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Milk thistle (Silybum marianum)

Milk thistle (Silybum marianum) Image
Synonyms / Common Names / Related Terms
Bull thistle, cardo blanco, Cardui mariae fructus, Cardui mariae herba, Cardum marianum L., Carduus marianus L., Chardon-Marie, Emetic root, flavonolignans, Frauendistel, Fructus Silybi mariae, fruit de chardon Marie, heal thistle, Holy thistle, Isosilibinin, isosilybin, Kanger, Kocakavkas, kuub, lady's thistle, Legalon®, Marian thistle, mariana mariana, Mariendistel, Marienkrörner, Mary thistle, mild thistle, milk ipecac, natursil, natursilum, pig leaves, royal thistle, S. marianum, St. Mary's thistle, shui fei ji, silidianin, Silybi mariae fructus, silybin, silybinin, Silybum marianum, Silybum marianum Gaertn, silychristin, silydianin, snake milk, sow thistle, variegated thistle, venue thistle, wild artichoke.

Mechanism of Action


  • Constituents: Silymarin, a flavonoid complex that can be extracted from the seeds of milk thistle, is composed of three isomers7. Silymarin is typically extracted with 95% ethanol, yielding a bright yellow fluid, although one of the most studied and used milk thistle products, Legalon® (Madeus, Germany), is prepared via extraction with ethyl acetate. A standard milk thistle extract contains 70% silymarin, a mixture of the flavonolignans (silydianin, silychristin), and silibinin, which is the most biologically active constituent according to in vitro assays.45 Other constituents, including dehydrosilybin, desoxy-silydianin, and silybinomer have also been isolated.
  • Antibacterial effects: Silybin has a potent antibacterial activity, more potent than silymarin2, against Gram-positive bacteria without hemolytic activity, whereas it has no antimicrobial activity against Gram-negative bacteria or fungi.1
  • Anticancer effects: Multiple studies have been conducted on the anti-carcinogenic activity of milk thistle31,17,32, including reviews of milk thistle's historical and clinical role as a cancer adjuvant46. Researchers from the University of Texas Cancer Center have proposed that silymarin mediates suppression of a nuclear transcription factor via regulation of genes involved in inflammation and carcinogenesis.22 Ongoing research on the anti-carcinogenic effects of silymarin and silibinin in human breast, cervical, and prostate cancer cells reported significant inhibition of cell and deoxyribonucleic acid (DNA) growth; growth of human breast and prostate carcinoma cells was almost completely inhibited by silymarin (75-100mcg/mL medium), while cyclin-dependent kinase inhibitor Cip1/p21 expression drastically increased, resulting in G-1 arrest.23,2,3,24 In human leukocytes, silymarin has been found to protect against DNA damage caused by hydrogen peroxide. In a mouse skin model, topically applied silymarin dramatically reduced UVB and chemically induced carcinogenesis, an effect possibly attributable to strong antioxidant properties of silymarin.47,6,43 Almost complete abortion of chemically induced tumor promotion in rats by silymarin was accompanied by inhibition of the hypothetical endogenous tumor promoter TNFα.25 Hydrolysis of glucuronides may expose the intestinal mucosa to carcinogens, and inhibition of β-Glucuronidase by silymarin, as demonstrated in rats26, may play a preventive role against intestinal carcinogenesis. Silymarin has been demonstrated to protect against chemically-induced bladder carcinogenesis in mice27, and to inhibit mitogenic signaling pathways involved in proliferation of androgen-independent and androgen-dependent prostate cancer cells28,29. Milk thistle may also be effective for EGF-R expressing tumors.30 Silibinin or silipide, silibinin formulated with phospholipids, inhibits progression of tumors48, while also protecting against angiogenesis and late stage metastasis49,50, with protection possibly due to attenuation of mast cell recruitment51.
  • Cholesterol inhibitory effects: Early animal experimentation with silybin demonstrated decreased cholesterol synthesis18, and reduced biliary excretion of cholesterol salts by 60-70%, while leaving biliary flow rates unchanged12. In perfused livers from rats fed a high cholesterol diet, silymarin normalized the clearance of low-density lipoproteins, providing significant protection against dietary-induced hypercholesterolemia.19 In laboratory study, silymarin and silibinin inhibit the generation of oxidatized-LDL and oxidation-specific neoepitopes, likely through antioxidant and free radical scavenging mechanisms of action.52 Other animal studies using high cholesterol diets have reported anti-atherosclerotic effects.53
  • Glucose effects: In rats, silymarin was observed to play a protective role and spare the pancreas from damage in experimentally-induced diabetes mellitus.54 In rats pretreated with cyclosporin, silybin did not affect glucose levels; silybin and cyclosporin were found to have an additive inhibitory effect on insulin secretion.55 Silymarin has been reported to decrease fasting plasma glucose, hemoglobin A1c (HbA1c), and fasting insulin levels in patients with insulin-dependent diabetes associated with cirrhosis.8 Silibinin also has dose-dependently reduced glycolysis from carbohydrates via an inhibitory effect targeted on pyruvate kinase activity, affected oxidative phosphorylation, and mitigated the rise in metabolic flow-driven reactive oxygen species (ROS) formation in vitro study.56
