E-viniferin

Other Names

(+)-E-ε-Viniferin(-)-trans-epsilon-viniferin(E)-epsilon-viniferin(Z)-epsilon-Viniferin1,3-Benzenediol, 5-[(2R,3R)-2,3-dihydro-6-hydroxy-2-(4-hydroxyphenyl)-4-[(E)-2-(4-hydroxyphenyl)ethenyl]-3-benzofuranyl]-1,3-Benzenediol, 5-[(2S,3S)-2,3-dihydro-6-hydroxy-2-(4-hydroxyphenyl)-4-[(E)-2-(4-hydroxyphenyl)ethenyl]-3-benzofuranyl]-5-((2R,3R)-6-Hydroxy-2-(4-hydroxyphenyl)-4-((E)-4-hydroxystyryl)-2,3-dihydrobenzofuran-3-yl)benzene-1,3-diol5-(2,3-Dihydro-6-hydroxy-2(4-hydroxyphenyl)4-(2-(4-hydroxyphenyl)ethenyl)-3-benzofuranyl)-1,3-benzenediol5-[(2R,3R)-2,3-dihydro-6-hydroxy-2-(4-hydroxyphenyl)-4-[(E)-2-(4-hydroxyphenyl)ethenyl]-2,3-dihydro-1-benzofuran-3-yl]benzene-1,3-diol5-[(2S,3S)-6-hydroxy-2-(4-hydroxyphenyl)-4-[(E)-2-(4-hydroxyphenyl)ethenyl]-2,3-dihydro-1-benzofuran-3-yl]benzene-1,3-diol5-{(2R,3R)-6-Hydroxy-2-(4-hydroxyphenyl)-4-[(E)-2-(4-hydroxyphenyl)vinyl]-2,3-dihydro-1-benzofuran-3-yl}-1,3-benzenediol5-{(2S,3S)-6-Hydroxy-2-(4-hydroxyphenyl)-4-[(E)-2-(4-hydroxyphenyl)vinyl]-2,3-dihydro-1-benzofuran-3-yl}-1,3-benzenediolcis-epsilon-viniferincis-ε-Viniferinepsilon-viniferinresveratrol dimerstilbenoid resveratrol dimertrans-ε-ViniferinZ-viniferinε-Viniferin

Synopsis

ε-Viniferin (Epsilon-Viniferin)

1. Identity: Chemical and Botanical Profile

1.1 Chemical Names and Classification

ε-Viniferin (epsilon-viniferin) is a naturally occurring phenol belonging to the stilbenoids family and is a resveratrol dimer. Its systematic IUPAC name is 5-{6-hydroxy-2-(4-hydroxyphenyl)-4-[2-(4-hydroxyphenyl)vinyl]-2,3-dihydroxybenzofuran-3-yl}benzene-1,3-diol. It is also known as trans-ε-viniferin, epsilon-viniferin, and is distinguished from other viniferin isomers by its specific dehydrodimer structure. It is heterocyclic and has an empirical formula of C₂₈H₂₂O₆ and a molecular weight of 454.48. Its CAS registry number is 62218-08-0.

Viniferin is a phenolic compound within the group of stilbenoids, also known as phytoalexins. The molecule is a derivative of resveratrol, the most researched compound in this group. Different viniferin forms are determined by the oligomerization of resveratrol as dimers, trimers or tetramers: α-viniferin, a trimer of resveratrol; ε-viniferin, δ-viniferin and ω-viniferin, which are dimers of resveratrol; and resveratrol tetramers such as R2-viniferin (Vitisin A) and R-viniferin (Vitisin B). Among these, ε-viniferin is probably the most studied form of viniferin, due to its many biological activities, such as anti-inflammatory, antioxidant, antineoplastic, antiobesity, cardioprotective and neuroprotective actions.

1.2 Stereochemistry and Isomers

Viniferin exists in multiple structural forms including α-, ε-, δ-, ω-, R-, R2-, cis-, and trans-viniferin, each distributed across various plant species. The stereochemistry of the primary viniferin isomers substantially affects their interactions with biological targets. The trans-configuration, the predominant form of ε-viniferin, exhibits superior antioxidant and anti-inflammatory properties compared to the cis-isomers. There are two stereochemical centers at positions 7a and 8a on the dihydrofuran ring, allowing the formation of four potential stereoisomers. Epsilon-(ε-) viniferin is specifically categorized as a distinct dehydrodimer within the viniferin family.

