Flaxseed is the richest known dietary source of mammalian lignans. Thompson et al. demonstrated that secoisolariciresinol diglucoside (SDG), isolated fromflaxseed, was metabolized into both enterodiol
(END) and enterolactone (ENL), and showedchemopreventive properties in the DMBA-induced mammary tumormodel in rats.
The inverse association between a high enterolactone (ENL) concentrationin both urine and serum, and the risk of breast cancer foundin epidemiological studies suggests a chemopreventive actionfor ENL.
Plant lignans, such as secoisolariciresinol (SECO) and matairesinol found in many edibleplants, are transformed by intestinal microbiota into mammalianlignans ENDand ENL, respectively. ENLis the quantitatively most important lignan in human serum.An inverse association between the urinary or serum ENL contentsand the risk of breast cancer has been described in severalepidemiological studies. The finding has stimulatedconsiderable interest in the possible chemopreventive actionof ENL and its precursors.
In pilot human studies, dietary flaxseed given preoperativelyto newly diagnosed breast cancer patients markedly reduced theKi67 labeling index and c-erb2 of the breast cancer tissue,suggesting direct antiproliferative effects. As expected,there was a marked increase in the urinary excretion of mammalianlignans after the ingestion of flax. A recent study of short-termflaxseed supplementation and fat restriction in diet additionallyshowed significantly lower proliferation rates and higher ratesof apoptosis in prostate cancer of men before operation.
However, the observed effects of flax do not allow for any conclusionson the possible role of lignans in the inhibition of cancergrowth, because other potentially bioactive multiple compoundsare present in flaxseed. ENL is assumed to mediate the anticarcinogenic action of plantlignans shown in experimental breast cancer and account forthe antiproliferative effects seen in the clinical studies offlaxseed supplementation. Until recently, there was no direct evidencefor the anticarcinogenic action of ENL in humans or experimentalcancer models in animals. The possible anticarcinogenic effectsof ENL on breast cancer were tested for the first time by usinga DMBA-induced mammary carcinoma of the rat in this study
Hutchins et al. reported increasedserum prolactin concentrations, and decreased serum 17ß-estradioland estrone concentrations in postmenopausal women after a 7-weekadministration of flaxseed in a daily dose of 10 g. It is possible that a long-term exposure to elevated concentrationsof lignans may alter the composition and metabolic activitiesof intestinal microbiota, possibly resulting in altered metabolismof other dietary polyphenols. This study showed elevated serumconcentrations of equol (EQ) and O-desmethylangolensin (O-DMA), metabolites of daidzein (DA), were observed.In premenopausal women, high EQ excretion has been associatedwith lower serum concentration of estrogens and androgens, andhigher concentration of sex hormone-binding globulin, a hormonalpattern consistent with lower risk for breast cancer. Thus,the increased serum concentrations of EQ and O-DMA could accountfor chemopreventive effects observed in this study
ENL and Breast Cancer - The study by Saarinen N et al provided the first evidence that ENL (derived from flaxseed) produced growth inhibition on cancer cells. In this study rats with 7,12-dimethylbenz(a)anthracene-induced mammary cancers were maintained on a standard open-formula chowdiet. Daily p.o. administration of ENL at a dose of 10 mg/kgof body weight for 7 weeks was shown to significantly inhibited tumor growth.The growth-inhibitory effect of ENL was more pronounced on thenew tumors, which developed during the treatment period, butENL also inhibited the growth of those tumors established beforethe start of the lignan administration. The rat serum concentrationof ENL, which illustrated a permanent positive effect on breastcancer growth, was 0.4 µM, which is >10-fold as comparedwith the serum concentrations found in the general human population.
