both tumor size and amount of tumors were significantly lower in flaxseed oil-fed rats.

The role of ALA in the etiology of prostate cancer has been studied in Uruguay with 217 men with advanced prostate cancer (De Stefani et al., 2000). ALA was found to be associated with a significantly increased risk of prostate cancer after controlling for total energy intake and for other types of fat. ALA from both animal and vegetable sources displayed increased risks of prostate cancer. In this study the main source of ALA was animal fat (red meat). The daily intake of ALA in all groups was below the recommended daily intake of 2 g. Therefore the suggested contribution effect of ALA on prostate cancer is questionable. The results are supported, however, by previous studies from US (Giovannucci et al., 1993; Gann et al., 1994), Spain (Ramon et al., 2000) and Norway (Harvei et al., 1997). In Gann’s study low serum ALA was found to reduce the prostate cancer risk without any significance seen with the red meat intake. In Ramon’s study positive correlation was found between animal fat intake, ALA intake and prostate cancer. In a Finnish cohort study with 2002 middle-aged, cancer-free men were followed for 12.6 years (Laaksonen et al., 2004). During that time 46 men developed prostate cancer and 151 men came out with some other type of cancer. It was found that the high intake of total polyunsaturated fatty acids, especially linoleic acid was associated with smaller risk for prostate cancer suggesting the substitution of moderate quantities of linoleic acid for saturated fat in diet to lower the risk of prostate cancer. A population-based study from Sweden (Andersson et al., 1996) with 526 prostate cancer patients and matched controls showed only the total energy and total fat intake to be an increased risk for prostate cancer. In a large cohort study with 29 133 male smokers, aged 50-59 years were followed for 5-8 years (Männistö et al., 2003). During the follow-up time 246 prostate cancer cases were diagnosed and for each case was a matched control selected. Serum and dietary fatty acids had no consistent association with prostate cancer risk nor did the serum ALA relate to prostate cancer risk. Recently, the correlation between plasma and prostate

tissue ALA levels, together with other n-3 polyunsaturated fatty acids, has been studied in a pilot study. The plasma and tissue samples were obtained from 20 patients with benign prostate hyperplasia and from 8 patients with prostate cancer (Attar-Bashi et al., 2004). There was no significant difference in plasma and prostate tissue ALA and n-3 polyunsaturated fatty acid levels between the patient groups. For each subject in the study, plasma ALA levels were significantly higher than prostate tissue ALA levels.

In a recent prospective study a cohort of 47866 US men aged 40-75 years with no cancer history were followed for 14 years to study the association between intakes of ALA, EPA, DHA, LA and AA (arachidonic acid) fatty acids and prostate cancer risk (Leitzmann et al., 2004). During the follow-up time 2965 new cases of total prostate cancers were detected of which 448 were advanced prostate cancers. ALA, LA or AA intakes were unrelated to the risk of total prostate cancer but there were a high correlation to ALA intake and advanced prostate cancer. Similar conclusion was shown in a recent meta-analysis of 5 prospective cohort studies and 3 clinical trials to estimate quantitatively the associations between intake of ALA and the occurrence of prostate cancer (Brouwer et al., 2004). High ALA intake was found to be associated with reduced risk of prostate cancer where also high ALA blood levels were combined.

Lignans and cancerBreast, prostate and colorectal cancers are the most common

malign diseases in the western world. Low urinary lignans detected in patients suffering from those diseases, similarities in molecular structures with estrogens and antimitotic-antiestrogenic properties of some lignans led to the hypothesis that lignans may have anticancer properties (Adlercreutz, 1984). Flaxseed is a major source of plant lignan precursors and therefore a natural target for investigations.

The effect of supplementation of flaxseed, flaxseed lignan secoisolaricirecinol-diglycoside (SDG) or flaxseed oil on established rodent mammary tumors and appearance of new tumors has been studied by Thompson et al., (1996). Tumors were induced with a single 5 mg dose of 7,12-dimethylbenzanthrazene (DMBA) and diet supplementation started 13 weeks after the induction. Purified SDG of 2200 ng/day was given by gavage in 1 ml of distilled water. This amount of SDG was equivalent to that in 15 g of the 5 % flaxseed diet. After 7 weeks of treatment the established tumor volume was 50 % smaller compared to control basal diet with the tendency of significance. Only SDG-fed rats had significantly smaller new tumors despite the lower urinary mammalian lignan excretion, which may indicate the antioxidant and anticarcinogenic effect of the hydrolysed SDG. The efficacy of oral enterolactone at doses of 1 or 10 mg/kg for 7 weeks to inhibit mammary cancer was studied with similar rodent experimental model (Saarinen et al., 2002). Enterolactone at 10 mg/kg significantly reduced the total tumor volume. The inhibition of tumor growth was more pronounced in tumors that developed during the 7-week enterolactone period, but


the inhibition was seen also with those tumors that were established before the start of the treatment. Enterolactone concentration in both serum and in urine doubled during treatment of 10 mg/kg. The study reports more than 10-fold higher enterolactone concentrations in rat serum compared to that found in general human population.

