Secoisolariciresinol diglucoside

Secoisolariciresinol Diglucoside (SDG): A Comprehensive Reference

1. Identity, Chemical Characterization, and Natural Sources

Nomenclature and Chemical Identity

Secoisolariciresinol diglucoside (SDG) is an antioxidant phytoestrogen present in flax, sunflower, sesame, and pumpkin seeds. Plant lignans are phenolic compounds generally containing a dibenzylbutane skeleton; SDG is the major lignan found in flaxseed. The compound is also referred to in scientific literature as secoisolariciresinol-diglycoside, abbreviated uniformly as SDG. Its aglycone (sugar-free) form is secoisolariciresinol, abbreviated SECO. SDG has two enantiomers, (+) and (−), whose distribution varies in different Linum species.

The principal dietary lignan present in flaxseed is SDG, which occurs as a component of a linear ester-linked complex. Chemically, the C₆-OH of the glucose of SDG is esterified to the carboxylic acid of hydroxymethylglutaric acid. SDG is further polymerized (or oligomerized) in flaxseed, where it exists as part of a larger complex comprised of five SDG residues linked by ester linkages to four 3-hydroxy-3-methylglutaric acids. Due to its inherent size of 687 Da, SDG will not pass the blood–brain barrier, which is somewhat limited to molecules smaller than 500 Da.

Primary Natural Sources and Concentrations

Flaxseed is particularly the richest known source of lignans (9–30 mg per g), with lignan production at 75–800 times that of other oil seeds, cereals, legumes, and fruit and vegetables. Flaxseed is the richest source of SDG; however, it also contains small amounts of other lignans, namely pinoresinol, lariciresinol, and matairesinol. Phenolic lignans are found in most fiber-rich plants, including pumpkin seed, sesame seed, grains such as wheat, barley, rye and oats; legumes such as beans, lentils, and soybeans; and vegetables such as garlic, asparagus, broccoli, and carrots.

SDG concentrations in twenty-seven flaxseed species were reported to range from 1.19 to 2.59% for (+)-SDG and from 0.22 to 0.5% (w/w) for its diastereoisomer, (−)-SDG; another survey found a range of SDG concentrations from 0.97 to 3.09% (w/w) in eight varieties of defatted flaxseed meals. In food, SDG can be found in commercial breads containing flaxseed.

Extraction and Isolation

Secoisolariciresinol diglucoside can be isolated from de-fatted (hexane extraction) flaxseed by extraction of the lignan polymer precursor with a water/acetone mixture, followed by acetone removal and alkaline hydrolysis. SDG has an important role in the diet due to its protection against onset of breast and prostate cancers, and can be solubilized from flaxseed under very basic conditions (e.g., 0.3 M sodium methoxide).

Common Supplement Forms and Preparations

The lignans of flaxseed were once marketed in a highly concentrated standardized formulation as BeneFlax®, a ~38% secoisolariciresinol diglucoside (SDG)-enriched product (Archer Daniel's Midland), approved by both the U.S. Food and Drug Administration and Health Canada, that ensured a significant source of lignan with oral consumption. BeneFlax® demonstrated good tolerability and safety with long-term supplementation. SDG is also available as proprietary extracts (e.g., Brevail®), standardized capsules containing flaxseed lignan complex, and as a component of functional foods and whole ground flaxseed preparations. Along with α-linolenic acid, lignans, mainly SDG, have made flaxseed derivatives (flax oil and lignan extracts) important sources of functional food or nutraceutical ingredients.

2. Traditional and Historical Use

Flaxseed (Linum usitatissimum, Linaceae) has been used for several millennia for medicinal purposes. It was apparently one of the first domesticated plants, with cultivation most likely beginning in the Fertile Crescent within the valleys of the Tigris and Euphrates some 8,000 years ago.