1.3 Botanical Sources

ε-Viniferin is found in Vitis vinifera grapevines, in wines, in the Oriental medicinal plant Vitis coignetiae and in the stem bark of Dryobalanops aromatica. Cis-epsilon-viniferin can be found in Paeonia lactiflora. ε-Viniferin is present in several plant genera, such as Vitis, Caragana, Carex, and Hopea.

Within Vitis species, content varies considerably. Vitis riparia stands out for its high ε-viniferin content. In fact, Vitis amurensis, Vitis riparia, and Vitis rupestris have exhibited the highest stilbene concentrations, related to the fact that they are the most resistant genera to fungal diseases. Among V. vinifera cultivars used in viticulture, some varieties may be suggested as the highest stilbene producers, such as Pinot noir and Gewurztraminer.

ε-Viniferin is mainly present in the woody parts of plants, and their use as a source of this bioactive compound is a very interesting issue in a circular economy. Grape canes, grape pomace and wine lees can be used for the extraction of viniferin. In terms of quantified concentrations in V. vinifera cane, the Hibernal variety is clearly the best source, with mean amounts of 3.24 g/kg for trans-ε-viniferin across all localities over three study years.

1.4 Dietary Occurrence

Trans-epsilon-viniferin is a trans-resveratrol dimer whose biosynthesis in various plant species, particularly high in the Vitaceae family, explains its presence in some red wines, which represent the main source of ε-viniferin in the human diet. The concentration of ε-viniferin in wine has been reported to be between 0.1 and 4.3 mg/L. ε-Viniferin is present at comparable concentrations to trans-resveratrol in red wines.

1.5 Forms and Preparations

ε-Viniferin is found in research settings primarily as an isolated and purified compound obtained from plant sources. The principal industrial matrix for extraction is the grape cane — the annual pruning waste of grapevines. Several extraction methods have been compared: maceration at laboratory temperature, extraction at elevated temperature, fluidized-bed extraction, Soxhlet extraction, microwave-assisted extraction, and accelerated solvent extraction have all been applied to obtain trans-resveratrol, trans-ε-viniferin and r2-viniferin from grape cane. The largest concentrations found were 2260 ± 90 µg/g dry weight for trans-ε-viniferin; the highest total stilbene amounts (8500 ± 1100 µg/g d.w.) were obtained using accelerated solvent extraction in methanol. A mixture of alcohol and water (70–80% alcohol) has been recommended for the quantitative extraction of trans-resveratrol and trans-ε-viniferin.

The use of elevated temperatures during extraction is, in the case of trans-ε-viniferin, less favorable due to the lower thermal stability of this stilbene. To address the compound's poor water solubility and bioavailability, encapsulation in lipid-based delivery systems has been investigated; encapsulation in phospholipid-based multi-lamellar liposomes (MLLs) called spherulites or onions has been shown to improve photosensitivity and significantly increase water solubility.

2. Traditional and Historical Use

ε-Viniferin as an isolated, characterized compound is a product of modern phytochemistry and does not carry a documented history of isolation-specific traditional use. However, the botanical sources from which it is derived have long and well-recorded histories of use in traditional medicine across multiple cultures, with some evidence suggesting that stilbene-containing plant fractions were employed for purposes that align with the biological activities now attributed to ε-viniferin.

Viniferin is a resveratrol-derived compound that belongs to a group of plant-produced stilbenoids, and functions as a natural defense against microbial invasion, toxins, infections, and ultraviolet radiation. Vitis vinifera and related grapevines have been cultivated and used medicinally across the Mediterranean, Middle East, Central Asia, and East Asia for millennia. Within traditional East Asian medicine, Vitis coignetiae (identified as an Oriental medicinal plant) has been used in Korean and Japanese herbal traditions, and the root, cane, and leaf preparations of various Vitis species have been employed in those traditions. Paeonia lactiflora, another host plant of cis-ε-viniferin, has been a cornerstone of Traditional Chinese Medicine for more than 1,200 years, used for pain, inflammation, and gynecological conditions.