The antioxidant potential of SDG and its mammalian lignan metabolites enterolactone (EL) and enterodiol (ED) were studied afterwards (Kitts, 1999). It was discovered that all three compounds were similarly effective at lowering lipid peroxidation. Both EL and ED displayed efficacy in reducing deoxyribose oxidation and DNA strand breakage. This may be important especially within colonic lumen where these metabolites are actually created.

Flaxseed lignan SECO, as precursor to enterodiol and enterolactone have been proven to be antioxidant in experimental studies (Prasad, 2000). It has been suggested that the cancer preventive and protective effect of high-lignan, low-fat diet works best when it is maintained throughout lifetime, especially before and during adolescence (Adlercreutz, 2002). The early development and differentiation of mammary glands is hormone dependent with promotion of rising endogenous estrogen. The phenomenon is sensitive for precarcinogenic disturbances and the possibility to achieve a reduction of the highly proliferative terminal end bud structures in the developing mammary gland has been studied experimentally with rats (Tou and Thompson, 1999). SDG, basal diet with flaxseed of 5 % and 10 % supplementation given during lifetime or gestation and lactation periods altered mammary gland structure development. Because changes in endocrine functions, such as delayed puberty onset and reduced number of estrous cycles were observed, it was assumed the reduced exposure to endogenous estrogens to have led to atrophy of terminal end bud mammary gland structures. When the flaxseed feeding was started at weaning (age 21 days), there was no effect detected. Further findings with lactation period show similar effects (Ward, 2000). The possible mediator(s) of this diet-induced mammary gland differentiation, leading to the mammary gland structural changes with less proliferative alveolar buds and lobules was investigated recently (Tan et al., 2004). Rat offspring were exposed to flaxseed or flaxseed lignan SDG during the suckling period only. At weaning (day 21 after birth) and at proestrus phase (day 49-51 after birth) the mammary glands were analyzed for morphology, cell proliferation, expression of epidermal growth factor receptor, epidermal growth factor transforming growth factor alpha, estrogen receptor alpha and estrogen receptor beta. Enhanced mammary gland morphogenesis was seen by modulation of epidermal growth factor receptor and estrogen receptor signaling, which led to more differentiated mammary glands at proestrus phase rats. These findings are supported by the earlier studies with flaxseed effects on reproductive development in rats (Tou and Thompson, 1999; Tou et al., 1998).

The effect of flaxseed feeding on rodent spermatogenesis has been studied, as it has raised a concern about lignans possible estrogenic effect on male reproductive organogenesis. Rats

were fed with flaxseed 20 % or 40 % diets or flaxseed meal 13 % or 26 % diets during gestation and lactation periods. After weaning at 21 days the male offspring continued the same diets for 70 days. No differences between diet groups were observed in testis weights, homogenization resistant spermatid counts, daily sperm production rates, epididymal weights, seminal vesicle weights, seminiferous tubule fluid testosterone concentrations or the percentage of sperm abnormalities. Flaxseed diets caused significant increases in serum LH and testosterone levels, in cauda epididymal weights, cauda epididymal sperm numbers/g, and decrease in prostatic weight. Additionally, the morphometric measurements on the testes showed significant decreases in the absolute volume of the seminiferous tubules after flaxseed 20 % and 40 % diets. This was not considered biologically significant because other parameters of male reproductive function appeared normal (Sprando et al., 2000a; Sprando et al., 2000b).

Breast cancerThe association between lignans and human breast cancer

risk has been studied using estrogen-receptor negative human breast cancer cell lines in vitro or embedded in mice mammary fat pads (Chen et al., 2002; Chen and Thompson, 2003). Flaxseed 10 % diet for 7 weeks resulted in significant inhibition in the established human breast cancer growth and metastasis, due to, at least partly, the recorded down-regulation of insulin-like growth factor I and epidermal growth factor receptor expression. The estrogen-receptor positive breast cancer cell line showed enterodiol, enterolactone and antiestrogen drug tamoxifen in vitro to be inhibitory against cancer cell adhesion, invasion and migration.

