Description
Lignans are phenylpropanoid dimers widely distributed in the plant kingdom. Flaxseed (Linum usitatissimum L.) is one of the richest sources of dietary lignans. Plant lignans comprise one of the two main groups of phytoestrogens, the other group being the isoflavonoids.
The major flax lignan is secoisolariciresinol diglucoside (SDG). Flaxseed is the richest food source of SDG. Flaxseed also contains much smaller amounts of matairesinol, lariciresinol and pinoresinol. The plant lignans are converted by the intestinal microflora in the proximal or upper part of the large intestine to enterodiol (END) and enterolactone (ENL). END and ENL are not themselves plant lignans and are called mammalian lignans or enterolignans. Plant lignans are precursors of mammalian lignans. It is thought that many of the possible biological actions of SDG are due to its conversion to END and ENL.
SDG is a dibenzylbutyrolactone. This is one of the two major structural types of plant lignans. The spruce lignan 7-hydroxymatairesinol also possesses this type of chemical structure. (See Spruce Lignans.) The other major chemical type is the tetrahydrofuran type that can be found in the sesame seed lignans sesamin and sesaminol. (See Sesame Seed Lignans.) The biphenolic nature of SDG resembles many of the substances known to exert estrogenic action or to block estrogen receptor sites. Lignans have been observed in some epidemiological studies to be correlated with reductions in prostate cancer and breast cancer incidence. Experimental evidence in animals has shown anticarcinogenic effects of SDG as well as cardiovascular and renal protective effects. Plant lignans began receiving much attention in the field of natural product chemistry ever since the discovery of the plant lignan podophyllotoxin, which is used as the starting compound for a few cancer drugs, including etoposide.
The chemical name for SDG is beta-D-Glucopyranoside, 2,3-bis[(4-hydroxy-3-methoxyphenyl methyl]-1,4-butanediyl bis-,[R-(R*,R*)]. Its molecular formula is C32H46O16 and its molecular weight is 686.7. Its CAS number is 158932-33-3. END is also known as 2,3-bis[(3-hydroxyphenyl)methyl]-1,4-Butanediol and has a molecular weight of 302. ENL is also known as trans-dihydro-3,4-bis[(3-hydroxyphenyl)methyl]-2(3H)-Furanone and has a molecular weight of 298. The aglycone of SDG is secoisolariciresinol (SECO). SECO is also known as [R-(R*1,R*)-2,3-bis[(4-hydroxy-3-methoxy phenyl)methyl]-1,4-Butadiol and has a molecular weight of 362. The chemical structures below are described within this monograph.
Chemical Structure
Enterodiol
Chemical Structure
Enterolactone
Chemical Structure
Secoisoariciresinol
Chemical Structure
Seicoisolariciresinol-diglucoside
Lignans should not be confused with lignins. A lignin is a cross-linked phenolic polymer which combines with cellulose to give woody plant tissue its rigidity.
Actions & Pharmacology
Actions
SDG has antioxidant activity. It also may have hypoglycemic, hypocholesterolemic, estrogenic, anti-estrogenic, anti-cancer, antiproliferative and renoprotective properties.
Mechanism of Action
SDG, SECO and the enterolignans END and ENL have been shown to be effective antioxidants against lipid peroxidation and oxidative DNA damage, potentially due to their free radical scavenging activity.
SDG was found to be protective against streptozotocin-induced diabetes in rats, an animal model of type 1diabetes. It delayed the onset of diabetes in the rats and was thought to act by an antioxidant mechanism. Streptozotocin is known to induce oxidative stress. SDG was also found to delay the development of type 2 diabetes in Zucker rats, an animal model of type 2 diabetes. Again, it was thought this effect was due to SDG acting as an antioxidant.
SDG was found in a human study which took place in China to lower total cholesterol and LDL-cholesterol. The mechanism of this effect is unclear.
SDG, END and ENL may block some of the cancer-inducing effects of estrogen and may have selective estrogen receptor modulating (SERM) activity.
END and ENL may also have anti-platelet-activating factor activity, which would produce anti-thrombotic activity.
END and ENL have been shown to have anti-proliferative activity against the human breast carcinoma cell line, ZR-75-1. These enterolignans also inhibit the growth of estrogen-independent human colon tumor cells.
SDG has been found to reduce chemically-induced mammary and colon tumorigenesis in rats. SDG inhibits the initiation, promotion and progression of mammary carcinogenesis in rats and inhibits tumor growth and metastasis in nude mice. SDG has also been shown to reduce experimental metastasis of melanoma cells in mice.