The isolated compound SDG is a relatively recent scientific discovery, and traditional cultures used whole flaxseed or unrefined flaxseed preparations rather than SDG in purified form. While the isolated compound itself is a relatively recent discovery, whole flaxseed and flaxseed extracts—rich in SDG—have been used for centuries in traditional medicine. Ancient civilizations such as the Egyptians and Greeks consumed flaxseed to promote digestive health and alleviate discomfort, while in Ayurvedic and traditional Chinese medicine, flaxseed was valued for its soothing and anti-inflammatory properties.

As research into lignans advanced, SDG was identified as a key component responsible for many of flaxseed's therapeutic effects. Throughout history, flaxseed preparations were commonly used in polyherbal remedies. Fennel seeds and flaxseed have been traditionally used against many medical ailments due to their medicinal characteristics. The phytoestrogenic, anticarcinogenic, and antiatherogenic effects that have been attributed to flaxseed in these traditions are now specifically linked to its lignan content. Although flaxseed possesses beneficial fatty acid composition and high fiber content, the phytoestrogenic, anticarcinogenic, and antiatherogenic effects have been attributed to its lignan content.

3. Key Constituents, Metabolites, and Mechanisms of Action

Metabolic Activation: From SDG to Enterolignans

The human intestinal microbiota is essential for the conversion of the dietary lignan secoisolariciresinol diglucoside (SDG) via secoisolariciresinol (SECO) to the enterolignans enterodiol (ED) and enterolactone (EL). After consumption, the lignan macromolecule complex is hydrolyzed, SDG is deglucosylated into SECO and absorbed in the gut. Non-absorbed SECO (50–72% of ingested SECO) is subsequently metabolized into the enterolignans enterolactone (ENL) and enterodiol (END) mainly in the colon by the intestinal microflora.

Specific bacterial species have been identified as responsible for discrete steps in this transformation. Strains of Bacteroides distasonis, Bacteroides fragilis, Bacteroides ovatus, and Clostridium cocleatum, as well as a newly isolated Clostridium sp., deglycosylated SDG. Demethylation of SECO was catalyzed by strains of Butyribacterium methylotrophicum, Eubacterium callanderi, Eubacterium limosum, and Peptostreptococcus productus. Dehydroxylation of SECO was catalyzed by strains of Clostridium scindens and Eggerthella lenta.

Pharmacokinetics in Humans

Secoisolariciresinol-diglycoside was efficiently hydrolyzed and converted to secoisolariciresinol. Serum concentrations increased rapidly after oral intake, peaking after 5–7 hours and disappearing with a plasma elimination half-life of 4.8 hours. Maximum serum concentrations of the biologically active metabolites, enterodiol and enterolactone, were established after 12–24 hours and 24–36 hours, respectively, and the half-lives were 9.4 hours and 13.2 hours. Linear dose-responses were observed and secoisolariciresinol bioavailability correlated (r²=0.835) with cumulative lignan excretion. There were no significant differences in the pharmacokinetics of extracts differing in purity, and steady-state serum lignan concentrations were obtained after one week of daily dosing.

Core Mechanisms of Action

A growing body of evidence suggests that SDG metabolites may provide health benefits due to their weak oestrogenic or anti-oestrogenic effects, antioxidant activity, ability to induce phase 2 proteins and/or inhibit the activity of certain enzymes, or by mechanisms yet unidentified. The principal established mechanisms include:

• Antioxidant / Free Radical Scavenging: The health benefits of SECO and SDG may be partially attributed to their antioxidant properties. To better understand their antioxidant properties, SECO and SDG were oxidized using 2,2'-azobis(2-amidinopropane), an in vitro model of radical scavenging. The ability of SDG to scavenge hydroxyl radicals might contribute to its effects in cancer and lupus nephritis. SDG and its metabolites have also been shown to prevent DNA oxidative damage and lipid peroxidation.
• Phytoestrogenic / Anti-estrogenic Activity: SDG is converted by colonic bacteria during digestion into metabolites that exhibit both estrogenic and anti-estrogenic activities. SDG and its metabolites (mammalian enterolignan) are partial agonists to estrogen receptor and inhibitors of tyrosine kinase and topoisomerase.
• Sex Hormone-Binding Globulin (SHBG) Modulation: Postmenopausal women excreting large amounts of mammalian lignans have higher levels of SHBG than omnivores or breast cancer patients, and other studies have shown that mammalian lignans and isoflavonoids interact with SHBG in a dose-dependent manner, with enterolactone displacing estradiol more effectively than equol or genistein.
• NF-κB Signaling Suppression: SDG inhibits E0771 tumor growth in association with decreased tumor activity of the inflammation-regulating transcription factor nuclear factor-kappa B (NF-κB).
• Lipid Metabolism and Antihyperlipidemics: The antioxidant activities of SECO, SDG, END, and ENL were shown to be involved in the hypocholesterolemic and antiatherogenic effects.
• Anti-inflammatory Action: SDG, the main lignan in wholegrain flaxseed, is known for its beneficial effects including anti-inflammatory, antioxidant, anti-mutagenic, anti-microbial, anti-obesity, hypolipidemic, and neuroprotective effects. SDG ameliorates different types of diseases and has been studied for its effects on inflammation, oxidative stress, heart disease, tumor progression, atherosclerosis, and diabetes.
• Radioprotective Properties: Flaxseed's protective properties against ionizing radiation are attributed to its main biphenolic lignan, SDG. SDG is a free radical scavenger, shown in cell-free systems to protect DNA from radiation-induced damage. SDG protected cells from radiation-induced death and ameliorated DNA damage by reducing mean comet tail length and percentage of γ-H2AX positive cells. Importantly, SDG significantly increased gene and protein levels of antioxidant HO-1, GSTM1, and NQO1.
• Gut Microbiota and Enteroligan Production: Gut microbiota converts dietary lignans into bioactive enterolignans, primarily enterodiol (END) and enterolactone (ENL), which are considered the main physiologically active forms. These metabolites are absorbed systemically and contribute to the biological effects of lignans. Consequently, the gut microbiota significantly influences the bioavailability and biological activity of lignans.

4. Scientific Evidence by Area of Use

4.1 Cardiovascular Health and Lipid Profiles

Human and animal studies identify the benefits of SDG consumption. SDG metabolites may protect against cardiovascular disease (CVD) and the metabolic syndrome by reducing lipid and glucose concentrations, lowering blood pressure, and decreasing oxidative stress and inflammation.

Key Human Clinical Trials: An 8-week, randomised, double-blind, placebo-controlled study was conducted in fifty-five hypercholesterolaemic subjects, using treatments of 0 (placebo), 300, or 600 mg/d of dietary SDG from flaxseed extract to determine the effect on plasma lipids and fasting glucose levels. Significant treatment effects were achieved (P < 0.05 to < 0.001) for the decrease of total cholesterol (TC), LDL-cholesterol (LDL-C), and glucose concentrations, as well as their percentage decrease from baseline. At weeks 6 and 8 in the 600 mg SDG group, the decreases of TC and LDL-C concentrations were in the range from 22.0 to 24.38%, respectively.

A double-blinded, randomized, and placebo-controlled study in moderately hypercholesterolemic men investigated oral administration of SDG (20 or 100 mg). Thirty men with total cholesterol levels of 4.65 to 6.21 mmol/L (180–240 mg/dL) were randomly assigned to three groups; two groups received flaxseed lignan capsules (SDG at 20 or 100 mg/d) and the other received placebo capsules for 12 weeks.

In a randomized clinical trial in older adults (60–80 years old) given secoisolariciresinol diglucoside (600 mg/day) for 6 months, a significant decrease in systolic blood pressure was observed.