Human case-control studies have been conducted to determine the association between dietary phytoestrogen intake and breast cancer risk. The low urinary enterolactone excretion was found in an Australian study (Ingram et al., 1997) confirming the earlier observations with the association to breast cancer risk (Adlercreutz and Mazur, 1997). This was further confirmed in a Finnish study with 194 breast cancer patients (Pietinen et al., 2001). However, recent prospective study in 15 555 Dutch women aged 49-70 years showed different results (Keinan-Boker et al., 2004). During the 8 years of follow-up, 280 women were diagnosed with breast cancer but no association with low intake of isoflavones or lignans was found. This study involved both pre- and postmenopausal aged women which may bias the results as it has been reported recently that high dietary lignan intake and low risk of breast cancer especially associate in premenopausal but not in postmenopausal women (Linseisen et al., 2004; McCann et al., 2004). Parallel to these results, no association with breast cancer risk and low serum enterolactone concentration was found in a follow-up study of 8 years with 206 breast cancer patients in Finland (Kilkkinen et al., 2004). In this study, serum enterolactone levels were almost equal in both patients and controls: 25.2 and 22.2 nmol/l, respectively. Similarly, low serum enterolactone concentrations both with postmenopausal breast cancer patients (14.3 nmol/l) and controls (13.9 nmol/


l) were observed in a study (Zeleniuch-Jaquotte et al., 2004). In a Swedish nested case-control study (Hultén et al., 2002) with 248 breast cancer cases and 492 controls, low plasma enterolactone concentration was associated with a significantly increased risk of breast cancer. In this study, however, an increased risk was found also with high plasma enterolactone values with only incident cases.

The occurrence of breast cancer among 383 women with palpable cysts in breasts and the relationship to serum enterolactone concentration was studied by Boccardo et al. (2003). During the follow-up time of 6.5 years 18 cases with breast cancer were found with significantly lower serum enterolactone levels than women with no cancer. The mean serum enterolactone values were 8.5 nmol/l (low) versus 16 nmol/l (high). There has been observed an inhibition of aromatase enzyme in human preadiposytes in vitro by lignans and flavonoids (Wang et al., 1994). Since aromatase-inhibitors are used as medication in the treatment of breast cancer, this raises a question of the possibility to reduce this disease by increased consumption of lignan and flavonoid-rich foods.

In the onset of cancer, many dietary, genetic and environmental factors matter. The initial, promotion, metastatic or advanced stages of carcinogenesis may react differently to bioactive molecules in blood stream and in tissues. Referring to Adlercreutz (2002), maybe there really needs to be “a lifetime dietary prophylaxia” which can be measured as adequate levels of certain nutrients in blood and the addition of nutrients into diet in later life does not necessarily work.

The hypothesis that use of antimicrobial drugs may increase the risk of breast cancer via impairing the intestinal bacterial formation of mammalian lignans goes back two decades (Setchell et al., 1981). The possible relation between the long-term use of antibiotics for urinary tract infections and the incidence of breast cancer was studied by Knekt et al. (2000). A total of 9461 Finnish women, originally cancer-free were followed for 4 years. During that time 157 breast cancer cases were diagnosed. Women reporting previous or present medication for urinary tract infection at baseline showed an elevated breast cancer risk in comparison with other women. The association was concentrated to women under 50 years of age. Later, it was found that serum enterolactone concentration is significantly lower in those people that had used oral antimicrobials up to 12-16 months before serum sampling than in nonusers (Kilkkinen et al., 2002). This study was conducted with 2753 Finnish men and women aged 25-64 years of age. A recent case-control study among 2266 women with breast cancer and matched controls showed an association between use of antibiotics and the increased risk of breast cancer (Velicer et al, 2004). In this study, different classes of antibiotics showed similarly increased risk of breast cancer.

The homeostasis of intestinal bacteria is disturbed with antimicrobial drugs. The immune functions in humans may be impaired by the use of antibiotics that abolish the non-pathogenic, aerobic E. coli. Acute inflammation itself (O’Byrne and Dalgleish, 2001) and chronic inflammation

with consistent cytokine effects is causing intracellular changes promoting tumor invasion and preventing apoptosis (Ames et al., 1995; Christensen et al., 1999).

All functional elements of flaxseed – fibers, fatty acids and lignans – are affected if the balance of intestinal microbial flora is disturbed. It is not known if the amount of substrate in the disturbed colon has any function, i.e. is there a possibility to achieve high enterolactone concentrations by providing high dietary amounts of lignans.

Prostate cancer The most evidence of the protective effect of phytoestrogens

against prostate cancer is based on the isoflavones (Adlercreutz, 2002) and the reporting of the effect of lignans has been sparse. In a prostate cancer cell line study the treatment of cells with enterolactone, enterodiol or genistein (isoflavone), showed a significant inhibition of cell growth but genistein had the highest potency (Lin et al., 2001). The same group of investigators found that 5% flaxseed diet fed to transgenic adenocarcinoma (TRAMP) mice resulted in inhibition of the growth and development of prostate cancer (Lin et al., 2002).