  • Hepatoprotective effects: Silymarin is composed of six major flavonolignans, each of which may contribute to silymarin's hepatoprotective properties. There have been numerous proposed hepatoprotective mechanisms of milk thistle. Antioxidant or free radical-antagonizing actions from flavonoids present in milk thistle, such as silymarin and silybin, have been cited as a likely mechanism of action of milk thistle47,33,34,35,36,37,38,39,40,41,42; however, other suggested effects include increased protein synthesis, decreased tumor promotor activity, stabilized immunologic response, protection against cellular radiation damage, and alteration and increased stability of cellular membranes. Silymarin abolishes hepatotoxicity of microcystin-LR (a toxin from the alga Microcystis aeruginosa) in rats and mice, possibly due to prevention of oxidation of protein-thiol groups.57 Silymarin may also exert an antioxidant effect on human platelets, and provides antioxidant protection against liver toxicity in iron-overloaded rats.58 In human subjects with alcoholic cirrhosis, levels of erythrocyte/lymphocyte superoxide dismutase are raised in the presence of silymarin.59
  • In vitro and animal studies have demonstrated protective effects of silymarin, particularly silybin, against hepatotoxins as diverse as acetaminophen, alcohol, carbon tetrachloride, tetrachloromethane, thallium, toluene, and xylene.60,61,62,63,64,65,66,67,68 The antidote effects of silymarin against Amanita phalloides, observed in preliminary clinical and animal studies69,70,71,13,14,72, have been attributed to inhibition of binding to hepatocyte membranes. A membrane-stabilizing effect of silymarin has been demonstrated in rat hepatocytes.73 The protection of silymarin on rat livers from D-galactosamine toxicity has been attributed to an activation of enzymes involved in the UDP-glucuronic acid biosynthesis pathways, involved in detoxification of phenols and other toxic substances.74 Silymarin given to rats restored the CCl4-induced damage of liver, decreased the elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase in serum, and also reversed the altered expressions of alpha-smooth muscle actin in liver tissue.44
  • Silibinin has also been shown to have a regenerating effect on the livers of hepatectomized rats, increasing deoxyribonucleic acid (DNA) synthesis by 23-25%.75,76,77 A similar effect was observed in cells exposed to various nephrotoxic agents.78 Silybin stimulated DNA polymerase, increasing the synthesis of ribosomal ribonucleic acid (RNA) and stimulating liver cell regeneration; it also stabilized cellular membranes and increased the glutathione content of the liver.79,80,16,81 Malignant cell lines, specifically HeLA and Burkitt lymphoma cells, were not stimulated by this compound.75,76
  • Lipid peroxidation inhibitory effects: In human mesangial cell cultures, silybin inhibited the formation of malondialdehyde, a product of lipid peroxidation.82 Silybin has also been found to inhibit peroxidation of low-density lipoproteins (LDL) in vitro83 and in human mesangial cells82. Two weeks of silybin administered to rats was found to inhibit cyclosporin-induced lipid peroxidation.84 In human and rat lung/liver microsomes, silybin protects against chemical-induced lipid peroxidation85,86 and cell damage87.
  • Leukocyte effects: Silymarin exerted no significant effects on unstimulated polymorphonuclear (PMN) cell motility, phagocytic, or chemotactic activities. However, when PMNs were stimulated, silymarin inhibited myeloperoxidase release. Incubation of PMNs with silybin prevented the action of the leukocyte motility inhibitor, fMLP.88,89 Silymarin inhibited leukotriene production and had an anti-fibrotic effect.90 In healthy volunteers, silybin enhanced leukocyte motility.89 Silybin may selectively inhibit Kupffer cell leukotriene and free radical formation, and inhibit nitric oxide production.5,38
  • Neuronal/CNS effects: Milk thistle enhanced nerve growth factor (NGF)-induced neurite outgrowth in PC-12 neural cells and prolonged their survival in culture.4 Milk thistle extract also protected cultured rat hippocampal neurons against oxidative stress-induced cell death. Data demonstrated that milk thistle extract can promote neuronal differentiation and survival, suggesting potential benefits of chemicals in this plant on the nervous system.
  • Renal protective effects: Renal protective effects have also been evaluated. In rats, silybin prevented cisplatin-induced glomerular and tubular nephrotoxicity as measured by BUN, creatinine and fibronectin and histological changes in renal tubules.91,92 In rats, two weeks of treatment with silybin did not prevent cyclosporine-induced decreases in glomerular filtration rate or increase in serum creatinine, but it did prevent cyclosporin-induced lipid peroxidation.84 Several animal studies suggested renal protective effects of silymarin against cyclosporin and chemotherapeutic agents, such as cisplatin and ifosfamide.91,92,84 These possible results of the stimulatory effect of silymarin on kidney cells were demonstrated in vitro studies.78
  • Other effects: Silibinin has been found to inhibit 5-lipoxygenase products by Kupffer cells in vitro.5 The general health effects of milk thistle have been reviewed.93