The effect of ENL was not restricted to any specific histologicaltumor type. ENL was demonstrated to act as a weak aromatase inhibitor in vitro and to reduce the relative uterine weightof the 7,12-dimethylbenz(a)anthracene-treated nonovariectomizedrats. (1)
Additional Reading On Flaxseed
Flaxseeds are a rich source of secoisolariciresinol diglycoside (SLD) and other mammalian lignan precursors. Flaxseed contains 800-times more of these mammalian lignan precursors than is found in any other food (i.e. beans, nuts). The presence of SLD and related lignan precursors as well as its rich alpha-linolenic acid (omega-3 fat) content makes Flaxseed a very unique dietary supplement providing a broad range of health-promotion effects. The consumption of Flaxseed or processed Flaxseed (i.e. muffin or bread) has been shown to significantly raise blood levels of the mammalian lignans enterolactone and enterodiol in a dose-dependent manner. Enterolactone and enterodiol are produced in the colon by the action of bacteria on SLD.1,4 Both enterolactone and enterodiol act as phytoestrogens and can thus, bind to estrogen receptors on breast (and other reproductive tissues) cells and inhibit certain enzymes (i.e., aromatase enzyme in adipose tissue, also known as estrogen synthase) 2
These, and other synergistic effects have made Flaxseed a target for breast cancer research. Other Flaxseed attributes have stimulated research to examine its potential benefits in the prevention of cardiovascular disease, cancer (i.e. breast, prostate, colon), osteoporosis and the management of menopausal symptoms. 3,4
Principle Active Constituents
Clinical Application and Mechanism of Action
a) Experimental Evidence- Enterolactone and enterodiol have been shown to exhibit the following anti-cancer functions on an experimental basis:
b) Human Evidence - Enterolactone and enterodiol have been shown to exhibit the following anti-cancer functions in human studies:
In a double blind placebo-controlled study by Plu-Bureau et al, they demonstrated that patients ingesting the flaxseed muffin (25gm Flaxseed ) reported a significant improvement in breast pain reduction compared to the placebo group, during the three consecutive menstrual cycle duration of the trial. Results were attributed to the antiestrogen effects of Flaxseed lignans. 16
Animal studies originally suggested that Flaxseed intake had a hypocholesterolemic effect, that is due to its soluble fiber concentration, not to its alpha-linolenic acid content.16
In human trials including men and postmenopausal women with high blood cholesterol levels, Flaxseed Powder or Flaxseed supplementation in various forms has been shown to reduce total cholesterol (approximately 7-10 percent), reduce LDL-cholesterol (approximately 15 percent), reduce lipoprotein (a) (Lp(a)) concentrations by approximately 7 percent. Lp(a) is emerging as an important risk factor for cardiovascular disease as it increases clotting behaviour of platelets, cholesterol deposition in the artery wall and it oxidizes LDL-cholesterol, making it very atherogenic.
Flaxseed supplementation is the only dietary factor shown to reduce Lp(a) to date.
Estrogen replacement therapy reduces Lp(a) levels, but cholesterol lowering drugs (i.e. statin drugs) do not 17,18,19
Flaxseed lignans inhibit the cholesterol-7-alpha hydroxylase and acyl CoA cholesterol transferase enzymes, involved in cholesterol synthesis, thus reducing total cholesterol. 24
Animal and human studies indicate that a diet rich in soy based protein and isoflavones, and/or Flaxseed lignans retard the development and progression of chronic renal disease. The protective effect is considered to be due to effects on cell growth and proliferation, extracellular matrix synthesis, reduced oxidative stress and inflammation reduction 20
In humans (and animals) Flaxseed supplementation has demonstrated renoprotective effects in human lupus nephritis, with significant delay in the onset of proteinuria, and preservation of the glomerular filtration rate (GFR) and renal size.
Preliminary evidence in women suggests that the phytoestrogen influence of enterolactone and enterodiol (from Flaxseed supplementation) has a positive effect on bone density and menopausal symptoms (i.e. hot flashes) 11
Flaxseed lignans interfere with steroid metabolism and bioavailablity in a fashion that is linked to reduced prostate cancer risk. They also inhibit enzymes such as tyrosine kinase and topoisomerase, which initiate the cellular proliferation rate. Epidemiological studies link the above endocrine and molecular events with up to an 80 percent reduction in risk of prostate cancer 22
Human studies reveal that Flaxseed supplementation improves laxation 5 It appears that Flaxseed intake increases fecal excretion of bile acids, increasing laxation and reducing the conversion of bile acids to cholesterol in the liver; thereby lowering blood cholesterol 23,5
Adverse Side Effects and Toxicity
Ground Flaxseed is extremely non-toxic. It is well tolerated according to human trails with no significant side effects, other than the occasional report of mild abdominal discomfort 5,16,23,24
There are no well-known drug-nutrient interactions for ground Flaxseed , Flaxseed Powder or Flaxseed -containing products 1,16,25
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