In humans, controversial results have been achieved. Two case-control studies with large populations of diagnosed prostate cancer showed no association between serum enterolactone and prostate cancer (Stattin et al., 2002; Kilkkinen et al., 2003b). In both of these studies, the mean serum enterolactone was low ranging from 8.5 to 16.9 nmol/l that may have been too low to show any protection. However, the effect of a flaxseed-supplemented (30 g/day), fat-restricted (20 % or less of energy) diet was studied with 25 men with prostate cancer and awaiting prostatectomy (Demark-Wahnefried et al., 2001). The average of 34 days on this diet caused significant decreases in total serum cholesterol, total testosterone and free androgen index. The changes in proliferation and apoptotic indexes need further studies, as the authors conclude. Experimental support to these clinical intervention studies has been received recently. Pure plant lignan (7-hydroxymatairesinol, HMR) fed to athymic mice xenografted with human prostate cancer cells (LNCaP) had a tumor growth-inhibiting effect during a 9 week diet (Bylund et al., 2005). The effect of fatty acids was not investigated in this study despite the interesting composition of fats in the diet (corn oil, lard and flaxseed oil).

Colorectal cancerThere is an association between decreased risk of colorectal

cancer and dietary intake of fiber (Peters et al., 2003; Bingham et al., 2003) and a similar association seems to exist with the intake of rye bran, flaxseed or purified lignans in mice (Adlercreutz, 2002; Sung et al., 1998). However, a study failed to confirm the protective effect, when 5 % flaxseed or 30 % rye bran was added to a Western style diet (Van Kranen et al., 2003).

In a recent experiment, 0.5 % flaxseed diet failed to cause any inhibition of intestinal adenoma formation in multiple


intestinal neoplasia-type (Min) mice, despite the significant increase of plasma enterolactone and enterodiol (Oikarinen et al., 2004). An interesting finding in this study is that the wild-type mice with similar diets had a tendency for higher intestinal enterolactone and enterodiol than Min-mice indicating the disturbing effect of adenomas in the production of mammalian lignans.

Some encouraging results have been gained with pure enterolactone and enterodiol in prevention of human colon cancer cell growth (Qu et al., 2005). Lignan metabolites in concentration of 40 µmol/l blocked the growth of SW480 cells in S-phase. The blockage was suggested to be caused by the decrease of cyclin A protein that is needed for S/G2 transition in cell growth cycle. The increase of the amount in apoptotic cells in the culture lead to the theory of a cytostatic and apoptotic effect of enterolactone and enterodiol on colon cancer cells (Qu et al., 2005).

Benign prostate hyperplasia Recently, the same group of investigators studied the

effects of the same flaxseed-rich fat-restricted diet on benign prostatic epithelium (Demark-Wahnefried et al., 2004) with 15 men for 6 months. Statistically significant decreases were seen in prostate-specific antigen (PSA) from 8.47 to 5.72 ng/ml and in serum total cholesterol. No changes were seen in total testosterone values. The proliferation rates decreased significantly. Flaxseed-supplemented diet seems to have a beneficial effect on benign prostate hyperplasia. However, the low-fat diet included may have had an influence, too. Namely, in a healthy volunteer crossover study investigating the extent of isoflavone metabolism with high- or low-isoflavone diets it was noted that those volunteers excreting high concentrations of equol also had a significantly lower dietary fat intake. Equol is produced by intestinal microflora from isoflavonoid daidzein and was over 600-fold higher among good equol excretors compared to low-excretors (Rowland et al., 2000). It may be that a similar decrease in convertion of SECO and MATA into enterolactone and enterodiol occurs when the diet is rich in fats. Animal fat intake has been found to associate with prostate cancer also in two case-control studies (Ramon et al., 2000; Giovannucci et al., 1993).

FLAXSEED SAFETY The potential toxicity of flaxseed ingestion concentrates

mainly on the presence of the cyanogenic compounds. Also the cadmium content, originating from the soil, has been proposed as a possible factor that could cause unwanted toxic effects with flaxseed dietary use. Toxicity of plant lignans has been questioned and should be clarified as it has been recommended to ingest relatively high amounts of foods containing lignans to achieve beneficial health effects.

Cyanogenic compounds of flaxseedCyanogenic compounds are nitrogenous secondary plant

metabolites capable of liberating hydrogen cyanide upon hydrolysis. Two chemical types, cyanogenic glycosides and

cyanolipids, have these cyanophoric capabilities. Cyanogenic glycosides are known to occur in many crop species, cyanolipids are more restricted in distribution. Cyanogenic glycosides are important natural toxicants in both human and animal nutrition.

The primary precursors of the cyanogenic glycosides of flaxseed are restricted to the two hydrophobic protein amino acids, valine and isoleucine (Seigler, 1981). The cyanogenic glycosides, linamarin and linustatin, are derived from valine, while isoleucine is the biosynthetic precursor for lotaustralin and neolinustatin. The biochemical related valine series, linamarin and linustatin, dominates the isoleucine series during the growth of whole flax fruits from anthesis to maturity (Frehner et al., 1990). The ratio of monoglycosides to total cyanogenic glycosides shifts from 100 % to 0 % at maturity. Young flax fruits (0-18 days after flowering) contain mainly the monoglycosides linamarin and lotaustralin (>90 % of total cyanogenic glycosides), whereas about 30 % of the cyanogens in older fruits (25-45 days after flowering) are the diglycosides linustatin and neolinustatin (Frehner et al., 1990). It seems to be very important to harvest the flaxseed when it is fully ripened to minimize the amounts of cyanogenic compounds.