The mechanism of the anticancer activity of SDG is unclear. Biological properties of SDG may be responsible for its anticancer properties. These include antioxidant, estrogenic, antiestrogenic, antiproliferative and anti-aromatase activities. Further research on this is warranted and needed.
The MRL/lpr mouse model is an animal model of systemic lupus erythematosus (SLE). Lupus nephritis is one of the most serious manifestations of SLE. SDG was found to significantly delay the onset of proteinuria and preserve the glomerular filtration rate (GFR) and renal size in this mouse model. Platelet activating factor (PAF) has been implicated in the immunopathogenesis of SLE and in renal injury. The renoprotective effect of SDG may be explained by the dibenzylbutyl skeleton in the chemical structure of SDG. This type of structure has been shown to reversibly inhibit PAF.
In a human study that took place in China, SDG was found to significantly alleviate the lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). The mechanism of this effect remains unclear. Possibilities include inhibition of 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT) or by androgen receptor blockade. However, it is not clear if these possible mechanisms have anything to do with the observed effect.
Pharmacokinetics
The pharmacokinetics for SDG in humans is incomplete. After ingestion, SDG is converted to SECO. Deglycosylation of SDG can occur from the small intestine onward either via enzymatic activity at the brush border of the small intestine or via bacterial enzymatic activity.
SECO is then converted by the intestinal microflora in the proximal or upper part of the large intestine to END via demethylation and dehydroxylation, and END is converted into ENL via dehydrogenation. Following conjugation by colon epithelial cells or within the liver, SECO, END and ENL, but not SDG, are found in the portal circulation, plasma and urine as glucuronides and sulfates.
HT29 human colon cells show that measurable amounts of intracellular free END can be detected within up to four hours of incubation whereas ENL appears to be rapidly conjugated by the HT29 cells.
The pharmacokinetics of SDG in flaxseed is even more complex. In flaxseed, SDG occurs as a macromolecular structure bound by the linker molecule hydroxymethyl glutaric acid. Ferulic acid glucoside, herbacetin diglucoside, and coumaric acid glucoside are also found in the macromolecule. It is not known in which part of the gastrointestinal tract SDG is released from the macromolecule. Once it is released, the pharmacokinetics should be similar to that described above.
Indications & Usage
There are claims that the flaxseed lignan SDG may be useful in preventing heart disease, some cancers, insulin-dependent diabetes mellitus and obesity; that is has kidney-protective effects; that it may favorably alter estrogen metabolism in postmenopausal women to an equal or greater extent than supplementation with soy products; and that it may relieve the symptoms of benign prostatic hyperplasia (BPH). The best-supported claims relate to heart disease, BPH and cancer.
Overdosage
There are no reports of flaxseed lignan overdosage.
Dosage
SDG has been studied at doses of 300 mg to 600 mg daily for prolonged periods of time without any significant adverse events noted.
Doses of SDG of 300 mg to 600 mg daily have been used in clinical trials for hypercholesterolemia and BPH.
Doses of 25 mg to 50 mg of SDG daily are frequently used.
Pills typically contain at least 35% SDG by weight.
The amount of SDG in flaxseed varies from about 6 to 13 mg per gram of flaxseed.
