What Is Silybin — Structure, Benefits, Supplements, and Toxicity
Introduction
Silybin, or silibinin, is a polyphenolic flavonoid that naturally occurs in the plant known as milk thistle (Silybum marianum). This compound is often known for its health-beneficial effects and has been used in traditional medicine for centuries.
This article will delve into silybin and its properties, including structure, properties, and effects on health.
Table of contents
Structure, Properties, and Metabolism
The phytochemical silybin is a polyphenolic flavonoid, more specifically, a flavonolignan. It is the primary component of Silybum marianum plant extract, which is known as silymarin. Various studies have confirmed that silybin is not only the major element (50 to 70%) of silymarin but also its most active ingredient (1).
Other names of silybin include flavobin, silliver, silybine, silymarin I, silybina, and silybine. It has a chemical formula of C25H22O10.
Silybin's structure comprises two main units: one based on taxifolin - a flavonoid, and the other on coniferyl alcohol, a phenylpropanoid. These units are connected by an oxirane ring (1).
Silybum marianum, also known as milk thistle or wild artichoke, belongs to the Asteraceae family and produces purple-reddish flowers from July to August. It is a native plant of Southern Europe, Northern Africa, and most of Asia but has been naturalized in North and South America and South Australia (1).
Silybin is fat-soluble with very poor water solubility. Its bioavailability in the gastrointestinal tract depends on various factors, including the preparation concentration and additional solubilizing substances such as fats, proteins, amino acids, cholesterol, or other flavonoids (1).
Like other flavonolignans, silbyin has low water solubility, bioavailability, and poor intestinal absorption.
About 3 to 8% of orally administered silybin is excreted unchanged in the urine. Around 80% is excreted as glucuronide and sulfate conjugate in the bile, where its concentration is 60 to 100 times higher than in serum. It is estimated that 20 to 40% of silybin in bile is reabsorbed, while the rest is excreted in feces (1).
Sources and Supplements Of Silybin
Silybin is not found in typically consumed foods. It is found in milk thistle seeds, supplements, and herbal teas.
Milk thistle supplements come in various formulations, either as a single ingredient or combined with others. Raw milk thistle seeds are available as powders for infusions, but silymarin, the active component, has low water solubility, so only about 10% dissolves in an infusion. The most common supplements use standardized dry extracts from milk thistle seeds, available as capsules, tablets, pills, and liquid extracts. Advanced formulations, like phytosomes and liposomes, are also available to improve silymarin's bioavailability. Additionally, extracts from Schizandra berry, artichoke, or dandelion are sometimes added to enhance the effectiveness of milk thistle products (2).
More soluble derivatives of silybin have been developed to address the low bioavailability issues, including silybin bis-hemisuccinate, β-cyclodextrin complex, silybin-N-methyl-glucamine, silybin 11-O-phosphate, and silybin-phosphatidylcholine. Additionally, a soluble silybin prodrug has been created using a highly water-soluble polymeric carrier, polyethylene glycol (3).
Health Benefits
Milk thistle has a long history of use in treating various ailments. In recent decades, its active compounds - silymarin and silybin, have been extensively studied for their health benefits, including liver-protective, antioxidant, anti-inflammatory, anti-cancer, and cardioprotective properties.
Liver-Protecting Effects
There is evidence that milk thistle provides liver protection through several mechanisms, including antioxidant activity, blocking toxins at the cellular membrane level, enhancing protein synthesis, antifibrotic activity, and potential anti-inflammatory or immunomodulating effects (4).
A meta-analysis of clinical data revealed that silymarin significantly reduced liver-related mortality, with an odds ratio of 0.53 compared to placebo, indicating a 47% reduction in risk. Patients treated with silymarin experienced a lower overall death rate from liver disease compared to those receiving a placebo. Another study found that those who used silymarin had a lower hospital admission rate for liver-related diseases (5).
Eurosil 85® is a proprietary formulation designed to enhance silymarin's oral bioavailability and has been used in most clinical research. One academic review found that silymarin, mostly in the form of Eurosil 85, acts as a free radical scavenger and modulates enzymes linked to cellular damage, fibrosis, and cirrhosis. Clinical studies have shown its hepatoprotective effects in patients with alcoholic or non-alcoholic fatty liver disease, including cirrhosis. Studies indicate silymarin significantly reduces liver-related deaths. It also improves glycemic parameters in diabetic patients with alcoholic cirrhosis and has successfully treated drug-induced liver injuries (6, 7).
Most studies have shown potential benefits of milk thistle, particularly in improving aminotransferase levels and liver function tests, which are the most commonly examined outcomes. However, survival rates and other clinical outcomes have been studied less frequently, with mixed results. The available evidence is insufficient to determine whether milk thistle is more effective for certain liver diseases or if its effectiveness depends on the duration of therapy or the chronicity and severity of the liver disease (4).
Antioxidant Effects
Silybin exhibits antioxidant properties across all studied cells by preventing radical formation, scavenging radical species, and inhibiting lipid peroxidation in cell membranes, which helps maintain membrane permeability (3).
Under oxidative and nitrosative stress, silybin effectively reduces the formation of superoxide anion radicals and nitric oxide (NO), enhances ATP levels through ADP phosphorylation, lowers malondialdehyde levels, and completely prevents reductions in glutathione and key antioxidant enzymes like superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Silybin also acts as an iron chelator (3).
These antioxidant properties have been demonstrated in liver cells, Kupffer cells, monocytes, and cancer cells (3).