Variation of the cyanogenic glycoside content has been reported (Oomah et al., 1992). A range of 218-538 mg/100 g and 73-454 mg/100 g of linustatin and neolinustatin, respectively, has been reported for 48 flaxseed varieties grown in 1983 at one location in Germany. A narrower distribution range is found in Canadian flaxseed varieties.

Linustatin accounts for 54-76 % of the total cyanogenic glycoside content. The distribution of cyanogenic glycosides in flaxseed is dependent on species. Linamarin is absent in both Linum usitatissimum and Linum angustifolius. However, the individual variations in the neolinustatin level is considerable in Linum usitatissimum, ranging from zero to more than three times that of the mean values. Linum usitatissimum is the variety most commonly ingested as dietary supplement.

The processing of flaxseed can significantly effect on the concentration of cyanogenic glycosides. Defatting or solvent oil extraction produces an enrichment of all individual glycosides. Removal of gum (mucilage) can eliminate the cyanogenic compounds from flax. Dry fractionation using sieves results in particles of different sizes. The lowest concentration of cyanogenic glycosides is observed for particles smaller than 850 µm but larger than 450 µm. The ratio of linustatin to neolinustatin is also different for this fraction, the linustatin consisting over 56 % of the total cyanogenic glycoside content. This fraction consists mainly of the endosperm, with the seed coat or hull fraction larger than 850 µm staying on top of the sieve. Thus, mechanical sieving influences the redistribution of cyanogenic glycosides (Mazza and Oomah, 1995).

Toxic effects of cyanogenic glycosidesThe ability of cyanogenic glycosides to release cyanide as a

result of nitrile biotransformation implicates them in cyanide poisoning and depressed growth in livestock consuming feed containing cyanogenic compounds. Cyanide poisoning


symptoms include headache, tachycardia and disturbances in the central nervous system. Linamarin from cassava roots has been implicated in the development of a neurodegenerative disease known as cassavism (Spencer et al., 1993) and diabetes mellitus subtype (fibro-calculous pancreatic diabetes) (Ragoobirshing et al., 1993). Flaxseed contains very low levels of linamarin, but it does contain considerable levels of the diglycosides linustatin and neolinustatin (Smith et al., 1980; Oomah et al., 1992). There are no reported flaxseed poisonings, however.

Animal toxicology During gestation and lactation, six month old female

Wistar rats were fed diets containing various vegetable oils; thermopolymerized flaxseed oil at 275 °C for 12 hours under nitrogen atmosphere (group T), oxidized flaxseed oil at 200 °C for 100 hours under air atmosphere (group O) (Potteau, 1976). The two oils contained respectively 1,1 % of cyclic monomers (18C). Control groups were fed either fresh flaxseed oil or freshpeanut oil under the same conditions. In group T, most of the newborn rats died at birth or during the first three days of life; none of them survived more than 13 days after birth. In group O, mortality was not so high but was still significantly higher than in the control group. Moreover, dead young rats of group T have heavier livers and higher lipid content in the organ. Cyclic monomers were detected in liver fatty acids. In surviving young rats of group O, the body growth during lactation is significantly slower than in control animals. Young rats of group O were sacrificed at the age of 14 days. Liver weight and lipid content of the organ are increased and cyclic monomers were detected. The effects are however less pronounced than in group T. One can assume that among abnormal compounds formed during heating of flaxseed oil, cyclic monomers are responsible for the toxic effects observed in the present experiment since they have been transmitted to the litters either during gestation or lactation. Based on this animal study it may be preferable to use cold-pressing technique when pressing oil from flaxseeds.Cyanide has not been shown to accumulate in the blood

and tissues following chronic oral exposure. Following the treatment of rats with hydrogen cyanide in the diet at ≤10.4 mg CN-/kg/day for 2 years, virtually no cyanide was found in plasma or kidneys (Howard and Hanzal, 1955). Low levels were found in erythrocytes (mean of 1.9 mg/100 g). Increased levels of thiocyanate, the less toxic primary metabolite of cyanide, were found in plasma (1,123 µg/100 g), erythrocytes (246 µg/100 g), and kidney (1,188 µg/100 g).A recent study investigated the effects of 10 % flaxseed chow

fed to rats on their development after birth (Hemmings and Barker, 2004). Compared to regular chow-fed rats, there were no differences in growth, certain development criteria or blood glucose. The levels of liver enzymes alanine aminotransferase (ALT) and gamma-glutamyltranspeptidase (GGT) did not differ between groups indicating no hepatotoxic effects. However, after puberty it was seen an increase in GGT activity was observed especially in male rats that was considered

reflecting a normal regulatory influence.