Evidence Strength: The available literature makes it difficult to clearly identify SDG health effects because of the wide variability in study methods. However, the current evidence suggests that a dose of at least 500 mg SDG/d for approximately 8 weeks is needed to observe positive effects on cardiovascular risk factors in human patients. Overall, the cardiovascular evidence in humans is promising but based on a limited number of trials with relatively small sample sizes; larger-scale replication is needed.

4.2 Breast Cancer Prevention and Oncology

Exposure to the polyphenolic plant lignan SDG and its metabolite enterolactone (ENL) has been associated with reduced breast cancer progression, particularly for estrogen receptor alpha (ERα)-negative disease, and decreased preclinical mammary tumor growth. Studies have generally found significant inverse associations between lignan exposure and breast cancer mortality.

Preclinical (Animal/Cell) Evidence: Previous studies showed that dietary flaxseed can reduce the growth of established human breast tumors in athymic mice. A study determined the effect of flaxseed compared with pure SDG and found that ovariectomized, athymic mice injected with human estrogen receptor (ER)-positive breast cancer cells (MCF-7), then fed either control diet, FS (100 g/kg diet), SDG (1 g/kg diet), or flaxseed hull (18 g/kg diet) for 8 weeks. Compared with the basal diet, FS and SDG significantly decreased palpable tumor size. All treatments significantly inhibited cell proliferation, but only FS and SDG induced significantly higher apoptosis. Both FS and SDG significantly decreased mRNA expressions of Bcl2, cyclin D1, pS2, ERα, ERβ, epidermal growth factor receptor, and insulin-like growth factor receptor.

SDG supplementation in mice significantly reduced tumor volume and expression of phospho-p65 and NF-κB target genes. Markers of macrophage infiltration were decreased in the distal-to-tumor mammary fat pad of SDG-supplemented mice relative to controls.

Human Clinical Evidence: A multiinstitutional, placebo-controlled phase IIB trial of SDG from flaxseed was conducted. Benign breast tissue was acquired by random periareolar fine needle aspiration from premenopausal women at increased risk for breast cancer. Those with hyperplasia and ≥2% Ki-67 positive cells were eligible for randomization 2:1 to 50 mg SDG/day (Brevail) versus placebo for 12 months. The primary endpoint was difference in change in Ki-67 between randomization groups. A total of 180 women were randomized, with 152 ultimately evaluable for the primary endpoint. Median Ki-67 change was −1.8% in the SDG arm (P = 0.001) and −1.2% for placebo (P = 0.034), with no significant difference between arms. In a secondary analysis, the significant Ki-67 decrease persisted for SDG (median = −2.2%; P = 0.002) but not placebo. Twenty-two subjects had significant ERα gene expression changes, with 10 of 12 decreases for SDG (P = 0.028), and a difference between arms (P = 0.017). Adverse event incidence was similar in both groups, with no evidence that 50 mg/day SDG is harmful. Although the proliferation biomarker analysis showed no difference between the treatment group and the placebo, the trial demonstrated that use of SDG is tolerable and safe.

Evidence Strength: Preclinical evidence is substantial and mechanistically detailed. The single pivotal randomized human trial showed biological activity on secondary endpoints (ERα gene expression) but did not demonstrate a statistically significant difference on the primary endpoint (Ki-67 change between arms). Only one study included premenopausal women and another found that effects were limited to ERα-negative tumors. It is consequently uncertain whether all breast cancer patients would benefit from greater SDG intake post-diagnosis. Human evidence is therefore preliminary.

4.3 Diabetes and Glycemic Regulation

Reactive oxygen species (ROS) have been implicated in the development of streptozotocin (STZ)-induced diabetes mellitus. SDG isolated from flaxseed is an antioxidant, and an investigation was made of the effects of SDG on the development of STZ-induced diabetes in rat, to determine if SDG can prevent/reduce the development of diabetes and if this prevention/reduction is associated with reduction in oxidative stress. In that animal study, the incidence of diabetes was 100% in controls and 25% in the SDG group; SDG prevented the development of diabetes by 75%.