The bark of Dryobalanops aromatica (a Dipterocarp tree of Southeast Asia), which contains ε-viniferin, has been used by indigenous communities in Borneo and Sumatra in traditional preparations. Viniferin, one of the dimers of resveratrol, exhibits various physiological activities such as anti-cancer, anti-viral, anti-inflammatory, anti-aging, and antioxidant activities similar to resveratrol, and is thus used in functional health foods, cosmetics, pharmaceuticals, dyes, and functional livestock feed — applications that bridge traditional practice and modern formulation.

The identification of ε-viniferin as a discrete chemical entity occurred in the latter half of the twentieth century. Disease resistance of Vitis spp. and the production of the stress metabolites resveratrol, epsilon-viniferin, alpha-viniferin and pterostilbene was documented as a key scientific finding in the 1981 literature, establishing the compound's role as a plant stress metabolite. Systematic pharmacological characterization of ε-viniferin did not begin in earnest until the late 1990s and accelerated during the 2000s onward.

3. Key Constituents, Biosynthesis, and Active Compound Profile

3.1 Biosynthetic Origin

ε-Viniferin is derived primarily from plants such as grapevines (Vitis vinifera), where it is synthesized as a phytoalexin in response to pathogenic infection or physiological stress. Trans-ε-viniferin is a dehydrodimer of trans-resveratrol formed from resveratrol by oxidation. ε-Viniferin and α-viniferin have been successfully produced in vitro by ultraviolet-induced resveratrol oxidation, indicating that resveratrol is the biosynthetic precursor. This compound is typically formed through the peroxidase-mediated oxidative dimerization of resveratrol.

This natural stilbenoid is synthesized by V. vinifera in response to biotic and abiotic stresses, and can be constitutively found in all grapevine woody parts. Stilbenes are secondary metabolites belonging to the polyphenol family. These compounds are derived from the glycosylation, prenylation, methoxylation, hydroxylation, or also oligomerization of the well-known trans-resveratrol.

3.2 Relationship to Other Stilbenoids

Other oligomer stilbenoids that can be extracted and found in the roots of Vitis vinifera are the resveratrol tetramers, R2-viniferin (Vitisin A) and R-viniferin (Vitisin B), which may mediate some other important biological activities. The compound's dimeric structure, compared to the monomeric resveratrol, confers specific properties. Considerable attention has been paid to oligomeric stilbenes such as viniferins, which have been shown to possess similar and often more pronounced health-promoting properties than resveratrol.

4. Mechanisms of Action

4.1 Antioxidant Mechanisms

The mode of action of ε-viniferin includes its potent antioxidant properties, which enable it to scavenge free radicals and reduce oxidative stress. In comparative in vitro studies, epsilon-viniferin exhibits the best antioxidant capacity in the DMSO/O₂⁻ polar system (IC₅₀ = 0.14 mM) when compared to resveratrol and several synthetic stilbenic derivatives. Antioxidant studies showed that ε-viniferin exhibited a DPPH free radical scavenging IC₅₀ of about 80 µM.

4.2 Anti-Inflammatory Mechanisms

Suppression of nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2), and prostaglandin E₂ (PGE₂) are established anti-inflammatory mechanisms of ε-viniferin. Studies in LPS-stimulated macrophage cell lines have confirmed this: these effects are accompanied with the inhibition of transcription factor NF-κB activation, and trans-ε-viniferin has been shown to exert anti-inflammatory effects via suppression of NF-κB activation in RAW 264.7 cells. In an in vivo model of acute liver failure, the combination of resveratrol and ε-viniferin reduced the expression of TNFα, iNOS, and COX-2, and inhibited MMP-9; the combination also had a hepatoprotective effect by upregulating IL-10.

4.3 Anti-Adipogenic and Metabolic Mechanisms

ε-Viniferin showed anti-adipogenic effects by downregulating PPARγ mRNA levels at 50 µM concentration. Research has also demonstrated that ε-viniferin more effectively suppressed intracellular lipid accumulation than resveratrol. ε-Viniferin, but not resveratrol, reduced protein expression of PPARγ and fatty acid synthase that contribute to lipogenesis.

Regarding AMPK activation, molecular studies have shown that ε-viniferin bound AMPK in the hinge region between the α- and β-unit of the kinase, a binding site also reported for other AMPK activators. The molecular dynamics study revealed that ε-viniferin could induce a conformational change in AMPK after binding, further activating its physiological function.