Human toxicologyThe following study was performed with pure thiocyanate,

but it clarifies the kinetics of this substance, which is formed in the human body after ingesting flaxseed. The concentration of thiocyanate in the serum of eight test subjects with renal failure and seven healthy control subjects was measured, as it declined with time, after oral doses of thiocyanate or i.v. injections of nitroprusside, a drug with blood pressure lowering effect, had been administered (Howard and Hanzal, 1955). Additional measurements were taken, on the healthy subjects only, of the concentrations of thiocyanate in urine, and also of the influence of an increased chloride intake on the rate of elimination of thiocyanate. For the healthy subjects an elimination half-life of between one and five days (mean 3 days) was found. Increasing the chloride elimination rate to approximately twice normal did not significantly speed up the rate of thiocyanate elimination. The amounts of thiocyanate, which had been administered as doses, reappeared almost exclusively in the urine. For the subjects with renal failure, the elimination half-life had a mean value of approximately nine days. The elimination constants (ke) were found to be proportional to the creatinine-clearance rates. The ke value at a creatinine-clearance of 0 ml/min was approximately 15 % of the ke value at a creatinine-clearance rate of 120 ml/min. The distribution volumes for thiocyanate were greater for the patients with renal failure than for the healthy subjects.

There are only a few controlled intervention trials reported of flaxseed consumption. Schulz and coworkers (Schulz et al., 1983) report a study where resorption of hydrocyanic acid after ingestion of flaxseed was investigated in 20 healthy volunteers and five patients with constipation. Subjects took a single dose of 30 g or of 100 g of flaxseed or repeated doses of 15 g t.i.d. throughout several weeks. One volunteer took for purposes of comparison one dose of bitter almonds or potassium cyanide. Before, during and after the periods of ingestion plasma levels of hydrocyanic acid and of thiocyanate were normal. After one single dose of 30 g of flaxseed the blood samples were taken after 15, 30, 60, 120 and 180 minutes and the cyanide and thiocyanate were determined. The levels (in nmol/ml of cyanide/thiocyanate) were 0.7±0.7/147±67 (0-timepoint) to 0.4±0.4/137±54 (180 time-point). After the dosage of 3 x 15 g daily, the levels were respectively 0.5±0.4/134±48 (0 time-point) to 1.2±2.5/274±78 (five weeks). During long-term trials urinary excretion of thiocyanate was monitored regularly. Intake of flaxseed even in extremely high dosages (100 g) never caused significant rises of plasma thiocyanate levels; this, however, was the case after intake of bitter almonds (10 or 50) or potassium cyanide 3, 6 and 12 mg as single doses. The authors conclude that intoxication by hydrocyanic acid can not be caused by flaxseed. Long-term intake, however, raised plasma levels of thiocyanate significantly; at the same time the urinary excretion of thiocyanate increased.

In our own study (Tarpila et al., 2003) the mean value of serum thiocyanate elevated from 40.9±24.1 to 153.7±58.0


µmol/l after 3 months flaxseed treatment with a mean dose of 17 g/day. These patients were all non-smokers. After 3 more months of flaxseed diet the serum thiocyanate levels decreased to 104±56 µmol/l. We also found that the serum metabolite of cyanic acid, thiocyanate was reduced after regular use of ground flaxseed during 3-6 months. This may be because of the adaptation in the detoxification process in liver. There were no changes in serum alanineaminotransferase enzyme or in serum creatinine levels after 3 months’ flaxseed supplement compared to baseline. The reference value for serum thiocyanate is <250 µmol/l for smokers and <100 µmol/l for non-smokers. It seems that cyanic acid is not accumulating during long-term use.

Cadmium in flaxseedCadmium is, together with lead and mercury, one of the most

problematic metals in environmental toxicology. Cadmium is globally distributed in soil, usually together with lead and zinc. The most important source of exposure in humans is through food: all food contains some cadmium, but levels are higher in clams, liver and kidney. Tobacco includes also considerable amounts of cadmium.

Cadmium can form salts or oxides, which absorb from the gastrointestinal tract by 5 %. More is absorbed via the lungs; for instance from the cigarette smoke 10-40% is absorbed as tobacco includes considerable amounts of cadmium.

Cadmium accumulates in the liver and kidneys, where the proteins called metallothioneins bind it. The amount of these proteins increases after cadmium exposure. In the kidney, the metallothioneins seem to protect the tissue as long as the tissue concentration is below 200 µg (Meberg et al., 1979). Above this concentration damage to the kidney tubuli occurs, resulting in proteinuria. Cadmium has a half-life of 10-40 years and is eliminated probably via the kidneys or bile. The daily amount of cadmium, which can cause accumulation in body, is considered to be 200-300 µg (Meberg et al., 1979).