Apart from flaxseed fibers that may affect insulin secretion and plasma glucose homeostasis, studies have shown that SDG-containing nutrients also affect plasma glucose homeostasis. SDG reduced C-reactive protein concentration, which is related to insulin resistance in type 2 diabetes, and decreased the development of diet-induced obesity and glucosuria.

Human Evidence: Animal and human study evidence supports the hypothesis that flaxseed lignan complex (FLC) at a dose of 600 mg SDG/day for three months would combat hyperglycaemia, dyslipidemia, blood pressure, central obesity, prothrombotic state, inflammation, and LDL oxidation. Sixteen type 2 diabetic patients completed a double-blind, randomised crossover placebo-controlled study. Prior to multiple comparisons correction, FLC caused decreased fasting plasma glucose, A1c, inflammation (C-reactive protein and interleukin-6), and increased bleeding time. After correction for multiple comparisons, FLC induced a statistically significant increase in bleeding time and a smaller waist circumference gain.

Null findings were observed in a study of a flaxseed-derived lignan supplement (500 mg/day) on lipid profiles in 22 healthy women. Evidence of flaxseed or lignans on glucose metabolism in humans is limited.

Evidence Strength: Animal studies show pronounced anti-diabetic effects. Human data are limited to small pilot studies with mixed results; the clinical evidence is preliminary and cannot support definitive conclusions.

4.4 Bone Health and Osteoporosis

SDG is a phytoestrogen found in the mature seed of Linum usitatissimum L. which is similar to human estrogen. As a phenolic ingredient, SDG has preventive effects on estrogen-dependent diseases such as breast cancer, prostate cancer, menstrual syndrome, and osteoporosis. The clinical efficacy of SDG in the prevention and treatment of postmenopausal osteoporosis (PMOP) in women has been confirmed, which could increase the serum calcium content and bone mass of patients, improve the sensitivity of bone to parathyroid hormone, promote the formation of new bone matrix, and have significant effects on controlling bone loss.

Evidence Strength: Clinical citations in this area are derived from reviews citing earlier research. Although the mechanistic basis (phytoestrogenic activity at bone estrogen receptors) is plausible, large, well-controlled human trials confirming these specific effects of isolated SDG on fracture risk or bone mineral density are not robustly established in the literature reviewed here.

4.5 Neurological and Blood-Brain Barrier Protection

SDG might be an attractive natural compound that protects against neuroinflammation. There are no comprehensive studies to date investigating the effects of SDG on brain endothelium using relevant in vivo and in vitro models. One study evaluated the effects of orally administered SDG on neuroinflammatory responses using in vivo imaging of the brain microvasculature during systemic inflammation and aseptic encephalitis. Research in this area remains at the preclinical/in vitro stage.

Among the beneficial pharmacological activities of SDG on health, many are age-related, such as anticancer, antidiabetes, antioxidant, and neuroprotective effects. SDG is a phytoestrogen found in flaxseed, sunflower seeds, and sesame seeds. Studies in C. elegans showed that SDG could extend lifespan by up to 22.0%, delay age-related decline of body movement, reduce the lethality of heat and oxidative stress, alleviate dopamine neurodegeneration induced by 6-hydroxydopamine, and decrease the toxicity of Aβ protein.

Evidence Strength: Evidence for neuroprotective effects is currently limited to animal and invertebrate model studies. No human clinical data in this domain were identified. Evidence is preliminary.

4.6 Radioprotection

Dietary flaxseed ameliorated the adverse effects of thoracic radiation when given both prior to exposure and post-exposure. In these studies, dietary flaxseed decreased radiation-induced oxidative lung tissue damage, decreased lung inflammation, and prevented pulmonary fibrosis. Evidence from animal studies provides strong preclinical support that the bioactive ingredient in whole grain flaxseed responsible for its radiation mitigating properties is the lignan component and more specifically SDG.

