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Backgrounder
on Lignans
Phytoestrogens are plant chemicals that can have estrogen-like actions in humans and animals. The main phytoestrogens are isoflavones,coumestans, flavonoids and lignans (139). Lignans are widely distributedin the plant kingdom, play a role in plant growth and act as antioxidantsin human metabolism. In fact, the main lignan in flax and the formsderived from it are all antioxidants. The lignans are related to lignins,which are structural elements in plants (see Chapter 1) (140). This chapter reviews the metabolism and general effects of flax lignans. Theeffects of lignans on cancer are described in Chapter 6.
Phytoestrogens and Sex Hormones
Phytoestrogens are similar in their chemical structure to the natural and synthetic estrogens. Depending on their concentration and other factors, phytoestrogens can act like weak estrogens by binding to theestrogen receptor on cell membranes. At other times, they act as estrogenantagonists by preventing estrogens from binding to the receptors (141). Estrogens are female sex hormones. The main estrogens are estradiol and estrone. Testosterone is a male sex hormone. The estrogens andtestosterone are steroid hormones made from cholesterol by the sexorgans and to a lesser extent by the adrenal gland. The sex hormonescan be found in both men and women, although men produce considerably more testosterone than estrogens, whereas women producemore estrogens than testosterone. The estrogens and testosterone areresponsible for the development of adult sexual characteristics and mayinfluence cancer processes .
Dietary phytoestrogens and human estrogens interact in many complex ways that are not well understood. Nonetheless, because phytoestrogens are biologically active, there is interest in understandinghow they may help maintain health and prevent chronic diseases(139,142).
Flax Lignans
Flax is one of the richest sources of plant lignans, being very rich in the lignan secoisolariciresinol diglucoside (SDG). Flax contains other lignans as well – namely, matairesinol, pinoresinol, lariciresinol, isolariciresinol and secoisolariciresinol (often abbreviated Seco or SECO)(143,144). Metabolism of lignans
The lignans SDG, SECO, pinoresinol, lariciresinol and matairesinol in flax are converted by bacteria in the colon to the mammalian lignans,enterodiol and enterolactone. [The flax lignan isolariciresinol is not converted to mammalian lignans (145).] Enterodiol and enterolactone are called mammalian lignans or enterolignans because they are produced in the gut of humans and other mammals; they are not found in plants. A simplified diagram showing the conversion of flax lignans to mammalian lignans is given in Figure 4. Enterodiol can be converted to enterolactone (146). The biologic activity of flax and other plant lignans depends on the presence of certain bacteria in the gut (146). Some humans appear tolack either the right type or a sufficient number of gut bacteria to con-vert SDG and other lignans to mammalian lignans (147), and takingantibiotics virtually stops the production of enterodiol and enterolactonein the gut for several weeks (140).
Enterodiol and enterolactone have three metabolic fates: 1) They can be excreted directly in the feces; 2) They can be taken up by epithelialcells lining the human colon, conjugated with glucuronic acid or sulfateand excreted in the feces or enter the circulation (148); or 3) They canbe absorbed from the gut and transported to the liver, where free formsare conjugated before being released into the bloodstream (140).
Eventually, they undergo enterohepatic circulation – that is, they aresecreted into bile and reabsorbed from the intestine – and are excretedin the urine in conjugated form (149). Based on a kinetic study involving12 healthy adults, the mammalian lignans appear to be absorbed from F L A X – A Health and Nutrition Primer the colon about 8-10 hours after the plant lignans are eaten and reach amaximum concentration in the bloodstream about 7-10 hours later (150).
The concentration of enterodiol and enterolactone in the feces, blood and urine is related to the concentration of plants lignans in the diet –large intakes of plant lignans result in large amounts of these mammalian lignans in biological fluids. Eating flax or flax-containingfood products increases the blood levels of mammalian lignans (151-154)and the excretion of mammalian lignans and/or total lignans in feces(155) and urine (151,152,154,156-159). Consuming a diet supplementedwith a lignan/SDG complex derived from flax also increases mammalianlignan excretion in urine (160). The bioavailability of the mammalian lignans can be enhanced by crushing and milling flax (161).