Literature
Adlercreutz H. Lignans and human health. Crit Rev Clin Lab Sci. 2007;44(5-6):483-525.Bergman Jungeström M, Thompson LU, Dabrosin C. Flaxseed and its lignans inhibit estradiol-induced growth, angiogenesis, and secretion of vascular endothelial growth factor in human breast cancer xenografts in vivo. Clin Cancer Res. 2007;13(3):1061-1067.Brooks JD, Ward WE, Lewis JE, et al. Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy. Am J Clin Nutr. 2004;79(2):318-325.Clark WF, Muir AD, Westcott ND, et al. A novel treatment for lupus nephritis: lignan precursor derived from flax. Lupus. 2000;9(6):429-436.Danbara N, Yuri T, Tsujita-Kyutoku M, et al. Enterolactone induces apoptosis and inhibits growth of Colo 201 human colon cancer cells both in vitro and in vivo. Anticancer Res. 2005;25(3B):2269-2276.Fukumitsu S, Aida K, Ueno N, et al. Flaxseed lignan attenuates high-fat diet-induced fat accumulation and induces adiponectin expression in mice. Br J Nutr. 2008:1-8.Hosseinian FS, Muir AD, Westcott ND, et al. AAPH-mediated antioxidant reactions of secoisolariciresinol and SDG. Org Biomol Chem. 2007;5(4):644-654.Hu C, Yuan YV, Kitts DD. Antioxidant activities of the flaxseed lignan secoisolariciresinol diglucoside,its aglycone secoisolariciresinol and the mammalian lignans enterodiol and enterolactone in vitro. Food Chem Toxicol. 2007;45(11):2219-2227.Jenab M, Thompson LU. The influence of flaxseed and lignans on colon carcinogenesis and beta-glucuronidase activity. Carcinogenesis. 1996;17(6):1343-1348.Kitts DD, Yuan YV, Wijewickreme AN, et al. Antioxidant activity of the flaxseed lignan secoisolariciresinol diglycoside and its mammalian lignan metabolites enterodiol and enterolactone. Mol Cell Biochem. 1999;202(1-2):91-100.Li X, Yuan JP, Xu SP, et al. Separation and determination of secoisolariciresinol diglucoside oligomers and their hydrolysates in the flaxseed extract by high-performance liquid chromatography. J Chromatogr A. 2008;1185(2):223-232.Li D, Yee JA, Thompson LU, et al. Dietary supplementation with secoisolariciresinol diglycoside (SDG) reduces experimental metastasis of melanoma cells in mice. Cancer Lett. 1999;142(1):91-96.Muir AD. Flax lignans—analytical methods and how they influence our understanding of biological activity. J AOAC Int. 2006;89(4):1147-1157.Pan A, Sun J, Chen Y, et al. Effects of a flaxseed-derived lignan supplement in type 2 diabetic patients: a randomized, double-blind, cross-over trial. PLoS ONE. 2007;2(11):e1148.Penumathsa SV, Koneru S, Thirunavukkarasu M, et al. Secoisolariciresinol diglucoside: relevance to angiogenesis and cardioprotection against ischemia-reperfusion injury. J Pharmacol Exp Ther. 2007;320(2):951-959.Prasad K. A study on regression of hypercholesterolemic atherosclerosis in rabbits by flax lignan complex. J Cardiovasc Pharmacol Ther. 2007;12(4):304-313.Prasad K. Secoisolariciresinol diglucoside from flaxseed delays the development of type 2 diabetes in Zucker rat. J Lab Clin Med. 2001;138(1):32-39.Prasad K, Mantha SV, Muir AD, et al. Protective effect of secoisolariciresinol diglucoside against streptozotocin-induced diabetes and its mechanism. Mol Cell Biochem. 2000;206(1-2):141-149.Rickard SE, Yuan YV, Chen J, et al. Dose effects of flaxseed and its lignan on N-methyl-N-nitrosourea-induced mammary tumorigenesis in rats. Nutr Cancer. 1999;35(1):50-57.Serraino M, Thompson LU. Flaxseed supplementation and early markers of colon carcinogenesis. Cancer Lett. 1992;63(2):159-165.Serraino M, Thompson LU. The effect of flaxseed supplementation on early risk markers for mammary carcinogenesis. Cancer Lett. 1991;60(2):135-142.Sung MK, Lautens M, Thompson LU. Mammalian lignans inhibit the growth of estrogen-independent human colon tumor cells. Anticancer Res. 1998;18(3A):1405-1408.Thompson LU. Experimental studies on lignans and cancer. Baillieres Clin Endocrinol Metab. 1998;12(4):691-705.Thompson LU, Rickard SE, Orcheson LJ, et al. Flaxseed and its lignan and oil components reduce mammary tumor growth at a late stage of carcinogenesis. Carcinogenesis. 1996;17(6):1373-1376.Thompson LU, Seidl MM, Rickard SE, et al. Antitumorigenic effect of a mammalian lignan precursor from flaxseed. Nutr Cancer. 1996;26(2):159-165.Zhang LY, Wang XL, Sun DX, et al. Regulation of zinc transporters by dietary flaxseed lignan in human breast cancer xenografts. Mol Biol Rep. Epub: 2007 Sep 5.Zhang W, Wang X, Liu Y, et al. Effects of Dietary Flaxseed Lignan Extract on Symptoms of Benign Prostatic Hyperplasia. J Med Food. 2008;11(2):207-214.Zhang W, Wang X, Liu Y, et al. Dietary flaxseed lignan extract lowers plasma cholesterol and glucose concentrations in hypercholesterolaemic subjects. Br J Nutr. 2008;99(6):1301-1309.Research & Summary
A variety of research efforts, spanning more than 20 years, indicates that flaxseed and flaxseed oil have the ability to favorably modify lipid metabolism and to exert cardioprotective effects. One recent, eight-week, randomized, double-blind, placebo-controlled study sought to determine whether the SDG component of flaxseed can duplicate favorable lipid-modifying results seen with flaxseed and flax oil. The study enrolled 55 hypercholesterolemic subjects who were given various doses of an SDG-rich flaxseed extract. Effects related to LDL-cholesterol levels and glucose concentrations were measured. Compared with controls, who received no SDG, the experimental subjects exhibited significant reductions in LDL-cholesterol and fasting plasma glucose concentrations in a dose-dependent manner. Doses administered were 300 mg and 600 mg daily.