Evidence Strength: The radioprotective evidence is confined to in vitro cell studies and mouse models. No human clinical data for radioprotection by isolated SDG were identified.

4.7 Lupus Nephritis and Kidney Disease

The majority of studies demonstrate that SDG interferes with the development of different types of diseases like cardiovascular, diabetic, lupus nephritis, bone, kidney, menopause, reproduction, mental stress, immunity, atherosclerosis, hemopoietic, liver necrosis, and urinary disorders, due to its various biological properties including anti-inflammatory, antioxidant, antimutagenic, antimicrobial, antiobesity, antihypolipidemic, and neuroprotective effects. Flaxseed lignan precursors and their mammalian metabolites may be appreciated as health-promoting dietary micronutrients having chemopreventive properties in animals and humans, by utilizing as nutraceutical agents against different chronic diseases like cancer, atherosclerosis, diabetes, kidney disorders, and lupus nephritis.

Evidence Strength: Evidence in lupus nephritis and renal disease is derived primarily from animal model studies. Human clinical evidence in this specific area remains very limited.

4.8 Anti-obesity and Metabolic Syndrome

Lignans exhibit promising anti-obesity effects through multiple interconnected mechanisms, including modulation of appetite-regulation hormones such as leptin and adiponectin, improvement of lipid metabolism, regulation of gut microbiota composition, enhancement of insulin sensitivity, reduction in inflammation, and attenuation of visceral fat accumulation. After ingestion, lignans are metabolized by the gut microbiota into enterodiol and enterolactone, which in turn promote the production of various metabolites—such as short-chain fatty acids (SCFAs), bile acids, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY).

Flax lignan complex decreased the metabolic syndrome composite score in males; however, no effects were observed in females. Since rat visceral fat is considered to be equivalent to abdominal fat in humans, data from animal studies suggest that SDG supplementation may alleviate central obesity-related conditions in humans. However, there is still limited information about changes in fat accumulation in human adipose tissues and organs, although SDG has been reported to have some positive effects on central obesity.

Evidence Strength: Mechanistic plausibility is supported by preclinical research, but human data are scarce and inconsistent by sex. Evidence is preliminary.

5. Body Systems and Health Areas Associated with SDG

Various studies have shown that SDG offers several health benefits, including protective effects against cardiovascular diseases, diabetes, cancer, and mental stress. The body systems most extensively studied in the scientific literature include:

• Endocrine/Hormonal System: SDG's phytoestrogenic and anti-estrogenic activity interacts with estrogen receptors and sex hormone-binding globulin, relevant to hormone-sensitive cancers, menopause, and reproductive health.
• Cardiovascular System: Lipid-lowering, antihypertensive, and antiatherogenic effects documented in animal and limited human studies.
• Gastrointestinal Tract / Microbiome: The gut microbiota is central to SDG's activation and bioavailability, and SDG has demonstrated effects on gut microbial composition.
• Oncology (Breast, Prostate, Colon, Lung): Antiproliferative, pro-apoptotic, and anti-angiogenic properties demonstrated predominantly in preclinical models.
• Immune System: NF-κB pathway suppression and anti-inflammatory activities relevant to autoimmune and inflammatory conditions.
• Skeletal System: Phytoestrogenic modulation of bone metabolism relevant to postmenopausal osteoporosis.
• Nervous System: Neuroprotective effects at the blood-brain barrier and against dopaminergic neurodegeneration in preclinical models.
• Metabolic System: Effects on glucose homeostasis, insulin sensitivity, and visceral adiposity.