4.4 Anticancer Mechanisms

The mechanisms underlying the cytotoxic and antiproliferative activities of ε-viniferin have been explored, with most being linked to apoptosis. This form of programmed cell death is essential for the development of the organism and tissue homeostasis. Apoptosis can be initiated by two main mechanisms: the intrinsic pathway, mediated by mitochondria, and the extrinsic pathway, mediated by death receptors.

4.5 Neuroprotective Mechanisms

In cellular models of Parkinson's disease, ε-viniferin's neuroprotective action involves mitochondrial pathways: ε-viniferin has been demonstrated to be a novel stabilizer of mitochondrial function, with a potential neuroprotective effect by promoting the SIRT3-mediated FOXO3 deacetylation pathway in response to rotenone-induced neurotoxicity in a cellular model of PD, thereby preserving mitochondrial transmembrane potential and ameliorating rotenone-induced oxidative stress injury. The SIRT3-mediated FOXO3 deacetylation pathway is required for the neuroprotective mechanisms of ε-viniferin, because SIRT3 inhibition abolished these neuroprotective effects.

4.6 Cytochrome P450 Modulation

ε-Viniferin shows inhibitory effects on human CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2E1, CYP3A4, and CYP4A activities. A particularly potent inhibitory effect was shown for CYP1A1, CYP1B1 and CYP2B6, which are involved in bioactivation of numerous carcinogens. ε-Viniferin was not a mechanism-based inhibitor of human CYPs. It displayed, like resveratrol, mixed-type inhibitions for all the CYPs tested, except for CYP2E1 (non-competitive).

4.7 Inhibition of Carbohydrate-Digesting Enzymes

A study demonstrated the inhibitory potential of ε-viniferin on D-glucose uptake into porcine jejunal and ileal enterocytes, showing that ε-viniferin exhibited the strongest impact. ε-Viniferin has proven positive effects concerning insulin resistance in obesity. This stilbene was shown to inhibit in vitro the activity of α-amylase (IC₅₀ = 793.64 ± 0.18 µM) and α-glucosidase (IC₅₀ = 23.98 ± 1.00 µM), both enzymes being part of carbohydrate catabolism.

5. Scientific Evidence by Area of Use

5.1 Obesity and Body Fat Accumulation

This is among the most studied areas for ε-viniferin, with both in vitro and in vivo (animal) evidence available, though no published human clinical trials exist.

In vitro evidence: In vitro studies carried out in pre-adipocytes and mature adipocytes show that ε-viniferin is able to reduce fat accumulation. Significant reductions were observed when pre-adipocytes were treated with ε-viniferin at doses of 25 and 50 µM, suggesting a decrease in the inflammatory state of the cells. Studies also tested lower doses of 2.5, 5, and 10 µM; all tested doses significantly reduced lipid accumulation in a dose-dependent manner (from 100% to 96%, 93% and 92%, respectively), indicating an inhibition of the adipogenic process.

In vivo animal evidence: ε-Viniferin is present at comparable concentrations to trans-resveratrol in red wines and has higher anti-adipogenesis activity in 3T3-L1 cells. In addition, ε-viniferin was more effective than trans-resveratrol in its anti-obesity and anti-inflammatory effects in high-fat diet fed mice. Liu et al. induced type II diabetes in rats and administered ε-viniferin (30 or 60 mg/kg bw) for 8 weeks.

Evidence strength assessment: Evidence is entirely preclinical (cell culture and rodent models). No human randomized controlled trials have been published to date. The preclinical evidence is, however, mechanistically consistent and has been replicated by multiple independent research groups.

5.2 Glucose Metabolism and Type 2 Diabetes

ε-Viniferin has been shown to prevent the development of some obesity co-morbidities, including type 2 diabetes. Western blot analysis revealed a reduction in hepatic AMPK phosphorylation in animals fed with a high-fat high-sucrose diet, and a decrease in the activity of this enzyme, which was partially prevented by both doses of ε-viniferin. The potential involvement of AMPK was further studied using molecular docking and dynamics simulation. The authors concluded that ε-viniferin could represent an effective preventive tool for the amelioration of metabolic disturbances such as type 2 diabetes.

Evidence strength assessment: Evidence for antidiabetic effects is preclinical: cell culture and animal models. Enzyme inhibition data (α-amylase, α-glucosidase) derive from biochemical assays. No human clinical trials have been identified.