Lignan metabolism is far more complex than originally thought. Plant lignans are not metabolized completely to mammalian lignans, and some FIGURE 4Metabolism of flax lignans by bacteria in the guta,b MAMMALIAN
aAbbreviations = SDG, secoisolariciresinol diglucoside; SECO, secoisolariciresinol.
plant lignans such as SECO can be detected in plasma. Furthermore, lignan metabolism may not stop at enterodiol and enterolactone, therebeing additional metabolites derived from these mammalian lignans.
These new findings raise questions about which lignan is the mostimportant and most biologically active form (38).
Lignan content of flax
Table 12 shows the lignan content of flax, based on figures given in two recent papers. In one paper the SDG content of flax was reported(38). The other paper reported individual flax lignans, not includingSDG, and calculated the total lignan content of flax (144).
Where flax is concerned, the problem of measuring its lignan content is compounded by the structure of the seed. SDG is the major flax lignan. It does not exist in the free form in the seed; rather, it exists as acomplex composed of five SDG molecules bound together with othermolecules in the outer fibre layer of the seed (38,140,145). ExtractingSDG from flax is difficult, and its incomplete extraction is responsible forsome of the variation in SDG values reported in the literature. Someresearchers have analyzed the SDG content of flax or estimated its SDGcontent based on the concentrations of its metabolites (e.g., SECO), assummarized by Muir (38). Other researchers, such as Thompson andcoworkers (144), analyzed flax samples to quantify the content of individual lignans, including SECO, which is a key end-product of SDGmetabolism (see Figure 4). Theoretically, the amount of SECO in flaxsamples reflects the amount of SDG present, provided the conversion iscomplete and the concentrations of pinoresinol and lariciresinol havebeen quantified. Whole flax seed contains 1-26 mg SDG/g, which works out to about 11-286 mg SDG/tbsp of whole seed or about 8-208 mg SDG/tbsp ofmilled flax (38). Whole flax seed contains about 42 mg of totallignans/tbsp, and milled flax contains about 30 mg of total lignans/tbsp,based on an analysis of four lignans in flax: matairesinol, pinoresinol,lariciresinol and SECO (144).
Flax oil containing added lignans has been available for several years.
One such product contained 0.1% SDG or about 14 mg SDG/tbsp flaxoil. The amount of SDG obtained from lignan-enriched oil depends onhow well the SDG particles mix with the oil. Adding SDG to flax oil is abit like mixing oil and water – because SDG is not soluble in oil, itresists mixing with the oil and tends to settle in the bottom of the container (162). F L A X – A Health and Nutrition Primer a Abbreviations = LAR, lariciresinol; MAT, matairesinol; PINO, pinoresinol; SDG, secoisolariciresinol diglucoside; SECO, secoisolariciresinol.
dThe values for total lignans in this column were calculated by summing the values for MAT, LAR, PINO Flax Lignan Content Compared with Other Foods
Flax is one of the richest sources of lignans identified to date, as shown in Table 13. Gram for gram, flax has 47 times the total lignancontent of sesame seeds and more than 600 times the total lignan con-tent of garlic (144). Lignans are found in most fibre-rich plants: oilseedslike flax and sesame seeds; nuts; cereals; breads made with flax and/orgrains; legumes and soy products; vegetables; and dried fruits (143,144).
TABLE 13 Lignan content of various foodsa Food group/food
Total lignans
a Source: Adapted from Thompson LU, et al. (144).
F L A X – A Health and Nutrition Primer How Mammalian Lignans Work
The mammalian lignans are believed to work by binding to estrogen receptors on cell membranes, much like the body’s own steroid estrogens do. The bound mammalian lignans affect the receptors’ actionswithin the cell and ultimately the response of tissues like those of thereproductive tract. Other phytoestrogens work in the same way.
The mammalian lignans are not as powerful as the body’s own estrogens, which are called endogenous estrogens. Even so, they can actas either weak estrogens or they can oppose the actions of estrogen,depending on the presence of stronger estrogens like estradiol (163).
During women’s reproductive years, when blood levels of endogenousestrogens are at their highest, the lignans can bind to the estrogenreceptor and block the actions of endogenous estrogens. In this case,they act as antagonists. After menopause, the levels of endogenousestrogens in the blood decrease naturally because the ovaries releaseless natural estrogens. In this case, the lignans act like weak estrogens(163).