6. Dosage Forms and Reported Dosages from Studies

The following dosages are reported as used in specific identified research studies and trials:

• 50 mg SDG/day (Brevail®) for 12 months, used in a phase IIB randomized controlled trial in premenopausal women at increased risk for breast cancer.
• 300 mg/d or 600 mg/d SDG from flaxseed extract over 8 weeks, in a randomized, double-blind, placebo-controlled study in hypercholesterolaemic subjects.
• 20 mg/d or 100 mg/d SDG (flaxseed lignan capsules) for 12 weeks, in a double-blinded, randomized, and placebo-controlled study in moderately hypercholesterolemic men.
• 600 mg SDG/day for three months, used in a double-blind, randomised crossover placebo-controlled study in older type 2 diabetic patients.
• 600 mg/day for 6 months, in a randomized clinical trial in older adults (60–80 years old), which observed a significant decrease in systolic blood pressure.
• 150 mg/day or 300 mg/day SDG (as a flaxseed extract, taken as 2 pills at breakfast and dinner) for 12 weeks, in a registered clinical trial examining flax lignans and heart health.
• Pharmacokinetic doses of 25, 50, 75, 86, and 172 mg SDG, studied in healthy postmenopausal women to establish bioavailability and dose-response relationships.
• In an animal study, SDG was given at 22 mg/kg body weight orally for 24 days in a rat model of streptozotocin-induced diabetes.

The current evidence suggests that a dose of at least 500 mg SDG/d for approximately 8 weeks is needed to observe positive effects on cardiovascular risk factors in human patients.

7. Safety Considerations and Interactions

General Safety Profile

Clinical studies have shown that secoisolariciresinol diglucoside and its metabolites are safe for long-term use. In the phase IIB randomized controlled trial at 50 mg/day, adverse event incidence was similar in both the SDG and placebo groups, with no evidence that 50 mg/day SDG is harmful. The trial demonstrated that use of SDG is tolerable and safe.

Pregnancy and Reproductive Safety

Flaxseed and its lignan extracts appear to be safe for most adult populations, though animal studies suggest that pregnant women should limit their exposure. In animal research, flaxseed had no effect on rat pregnancy outcome; however, a 10% flaxseed-containing diet lowered birth weight compared to other treatments. Additionally, it exhibited estrogenic effects, including greater uterine and ovarian relative weights, earlier age and lighter body weight at puberty in female offspring, as well as reduced postnatal weight gain and greater sex gland and prostate relative weights in males.

Bleeding Time / Anticoagulant Interactions

In a human clinical study, FLC (flaxseed lignan complex at 600 mg SDG/day) caused an increase in bleeding time that was statistically significant after correction for multiple comparisons. This observation has implications for individuals taking anticoagulant or antiplatelet medications.

Estrogenic Interactions

SDG and its metabolites interact with estrogen receptors and SHBG. Mammalian lignans and isoflavonoids interact with SHBG in a dose-dependent manner, displacing both estradiol and testosterone. This raises the theoretical potential for interaction with hormone therapies, oral contraceptives, or selective estrogen receptor modulators, though specific human pharmacokinetic interaction studies with these agents were not identified in the sources reviewed.

Blood-Brain Barrier

Due to its inherent size of 687 Da, SDG will not pass the blood–brain barrier, which is somewhat limited to molecules smaller than 500 Da. Biological activity in the central nervous system may therefore be mediated by smaller metabolites (e.g., enterolactone) rather than SDG itself.

Gut Microbiota Dependency

The human intestinal microbiota is essential for the conversion of SDG via SECO to the enterolignans enterodiol and enterolactone. Hence, the intestinal microbiota is essential for SDG activation. Individual differences in gut microbiome composition may therefore lead to substantial inter-individual variability in the biological activity of supplemental SDG.