Anti Inflammatory Effects
Silymarin and silybin generally disrupt the NF-κB signaling pathway, which is crucial for inflammation. Silybin’s anti-inflammatory effects also include interfering with various cytokine-induced signaling pathways, leading to reduced expression of inducible nitric oxide synthase (iNOS). It also inhibits cyclooxygenase-2 (COX-2) expression and activity, as well as leukotriene formation in human platelets, white blood cells, and endothelial cells. Additionally, silybin blocks the activation of certain protein kinases and c-jun N-terminal kinase, further contributing to its anti-inflammatory effects (3).
Cardiovascular Health and Metabolic Disease
One meta-analysis found silymarin supplementation to significantly reduce serum levels of fasting blood glucose, diastolic blood pressure, total cholesterol, triglycerides, fasting insulin, low-density lipoprotein, and hemoglobin A1C (HbA1c) in treated groups compared to untreated counterparts. However, there were no significant differences in body mass index (BMI), systolic blood pressure, C-reactive protein (CRP), body weight, or high-density lipoprotein (HDL) between the two groups (8).
These results indicate that silymarin may reduce certain cardiometabolic syndrome risk factors and positively impact lipid and glycemic profiles with potential hypotensive effects. Further studies with larger sample sizes and longer durations are needed to confirm these findings (8).
Anti-Cancer Effects
The anti-cancer efficacy of silibinin has been well-documented over the past two decades. It targets cancer cell proliferation, apoptosis, inflammation, angiogenesis, and metabolism. Recent research also highlights its strong anti-invasive and anti-metastatic properties against various cancers, such as liver, prostate, skin, lung, colon, breast, ovary, kidney, stomach, mouth cancers, glioblastoma, and leukemia (9).
Silibinin activates cellular checkpoints and cyclin-dependent kinase inhibitors (CDKIs), reduces cyclins and CDK levels, and induces cell cycle arrest in cancer cells. It affects CDK-CDKI interactions, CDK kinase activity, Rb phosphorylation, and E2Fs in cancer cells. Silibinin also triggers apoptotic processes and induces cell death in various cancer types. Additionally, it has notable anti-angiogenic effects by targeting VEGF, VEGF receptors, and iNOS. Silibinin influences multiple cellular signaling pathways and molecules, including EGFR, MAPKs, AP1, HIF-1α, STATs, PI3K/Akt, β-catenin, IGF-IGFBP3, NF-κB, and COX2, contributing to its biological effects (9).
Silybin Safety and Toxicity
Adverse effects associated with oral ingestion of milk thistle include (4):
- Gastrointestinal issues: nausea, diarrhea, dyspepsia, flatulence, abdominal bloating, fullness or pain, anorexia, and changes in bowel habits.
- Headache.
- Skin reactions: pruritus, rash, urticaria, and eczema.
- Neuropsychological events: asthenia, malaise, and insomnia.
- Arthralgia.
- Rhinoconjunctivitis.
- Impotence.
- Anaphylaxis.
However, causality is rarely addressed in available reports. In randomized trials, the incidence of adverse effects was approximately the same in both milk thistle and control groups (4).
Regarding legal standards, 88% of dietary silybin supplements met all requirements, but some had omissions, errors, or potential false claims. Supplements containing milk thistle often included Cynara scolymus and Taraxacum officinale plants. While dietary supplements can be safe and beneficial when used correctly, some products may lack sufficient information to protect consumers fully. It is important to carefully review supplement labels and claims to ensure their accuracy and safety (10).
History
The fruits of milk thistle have traditionally been used by mothers to stimulate milk production. A legend claims that the plant's white-veined leaves were created by a drop of milk from the mother of Jesus. According to the legend, while fleeing Egypt with the infant Jesus, she found shelter in a bower formed by the thorny leaves of the milk thistle. This legend has led to the plant being called names like Mary thistle, St. Mary’s thistle, holy thistle, blessed virgin thistle, and Christ’s crown (1).
Physicians and herbalists have used Silybum marianum to treat liver and gallbladder disorders since ancient times. The plant is mentioned in the Old Testament (Genesis 3:18) and was used in ancient Greece for liver dysfunctions. Additionally, traditional Indian and Chinese medicines have incorporated Silybum marianum for liver and gallbladder issues (1).
Numerous studies have confirmed its hepatoprotective properties Due to its beneficial effects, silymarin, an extract from milk thistle fruits, was recognized by the WHO in the 1970s as an official medicine with liver-protecting properties (1).
Summary
Silybin, or silibinin, is a polyphenolic flavonoid that naturally occurs in the plant known as milk thistle (Silybum marianum). It is the primary component of the milk thistle extract known as silymarine. Silybin is not only the major element (50 to 70%) of silymarin but also its most active ingredient.
Silybin is not found in typically consumed foods. It is found in milk thistle seeds, supplements, and herbal teas.
Milk thistle has a long history of use in treating various ailments. In recent decades, its active compounds - silymarin and silybin, have been extensively studied for their health benefits, including liver-protective, antioxidant, anti-inflammatory, anti-cancer, and cardioprotective properties.
Due to its beneficial effects, silymarin, an extract from milk thistle fruits, was recognized by the WHO in the 1970s as an official medicine with liver-protecting properties
References
- https://www.mdpi.com/1420-3049/22/11/1942
- https://www.mdpi.com/2218-1989/13/3/440
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098397/
- https://www.ncbi.nlm.nih.gov/books/NBK11896/
- https://onlinelibrary.wiley.com/doi/full/10.1002/fsn3.4010
- https://link.springer.com/article/10.1007/s12325-020-01251-y
- https://pubmed.ncbi.nlm.nih.gov/21633595/
- https://www.mdpi.com/2076-3921/13/4/390
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928361
- https://recipp.ipp.pt/handle/10400.22/18924