Biologic Effects of Lignans
Flax lignans and the mammalian lignans (enterodiol and enterolactone) are biologically active. Lignans have anticancer and antiviral effects, influence gene expression (activation) and may protectagainst estrogen-related diseases such as osteoporosis (139-141). Dietshigh in lignans may help maintain good cognitive function in post-menopausal women (164); reduce the risk of uterine fibroids in middle-aged women (165); reduce breast cancer risk in women (166);and reduce the risk of acute fatal coronary events (167) and prostatecancer (168) in men. Specific actions of lignans include the following: • The main flax lignan SDG is an antioxidant. It scavenges for certain free radicals like the hydroxyl ion (•OH) (169). Our bodies producefree radicals continually as we use (oxidize) fats, proteins, alcohol and some carbohydrates for energy. Free radicals can damage tissuesand have been implicated in the pathology of many diseases like atherosclerosis, cancer and Alzheimer disease (170). In a rat study,feeding flax at levels of 5% and 10% in the diet prior to administeringa liver toxin protected against oxidative stress in liver tissue compared with a normal diet not containing flax (171). The mammalian lignans,enterodiol and enterolactone, also act as antioxidants (172). Indeed,the antioxidant action of SECO and enterodiol is greater than that ofvitamin E (173).
• The mammalian lignans affect receptors found on the surface of cell membranes. For instance, they activate the pregnane X receptor,which is involved in the metabolism of bile acids, steroid hormonesand many drugs. Enterolactone is a moderate activator of the receptor,suggesting it has the ability to affect the metabolism of some drugs(174). A study conducted in France suggested that some plant lignans,along with enterodiol and enterolactone, affect hormone receptors inbreast tissue. Among 58,049 French women who did not eat soy regularly, a high dietary intake of lignans (>1395 µg/day) was associated with a reduced risk of breast cancer. The benefit was limited to women with estrogen receptor positive (ER+) and progesterone receptor positive (PR+) tumours, suggesting that the biologic effects of lignans derive in part from their effects on cell hormone receptors (166).
• The mammalian lignans stimulate the synthesis of sex hormone- binding globulin (SHBG) (175), which binds sex hormones andreduces their circulation in the bloodstream, thus decreasing their biologic activity. In a meta-analysis, higher blood levels of SHBG were associated with an 80% lower risk of type 2 diabetes inwomen and a 52% lower risk in men (176). Low blood levels ofSHBG have been found in postmenopausal women with breast cancer (177). • The mammalian lignans inhibit the activity of aromatase, an enzyme involved in the production of estrogens (178). Decreased aromataseactivity may be one way in which lignans protect against breast cancer (179).
F L A X – A Health and Nutrition Primer Flax and Hormone Metabolism
Dietary fibre and fat affect estrogen levels in the body. Specifically, the intake of total fat and saturated fat is positively correlated with plasma concentrations of estradiol and estrone, whereas the intake ofdietary fibre is negatively correlated with plasma levels of these hormones (180). Because flax contains both fat and dietary fibre, someresearchers have investigated its effects on hormone metabolism, asdescribed below.
Flax has hormonal effects in women. In 18 premenopausal women with normal menstrual cycles, eating 10 g of flax daily for 3 monthslengthened the luteal phase of the women’s menstrual cycle (181). In 25 postmenopausal women who ate 25 g of milled flax daily for 2 weeks, vaginal cell maturation was stimulated, suggesting an estrogenic effect of flax on women’s reproductive tract (182). However,several clinical studies lasting 2-12 weeks reported no effect of consuming 10-40 g (1+ to 5 tbsp) of milled flax daily on blood levels of estradiol, estrone, follicle-stimulating hormone or luteinizing hormonein young women of reproductive age (181) or in postmenopausalwomen (156,182-185). The effect of flax on menopause symptoms is discussed in Chapter 7. Flax consumption does not appear to affect sex hormone metabolism in men, based on findings of the one study published in this area. Eating 13.5 g milled flax daily for 6 weeks had no effect on plasma concentrations of testosterone, free testosterone or sex-hormone-bindingglobulin in six healthy young men. It is not known whether sex hormone metabolism in men is affected by long-term flax consumption (186).

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