Flaxseeds accumulate cadmium from soil, especially from artificially fertilized soil. The cadmium content of a flaxseed product investigated by Tarpila et al. (2004) was analyzed to be 0.84 mg/kg. In Finland there is no official limit value of cadmium for the food products. In Germany, the limit value is 0.3 mg/kg. It has been estimated that Finnish people are exposed to 70 µg of cadmium per week, which is 16% of the upper limit value set by World Health Organization (WHO). If a person is using flaxseed 6 g/day (one tablespoon), he will get 5 µg of cadmium daily and 35 µg weekly. If the daily dose of flaxseed were 4 x 6 g, the amount of cadmium would be 141 µg weekly that is below the recommended daily accumulating concentration of 200-300 µg (corresponding 1400-2100 µg weekly). In our study we determined the blood cadmium values after 6 months of flaxseed ingestion of an average, 17 g/day. The mean blood cadmium concentration was within normal limits (3.4±1.7 nmol/l), compared with the reference value of 10 nmol/l.

Lignan toxicityRecent studies by Hemmings and Barker, (2004) establish

the biosafety of 10 % flaxseed diet when fed to rats for 50 or 100 days. In their earlier study (Hemmings et al., 2004) they showed that long-term flaxseed feeding was without effect on development, behavior, physical characteristics and glucose balance and without signs of toxicity. To confirm these results to be due to either flaxseed oil or lignan component, two different strains of flaxseed were studied: strain with high in SDG (secoisolariciresinol diglucoside) but either high or low in ALA. The diets showed again no effects on growth, development or behavior when compared with control diet. No effect on plasma ALT (alanine aminotransferase) activity was detected. Significant increase in activity of the plasma membrane-bound form of liver �-glutamyltranspeptidase was detected. This enzyme activity increases the intracellular levels of reduced glutathione, a feature considered hepatoprotective.

There are no reported toxicity tests done with pure flaxseed lignans at the moment. However, a lignan complex containing SDG, cinnamic acid glucoside and hydroxymethyl-glutaric acid has been tested for possible effects on the hemopoietic system of rabbits (Prasad, 2004). A dosage of 40 mg/kg body weight given orally for two months did not express any adverse effects on red or white blood cells or on platelets. Toxicity studies have been performed with 7-hydroxymatairesinol potassium acetate (HMRlignan) isolated from the heartwood knots of spruce (Picea abies). HMRlignan is structurally very similar to matairesinol, a plant lignan found in flaxseed. Both HMRlignan and matairesinol are converted into mammalian lignans enterolactone and enterodiol by the gut microflora. A prenatal developmental toxicity study was performed with 4 groups of 24 pregnant rats each fed with HMRlignan supplemented rat chow (Wolterbeek et al., 2004). Calculated intake of HMRlignans was 0.14 g/kg in low dose group, 0.46-0.74 g/kg in mid-dose group and 1.19-2.93 g/kg in high-dose group. Despite decreased palatability and therefore decreased intake of food, the study results remain consistent and a no-observed-effect level (NOEL) could be set to be 460 mg/kg/day for maternal and 1190 mg/kg/day for the developmental effects.

Further, a subchronic oral toxicity study was performed with HMRlignan in rats (Lina et al., 2005). Daily intakes were 160, 640 and 2600 mg/kg in groups of rats with 20 males and 20 females each. After 13 weeks feeding, no-observed-adverse-effect-level (NOAEL) was placed at 160 mg/kg body weight/day. Relating to human lignan consumption at maximum of 1 mg/kg/day in Western populations (Adlercreutz, 2002), this given NOAEL is at least 160-fold. Interactions between vitamins and flaxseed

Early findings of Kratzer et al. (1954) showed that flaxseed feeding caused poor growth and typical vitamin B deficiency symptoms in chicks and turkey poults and that these symptoms were prevented by the addition of pyridoxine. The isolation of linatine from flaxseed by Klosterman et al. (1967) confirmed that it can form a toxic compound 1-amino-D-proline upon hydrolysis. This compound can form a stable derivative of pyridoxal phosphate (vitamin B6 ) that is inactive. Linatine is present in flaxseed in concentration of 100 ppm which can be


considered very low. An unexpected and significant lowering of vitamin E levels

in rat plasma and liver was observed after a 27-day diet with 0.1 % supplementation of dietary lignan secoisolariciresinol diglucoside (SDG) (Frank et al. 2004). There was also a significant elevation of liver cholesterol and of the percentage of cholesterol in the liver lipids. Since most antioxidants have shown an opposite effect this finding is surprising. The authors discuss the possibility of SDG increasing the rate of free radical generation and oxidative stress in the liver and thus leading to a reduction in vitamin E levels.

The reported interactions between vitamins and flaxseed or purified dietary lignan certainly need further investigation, especially as pure lignans are currently under consideration for supplementation in functional foods.