5.3 Cardiovascular and Endothelial Function

A published study compared the effects of resveratrol and its dimer ε-viniferin on vascular endothelial cell (VEC) functions, and on the blood pressure and cardiac mass of spontaneously hypertensive rats (SHRs). The study, published in Bioscience, Biotechnology, and Biochemistry (2012), reported that ε-viniferin was more effective than its monomer resveratrol in improving the functions of vascular endothelial cells and the heart. ε-Viniferin has been shown, in vitro, to possess antioxidant, anti-inflammatory, anti-carcinogenic, and cardioprotective activities. ε-Viniferin has also been associated with prevention of dyslipidemias and hypertension in animal models.

Evidence strength assessment: Evidence is preclinical (cell-based assays and spontaneously hypertensive rat models). No human trials have been conducted.

5.4 Anticancer Activity

A published study demonstrated that, in approximately half of the total cases, the determined IC₅₀ values for ε-viniferin were below 60 µM, highlighting the compound's potential in reducing the growth of cancer cells. Furthermore, comparative approaches on the anticancer activity of resveratrol and ε-viniferin have indicated that ε-viniferin is more active in one-third of the total cases.

In a 2021 study published in Food and Chemical Toxicology, ε-viniferin and α-viniferin have been shown to have antioxidant, anti-inflammatory, anti-diabetic, and anti-neurodegenerative activities, and viniferin was shown to induce apoptosis and necrosis in osteosarcoma and lung cancer cells.

The antiproliferative and proapoptotic effects of trans-resveratrol and its oligomers, including ε-viniferin, on HepG2 cancer cells and human colon cancer cells have also been previously suggested with isolated compounds.

Evidence strength assessment: To date, no in vivo trials have been conducted to compare ε-viniferin with resveratrol in studying its potential beneficial effects on the promotion, progression, or treatment of cancer. All available evidence is from in vitro cell lines; there are no published human clinical trials.

5.5 Neuroprotection: Parkinson's Disease Models

In a 2021 study published in Foods, the polyphenol trans-ε-viniferin was evaluated for its neuroprotective potential in NGF-differentiated PC12 cells, a dopaminergic cellular model of Parkinson's disease, and its anti-inflammatory properties were assessed in a N9 microglia–neuronal PC12 cell co-culture system. The neuronal cells were pre-treated with viniferin, resveratrol or their mixture before the administration of 6-hydroxydopamine (6-OHDA), recognized to induce parkinsonism in rats. Furthermore, N9 microglia cells were pre-treated with viniferin to investigate whether these polyphenols could reduce LPS-induced inflammation.

An additional study in a rotenone-induced cellular model found that ε-viniferin is a novel stabilizer of mitochondrial function, and that it has a potential neuroprotective effect by promoting the SIRT3-mediated FOXO3 deacetylation pathway in response to rotenone-induced neurotoxicity in a cellular model of PD, thereby preserving mitochondrial transmembrane potential and ameliorating rotenone-induced oxidative stress injury.

Evidence strength assessment: Evidence is exclusively from in vitro (cell culture) models of Parkinson's disease. No animal studies or human trials for this indication have been published.

5.6 Neuroprotection: Alzheimer's Disease Models

Trans ε-viniferin has been identified as an amyloid-β disaggregating and anti-inflammatory drug in a mouse primary cellular model of Alzheimer's disease (Vion et al., 2018, Molecular and Cellular Neuroscience). Alzheimer's disease affects many cellular and molecular targets; its therapy requires multi-target molecules. Caillaud et al. evaluated the effects of trans-ε-viniferin as a neuroprotective agent on transgenic APPswePS1dE9 mice.

Evidence strength assessment: Evidence is from in vitro cellular models and a limited transgenic mouse model. No human clinical data exist.

5.7 Liver Protection

In an animal study, researchers evaluated the effect of trans-resveratrol + ε-viniferin as an antioxidant mixture and its role in inflammatory development in an in vivo model of severe acute liver failure induced with thioacetamide (TAA). Trans-resveratrol + trans-ε-viniferin (5 mg/kg each) was administered to Wistar rats. Resveratrol + ε-viniferin significantly decreased TBARS and SOD activity and restored CAT and GST activities in the treated group. This stilbene combination reduced the expression of TNFα, iNOS, and COX-2, and inhibited MMP-9. The combination had a hepatoprotective effect, reducing DNA damage, exhibiting a protective role on the antioxidant pathway.