  • Bioavailability: Bioavailability data for milk thistle in humans is controversial because of the complexity of the composition and the diversity of the constituents.94 Onset for oral activity (hepatoprotection) has been measured at 3-4 hours with peak silipide levels in cholecystectomy patients at approximately four hours.95 In another study, peak plasma concentrations of free silybin were measured after 2-3 hours, with a half-life two hours thereafter.96 Bioavailability of orally administered silybin ranges from 23%-47%, and appears to be higher when administered in a softgel capsule.97 Due to poor water solubility, tea preparations of milk thistle are not recommended medicinally. A phosphatidylcholine-silybin complex has been developed to improve bioavailability by up to 10-fold, called Silipide® (IdB 1016).11 Dosing is expressed in silybin equivalents. Most IdB 1016 in the circulation is in conjugated form. The half-life is reported as less than four hours. Less than 3% of free or conjugated form is recovered in the urine.
  • P450 effects: There is equivocal data from animal studies, in vivo, and in vitro studies to suggest an interaction with the cytochrome P450 system, in particular, inhibition of enzymes CYP 3A4 and CYP 2C9. Silymarin has been found to increase the hepatic mixed function oxidation system in rats, whereas elimination half-life of aminopyrine in a small human sample was not affected.98 Miguez did not find evidence of involvement of CYP 2E1 in the hepatoprotective mechanism of silymarin.15 More recently, the major flavonoid of milk thistle, silibinin, had little in vitro effect on CYP 2E1, CYP 2C19, CYP 1A2, or CYP 2A6. While silibinin was found to be a minor competitive inhibitor of dextromethorphan metabolism (CYP 2D6) in vitro, the net effect did not increase with higher silibinin concentrations. Therefore, the authors did not believe this to be clinically important. Clear inhibition was reported for CYP 2C9. Contradictory results were observed for CYP 3A4 substrates; mixed activation (low silibinin concentration) and minor inhibition (high silibinin concentration) of erythromycin, compared to pronounced non-competitive inhibition of denitronifedipine.9 In another study, Venkataramanan et al. demonstrated significant reduction in activity of CYP3A4 by 0.1 and 0.25mM silymarin. Silymarin (0.5mM) also significantly decreased mitochondrial respiration as determined by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) reduction in human hepatocytes.10 However, some reports disagree, stating that milk thistle and black cohosh appear to have no clinically relevant effect on CYP3A activity in vivo.20
  • P-glycoprotein binding: The resulting isoprenoid dehydrosilybins from the flavonolignan silybin has been shown to display high in vitro affinity for direct binding to P-glycoprotein.21
  • Elimination: The elimination half-life is generally less than four hours with silymarin and silybinin.11
  • Excretion: Less than 10% was found excreted in the urine and 20-40% recovered in the bile as glucuronide and sulfate conjugate.99 Approximately 5% of a dose was excreted in the urine as total silibinin, representing a renal clearance of about 30mL per minute.100
  • Distribution: Silibinin is physiologically available in different organs of the body, including plasma and prostate, which is generally required for the pharmacological dosing and translational mechanistic studies of the compound.101
  • The lipid solubility of silybin can be enhanced by methylation, which supports its penetration through cell membrane and enhances its inhibitory effects.102
  • The pharmacokinetics of silymarin is altered in patients with liver disease (hepatitis C virus; noncirrhosis, nonalcoholic fatty liver disease) based on findings from a cohort study.103 The area under the curve for the sum of total silymarin flavonolignans was approximately 2 to 5-fold higher for patients with liver disease (p≤0.03) compared with healthy volunteers.


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