CONCLUSIONSConstipation, irritable bowel syndrome and diverticular disease The recommended amount of daily dietary fiber of >25g

is, according to many studies, useful in the treatment of constipation, irritable bowel syndrome and diverticular disease. Ground flaxseed consists of 40 % of dietary fiber, 2/3 of which is insoluble (cellulose, hemicellulose and lignin) and 1/3 is soluble fiber. Insoluble fiber binds water and thus increases the bulk in colon. Soluble fiber from flaxseed mucilage has similar effects than guar gum or ispaghula, e.g. delay in gastric emptying, improvement in glycemic control and alleviation of constipation. The mean dietary fiber intake in western countries is approximately 20 g/day. Flaxseed supplement of 10-20 g/d would increase the intake to the recommended level of 25-30 g/day. However, the use of flaxseed has to be long-term as the full effects are only observed after two months. Roughly ground flaxseed seems to have better water-binding capacity than the finely ground flaxseed meal.

Colorectal cancerThe association between dietary fiber and colorectal cancer

has been under investigation for three decades. Western diet is highly refined and therefore, fiber intake may be very low in some populations. Epidemiological studies show an inverse relationship between the intake of dietary fiber and colorectal cancer. However, study results had, until recently, been controversial. Two recent large studies show an association between dietary fiber and colorectal cancer (Peters et al., 2003; Bingham et al., 2003).

Use of flaxseed as a food supplement is suitable to increase the amount of fiber in the diet. Flaxseed is rich in plant lignans that can convert into mammalian lignans in the colon. The possible synergistic effect of fiber and phyto-estrogens needs further studies.

Breast cancerFlaxseed lignans and fatty acids have been investigated in

several cohort studies for their effects on breast cancer risk and there is some association between elevated serum enterolactone

and decreased incidence of breast cancer. Lilian Thompson has studied experimentally the lignan effects

and their mechanisms on the onset of rodent mammary cancer and shown that dietary lignans can diminish the growth of both initial and advanced mammary tumors. Flaxseed lignans have shown aromatase-enzyme as well as the down-regulation of EGF-receptor (Wang et al., 1994; Chen et al.,2002). It seems that the preventive effect of phyto-estrogens on mammary cancer incidence needs a lifelong use of them.

Prostate cancer and hyperplasia The effects of lignans and fatty acids on the risk of prostate

cancer have been studied during the last few years together with isoflavonoids. Two studies with lignans show no protection but the populations investigated had very low levels of serum enterolactone, perhaps unable to show any protective effect (Stattin et al., 2002; Kilkkinen et al., 2003b). The flaxseed-supplemented diet, however, was beneficial on biological cancer biomarkers both with prostate cancer patients and patients with benign hyperplasia (Demark-Wahnefried et al., 2001; Demark-Wahnefried et al., 2004).

In vitro and experimental animal studies have suggested that linoleic acid may promote prostate cancer cell proliferation, whereas alpha-linolenic acid appears to be antiproliferative. Flaxseed contains both of these fatty acids with majority of alpha-linolenic acid. Investigations in humans are required to further elucidate the effects of these fatty acids on human prostate cancer and benign hyperplasia.

Serum lipidsSoluble dietary fiber (such as flaxseed mucilage) decreases

blood total cholesterol by binding bile acids in the intestine to increase the excretion of cholesterol in faeces. Flaxseed linoleic acid and oleic acid, but not alpha-linolenic acid has a lipid-lowering effect in long-term use.

Cardiovascular diseasesElevated serum enterolactone level seems to associate with a

lower incidence of acute coronary infarctions and low serum enterolactone seems to be a risk factor for coronary deaths. High serum ALA seems to have parallel effect with high serum enterolactone. Flaxseed use increases the blood ALA and enterolactone and thus may be associated with lower incidence of coronary heart disease. Further, ALA seems to have antiarrhythmic effect on cell membranes of heart muscle. ALA seems to be protective against cerebrovascular stroke

and atherogenic carotid plaque formation. Omega-3 fatty acids show endothelial relaxing factor activity, presumably through nitric oxide. A potential hypotensive effect of flaxseed requires further investigations. Flaxseed ALA may have similar antithrombogenic actions to fish oil.

DiabetesThe dietary fiber, especially soluble fiber, causes a decrease

in glucose absorption and thus reduces glycemic response. Therefore, flaxseed may be useful in the diets of those in risk


developing type 2 diabetes.

Flaxseed in the dietDietary sources of fiber differ widely among populations

and therefore lignan precursors can be very different. It is known that populations are adjusted genetically to utilize best their endemic foods. This may cause a different composition for healthy food and its biomarkers for them. Therefore the worldwide generalization, for instance in cancer dietary prevention, may be difficult. In the Western world, however, there is no doubt that a change to a lower fat and higher fiber diet would be beneficial. Therefore we recommend the use of flaxseed in whole seed or ground form as a dietary supplement or added in bread or other foods. Flaxseed is also a good source of both plant lignans and plant α-linolenic acid which have been described to express beneficial effects in human health.

Diet, environmental and psychic factors, when thrown off balance, may lead to a disease when protection by immunological system fails. However, there is wisdom in the hypothesis of “lifetime dietary prophylaxia” for diseases.

CONFLICT OF INTEREST: None disclosed

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