Evidence strength assessment: Animal study only. No human clinical trials exist for hepatoprotection.

5.8 Skin / Depigmentation

The skin whitening potential of V. vinifera cane extracts was compared to pure trans-resveratrol and ε-viniferin. HPLC-MS analysis determined the main polyphenols presented in the ethanol-water (60/40 v/v) extract, including ε-viniferin. The highest tyrosinase inhibition results were obtained for ε-viniferin (76%) and trans-resveratrol (75%).

Evidence strength assessment: In vitro enzyme inhibition data only. No clinical trials on skin depigmentation.

6. Bioavailability and Pharmacokinetics

ε-Viniferin can be absorbed orally, but it shows a very low bioavailability. Bioavailability studies have shown poor absorption and high metabolism of this stilbene.

The only study about ε-viniferin pharmacokinetic characterization and bioavailability after oral administration showed a maximum plasma concentration (C_max) of 42 ng/mL for a time to maximum concentration (T_max) between 15 and 30 minutes after oral administration of 40 mg/kg body weight in mice, and calculated a bioavailability of 0.77%. This very poor bioavailability could be explained by a low absorption through the intestinal barrier and/or a strong intestinal and/or liver metabolism.

Stilbenes are subjected to biotransformations such as sulfation and glucuronidation, via sulfotransferase and UDP-glucuronosyltransferase, respectively. These detoxification processes take place mainly in the liver but also to a significant level in the enterocytes of the small intestine.

ε-Viniferin incubated with human or rat S9 liver fractions led to the formation of four glucuronoconjugates and four sulfoconjugates. In both species, ε-viniferin was subjected to intense metabolism as 70 to 80% of the molecule was converted to glucuronides and sulfates. In humans, ε-viniferin is mostly converted to glucuronides, and less often, to sulfates, whereas glucuronidation is the main pathway in rats.

In a study in 2018, it was reported that ε-viniferin accumulated in white adipose tissue, suggesting that these tissues may act as a reservoir for the native form, allowing slow release and long-term presence in the organism. Furthermore, ε-viniferin and its metabolites were found in higher concentrations in feces than in urine, signifying the main elimination pathway.

Research into encapsulation strategies has been undertaken to address this limitation. Trans-ε-viniferin is a resveratrol dimer exhibiting promising biological activities for human health. Its bioavailability being low, the development of encapsulation methods would be used to overcome this issue. After oral administration of ε-viniferin (20 mg/kg body weight), either as free or encapsulated forms, plasmas were sequentially collected (from 0 to 4 h) as well as liver, kidneys and adipose tissues (4 h after administration) and analyzed by LC-HRMS.

7. Dosages Reported in Scientific Studies

The following dosages are reported directly from the published scientific literature and refer to experimental or preclinical contexts. No established human clinical dosages exist for ε-viniferin as a dietary supplement.

Oral pharmacokinetic study (rodent): 20 mg/kg body weight administered orally, either as free or encapsulated forms, in rats.
Oral bioavailability study (mouse): 40 mg/kg body weight administered orally, yielding a C_max of 42 ng/mL and a bioavailability of 0.77%.
Antidiabetic animal model: 30 or 60 mg/kg body weight administered to rats with induced type II diabetes for 8 weeks.
Hepatoprotective rat model: Trans-resveratrol + trans-ε-viniferin (5 mg/kg each) administered to Wistar rats.
Anti-adipogenic cell culture (pre-adipocytes): 25 and 50 µM, with significant reductions in inflammatory markers observed.
Anti-adipogenic cell culture (lower dose): 2.5, 5, and 10 µM; all tested doses significantly reduced lipid accumulation in a dose-dependent manner.
Anti-adipogenic mechanism (cell culture): 50 µM for downregulation of PPARγ mRNA levels.
Enzyme inhibition (in vitro): IC₅₀ for α-amylase inhibition = 793.64 ± 0.18 µM; IC₅₀ for α-glucosidase inhibition = 23.98 ± 1.00 µM.