References

• Wikipedia: Secoisolariciresinol diglucoside
• Frontiers in Genetics / PMC: Secoisolariciresinol Diglucoside of Flaxseed and Its Metabolites: Biosynthesis and Potential for Nutraceuticals
• PMC: Potential protective properties of flax lignan secoisolariciresinol diglucoside
• PMC: UGT74S1 is the key player in controlling secoisolariciresinol diglucoside (SDG) formation in flax
• PMC: Induced Mutagenesis in UGT74S1 Gene Leads to Stable New Flax Lines with Altered SDG Profiles
• ScienceDirect Topics: Secoisolariciresinol Diglucoside — Overview
• PubMed: Health effects with consumption of the flax lignan secoisolariciresinol diglucoside (Adolphe et al., Br J Nutr, 2010)
• PubMed: Flaxseed and pure secoisolariciresinol diglucoside, but not flaxseed hull, reduce human breast tumor growth (MCF-7) in athymic mice
• PubMed: The effect of secoisolariciresinol diglucoside and flaxseed oil, alone and in combination, on MCF-7 tumor growth and signaling pathways
• AACR Cancer Prevention Research: Randomized Phase IIB Trial of the Lignan Secoisolariciresinol Diglucoside in Premenopausal Women at Increased Risk for Development of Breast Cancer
• PMC: The flaxseed lignan secoisolariciresinol diglucoside decreases local inflammation, suppresses NFκB signaling, and inhibits mammary tumor growth
• British Journal of Nutrition: Dietary flaxseed lignan extract lowers plasma cholesterol and glucose concentrations in hypercholesterolaemic subjects
• PMC: Flaxseed Lignan Complex Administration in Older Human Type 2 Diabetics Manages Central Obesity and Prothrombosis
• PMC: The cardiovascular effects of flaxseed and its omega-3 fatty acid, alpha-linolenic acid
• PubMed: Flaxseed lignan lowers blood cholesterol and decreases liver disease risk factors in moderately hypercholesterolemic men
• PMC: Effects of a Flaxseed-Derived Lignan Supplement in Type 2 Diabetic Patients: A Randomized, Double-Blind, Cross-Over Trial
• PubMed: Protective effect of secoisolariciresinol diglucoside against streptozotocin-induced diabetes and its mechanism
• PubMed: AAPH-mediated antioxidant reactions of secoisolariciresinol and SDG
• PMC: Secoisolariciresinol diglucoside is a blood-brain barrier protective and anti-inflammatory agent: implications for neuroinflammation
• PMC: Secoisolariciresinol Diglucoside Improves Ovarian Reserve in Aging Mouse by Inhibiting Oxidative Stress
• PMC: Secoisolariciresinol diglucoside regulates estrogen receptor expression to ameliorate OVX-induced osteoporosis
• PMC: The Flaxseed-Derived Lignan Phenolic SDG Protects Non-Malignant Lung Cells from Radiation Damage
• PMC: Radiation mitigating properties of the lignan component in flaxseed
• FEMS Microbiology Ecology: Phylogeny of human intestinal bacteria that activate the dietary lignan secoisolariciresinol diglucoside
• PubMed: Human intestinal bacteria capable of transforming secoisolariciresinol diglucoside to mammalian lignans, enterodiol and enterolactone
• PMC: Metabolism of Secoisolariciresinol-Diglycoside: The Dietary Precursor to the Intestinally Derived Lignan Enterolactone in Humans
• PubMed: Secoisolariciresinol Diglucoside Delays the Progression of Aging-Related Diseases and Extends the Lifespan of Caenorhabditis elegans via DAF-16 and HSF-1
• PMC: Flaxseed Lignans as Important Dietary Polyphenols for Cancer Prevention and Treatment: Chemistry, Pharmacokinetics, and Molecular Targets
• PMC: Molecular Mechanisms of Lignans in Lowering Blood Pressure and Anti-Obesity Effects: A Review
• ClinicalTrials.gov: Flax Lignans and Heart Health (NCT01314586)
• ClinicalTrials.gov Protocol: Prevention Strategy for Pre-Menopausal Women at High Risk for Development of Breast Cancer (NCT01276704)
• PMC: A combination of metabolite profiling and network pharmacology to explore the potential pharmacological changes of secoisolariciresinol-diglycoside
• PMC: Secoisolariciresinol diglucoside and anethole ameliorate lipid abnormalities, oxidative injury, hypercholesterolemia, heart, and liver conditions