In another recent study, this one utilizing several in vitro and in vivo animal models of ischemia-reperfusion injury, SDG was reported to have potent favorable angiogenic and antiapoptotic effects that the investigators believe help explain its cardioprotective properties. They further stated that this was the first time favorable myocardial neovascularization was achieved in this manner. They concluded that SDG may have the potential to improve the management of ischemic heart failure in patients with coronary artery disease. Follow-up is needed and warranted
Yet another recent study tested SDG for possible effects on diet-induced obesity in mice. Groups of animals were variously administered a low-fat diet, a high-fat diet or a high-fat diet that included SDG over a four-week period. Effects were noted that were said to significantly and favorably regulate gene expressions involved in the genesis of fat. The researchers concluded that SDG might thus have the potential to help control obesity and reduce the risk of dietary-induced diseases, including hypertension, atherosclerosis and diabetes. Further investigation of these possible gene expression effects is needed.
Flaxseed lignans, like flaxseed and flaxseed oil, have been postulated as possible agents for the prevention and treatment of some cancers, principally breast and prostate cancers. Previously, animal and human studies indicated that supplementation with flaxseed products could slow prostate tumor growths, but the substances were used in these studies with a low-fat diet. More recently one group of researchers presented results of a clinical study that they believe demonstrates that flaxseed alone can significantly slow prostate tumor growth. Yet another recent clinical study of 87 men with benign prostatic hyperplasia has also yielded positive results. In this study the men were given placebo or 300 mg- or 600 mg-doses of SDG daily over a four-month period. Appreciable improvement in lower urinary tract symptoms was seen in the SDG-dosed subjects. The efficacy of SDG in this context was hypothesized to be due to its estrogenic effects, although this was not clear.
Another group demonstrated that dietary flaxseed could inhibit experimental metastases of melanoma cells in mice. More recently, the same group has extended this research to see if SDG can similarly inhibit these metastases. Pulmonary metastases of melanoma cells were significantly inhibited by varying doses of SDG in a dose-dependent manner in this study. In addition, some animal studies have suggested that SDG may have positive effects in mammary and colon cancers. In vitro studies revealed that SDG has anti-proliferative, antiestrogenic, estrogenic, anti-aromatase and antioxidant effects, all or any of which may help inhibit some cancers. Research is ongoing.
Flaxseed has shown some renoprotective effects in both animals and humans. In one study, SDG exhibited renoprotection in a dose-dependent fashion in an animal model of lupus nephritis. Further research is needed.
One recent study concluded that supplementation with flaxseed alters estrogen metabolism to a possible less mitogenic form of estrogen to a greater extent in menopausal women than does soy. Experimentation with SDG itself in this context has apparently not been performed.
Contraindications, Precautions & Adverse Reactions
Contraindications
Flax lignans are contraindicated in those who are hypersensitive to any component of a flax lignan-containing product.
Precautions
Pregnant women and nursing mothers should avoid the use of flax lignan supplements pending long-term safety studies.
Men with prostate cancer or BPH should discuss the advisability of the use of flax lignan supplements with their physicians before deciding to use them.
Women with estrogen receptor-positive tumors should exercise caution in the use of flax lignan supplements and should only use them if they are recommended and monitored by a physician.
Adverse Reactions
None known.
Interactions
Drugs
Antibiotics may decrease the production of END and ENL from SDG.
Nutritional Supplements
No known interactions.
Foods
No known interactions.
Herbs
No known interactions.