8. Body Systems and Health Areas

Based on the available preclinical evidence, ε-viniferin has been associated with the following body systems and health areas:

Metabolic system: In vitro and in vivo studies show that ε-viniferin is able to reduce fat accumulation and prevent the development of some obesity co-morbidities, such as type 2 diabetes, dyslipidemias, and hypertension.
Cardiovascular system: ε-Viniferin has been shown in vitro to possess cardioprotective activities, including beneficial effects on vascular endothelial cell function.
Central nervous system (neuroprotection): ε-Viniferin has anti-neurodegenerative activities, with research in models of Parkinson's and Alzheimer's disease.
Hepatic / liver system: The combination of resveratrol + ε-viniferin demonstrated a hepatoprotective effect, reducing DNA damage and exhibiting a protective role on the antioxidant pathway.
Oncology (in vitro): ε-Viniferin, like other resveratrol oligomers, has been studied for its in vitro anticancer activities; the cytotoxic activities vary depending on the tumor cell line and the structure of the resveratrol oligomer studied.
Endocrine / adipose system: Through PPARγ and AMPK modulation, ε-viniferin exerts effects on adipocyte differentiation and lipid metabolism.
Skin: The highest tyrosinase inhibition results were obtained for ε-viniferin (76%), indicating potential relevance for skin depigmentation applications.
Immune / inflammatory system: The ε-viniferin exhibits strong activities against inflammatory and oxidative stress.

9. Safety Considerations and Drug Interactions

9.1 Cytochrome P450 Enzyme Inhibition

The most documented and pharmacologically significant safety consideration for ε-viniferin relates to its inhibition of cytochrome P450 enzymes. ε-Viniferin shows human cytochrome P450 enzyme inhibition activity. Specifically, the effects of resveratrol, ε-viniferin, and non-volatile compounds of red wine or Cognacs on CYP catalytic activities were studied in microsomes from human liver and from CYP-overexpressed cells. Ethoxyresorufin, coumarin, benzoxyresorufin, chlorzoxazone, testosterone and lauric acid were used as selective substrates for CYP1A1/CYP1A2, CYP2A6, CYP2B6, CYP2E1, CYP3A4 and CYP4A, respectively.

A particularly potent inhibitory effect was shown for CYP1A1, CYP1B1, and CYP2B6 — enzymes involved in bioactivation of numerous carcinogens. ε-Viniferin was not a mechanism-based inhibitor of human CYPs. It displayed, like resveratrol, mixed-type inhibitions for all the CYPs tested, except for CYP2E1 (non-competitive). Importantly, comparison of the inhibitory effects exerted on CYP activities by ε-viniferin, resveratrol, and non-volatile components from red wine showed that neither resveratrol nor ε-viniferin is the main CYP inhibitor present in red wine solids.

The CYP3A4 inhibition is particularly relevant from a drug interaction standpoint, as CYP3A4 is responsible for the metabolism of approximately 50% of all pharmaceuticals. The inhibition pattern described is from in vitro microsomal assays; clinical relevance at physiologically achievable concentrations has not been established.

9.2 Potential Toxicity Considerations

Trans-ε-viniferin may provide superior therapeutic properties than those observed with trans-resveratrol, but may also be more toxic. This observation has been noted in the peer-reviewed literature, but formal toxicological characterization in humans has not been published.

9.3 Metabolic Burden and Bioavailability Challenges

The metabolism of stilbenes seems to play a crucial role in their disposition and their biological effects. A recent study reported the extremely poor bioavailability of the resveratrol oligomers, and data about its metabolism are scarce and sometimes only partial. The rapid and extensive glucuronidation and sulfation of ε-viniferin means that the compound reaching systemic circulation in its native form is very limited after oral dosing.

9.4 Regulatory and Research-Stage Status

ε-Viniferin could be a promising candidate for future functional foods or supplement foods used for the management of many chronic diseases of concern in terms of public health. However, as of the current literature, ε-viniferin has not been assessed by major regulatory bodies such as the European Food Safety Authority (EFSA) or the U.S. Food and Drug Administration (FDA) specifically as an isolated dietary supplement ingredient with established safety and efficacy data. It is not the subject of a WHO monograph, a German Commission E monograph, or an ESCOP monograph as an isolated compound. Further research on animal models is needed to confirm the effects reported in a great number of studies; to determine which metabolites are involved, including the main one responsible for the biological activity.

References

Health Conditions

Health conditions that E-viniferin may help support.

No conditions available.

Body Systems

Body systems that E-viniferin may help support.

No body systems available.