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Plant Profiler

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

Pharmacology:

  • 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

Pharmacodynamics/Kinetics:

  • 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.

References

  1. Lee, D. G., Kim, H. K., Park, Y., Park, S. C., Woo, E. R., Jeong, H. G., and Hahm, K. S. Gram-positive bacteria specific properties of silybin derived from Silybum marianum. Arch Pharm Res 2003;26(8):597-600. 12967193
  2. Zi, X., Feyes, D. K., and Agarwal, R. Anticarcinogenic effect of a flavonoid antioxidant, silymarin, in human breast cancer cells MDA-MB 468: induction of G1 arrest through an increase in Cip1/p21 concomitant with a decrease in kinase activity of cyclin-dependent kinases and associated cyclins. Clin Cancer Res 1998;4(4):1055-1064. 9563902
  3. Zi, X., Grasso, A. W., Kung, H. J., and Agarwal, R. A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells. Cancer Res 5-1-1998;58(9):1920-1929. 9581834
  4. Kittur, S., Wilasrusmee, S., Pedersen, W. A., Mattson, M. P., Straube-West, K., Wilasrusmee, C., Lubelt, B., and Kittur, D. S. Neurotrophic and neuroprotective effects of milk thistle (Silybum marianum) on neurons in culture. J Mol Neurosci 2002;18(3):265-269. 12059045
  5. Dehmlow, C., Erhard, J., and de Groot, H. Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. Hepatology 1996;23(4):749-754. 8666328
  6. Katiyar, S. K., Korman, N. J., Mukhtar, H., and Agarwal, R. Protective effects of silymarin against photocarcinogenesis in a mouse skin model. J Natl Cancer Inst 4-16-1997;89(8):556-566. 9106644
  7. Gunaratna, C. and Zhang, T. Application of liquid chromatography-electrospray ionization-ion trap mass spectrometry to investigate the metabolism of silibinin in human liver microsomes. J Chromatogr B Analyt Technol Biomed Life Sci 9-5-2003;794(2):303-310. 12954381
  8. Velussi, M., Cernigoi, A. M., De Monte, A., Dapas, F., Caffau, C., and Zilli, M. Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol 1997;26(4):871-879. 9126802
  9. Beckmann-Knopp, S., Rietbrock, S., Weyhenmeyer, R., Bocker, R. H., Beckurts, K. T., Lang, W., Hunz, M., and Fuhr, U. Inhibitory effects of silibinin on cytochrome P-450 enzymes in human liver microsomes. Pharmacol Toxicol 2000;86(6):250-256. 10895987
  10. Venkataramanan, R., Ramachandran, V., Komoroski, B. J., Zhang, S., Schiff, P. L., and Strom, S. C. Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metab Dispos 2000;28(11):1270-1273. 11038151
  11. Barzaghi, N., Crema, F., Gatti, G., Pifferi, G., and Perucca, E. Pharmacokinetic studies on IdB 1016, a silybin- phosphatidylcholine complex, in healthy human subjects. Eur J Drug Metab Pharmacokinet 1990;15(4):333-338. 11038151
  12. Nassuato, G., Iemmolo, R. M., Strazzabosco, M., Lirussi, F., Deana, R., Francesconi, M. A., Muraca, M., Passera, D., Fragasso, A., Orlando, R., and . Effect of Silibinin on biliary lipid composition. Experimental and clinical study. J Hepatol 1991;12(3):290-295. 1940257
  13. Floersheim, G. L., Weber, O., Tschumi, P., and Ulbrich, M. [Clinical death-cap (Amanita phalloides) poisoning: prognostic factors and therapeutic measures. Analysis of 205 cases]. Schweiz Med Wochenschr 8-21-1982;112(34):1164-1177. 6291147
  14. Hruby K, Caomos G, and Thaler H. Silbinin in the treatment of deathcap fungus poisoning. Forum 1984;6:23-26.
  15. Miguez, M. P., Anundi, I., Sainz-Pardo, L. A., and Lindros, K. O. Hepatoprotective mechanism of silymarin: no evidence for involvement of cytochrome P450 2E1. Chem Biol Interact 1994;91(1):51-63. 8194125
  16. Valenzuela, A., Lagos, C., Schmidt, K., and Videla, L. A. Silymarin protection against hepatic lipid peroxidation induced by acute ethanol intoxication in the rat. Biochem Pharmacol 6-15-1985;34(12):2209-2212. 4039940
  17. Tyagi, A. K., Singh, R. P., Agarwal, C., Chan, D. C., and Agarwal, R. Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin-induced growth Inhibition, G2-M arrest, and apoptosis. Clin Cancer Res 2002;8(11):3512-3519. 12429642
  18. Schriewer, H. and Rauen, H. M. [The effect of silybin dihemisuccinate on cholesterol biosynthesis in rat liver homogenates (author's transl)]. Arzneimittelforschung 1977;27(9):1691-1694. 579140
  19. Skottova, N. and Krecman, V. Silymarin as a potential hypocholesterolaemic drug. Physiol Res 1998;47(1):1-7. 9708694
  20. Gurley, B., Hubbard, M. A., Williams, D. K., Thaden, J., Tong, Y., Gentry, W. B., Breen, P., Carrier, D. J., and Cheboyina, S. Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: comparison of a milk thistle and black cohosh product to rifampin and clarithromycin. J Clin Pharmacol 2006;46(2):201-213. 16432272
  21. Maitrejean, M., Comte, G., Barron, D., El Kirat, K., Conseil, G., and Di Pietro, A. The flavanolignan silybin and its hemisynthetic derivatives, a novel series of potential modulators of P-glycoprotein. Bioorg Med Chem Lett 1-17-2000;10(2):157-160. 10673101
  22. Manna, S. K., Mukhopadhyay, A., Van, N. T., and Aggarwal, B. B. Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N- terminal kinase, and apoptosis. J Immunol 12-15-1999;163(12):6800-6809. 10586080
  23. Bhatia, N., Zhao, J., Wolf, D. M., and Agarwal, R. Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin. Cancer Lett 12-1-1999;147(1-2):77-84. 10660092
  24. Zi, X. and Agarwal, R. Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci USA 6-22-1999;96(13):7490-7495. 10377442
  25. Zi, X., Mukhtar, H., and Agarwal, R. Novel cancer chemopreventive effects of a flavonoid antioxidant silymarin: inhibition of mRNA expression of an endogenous tumor promoter TNF alpha. Biochem Biophys Res Commun 10-9-1997;239(1):334-339. 9345320
  26. Kim, D. H., Jin, Y. H., Park, J. B., and Kobashi, K. Silymarin and its components are inhibitors of beta-glucuronidase. Biol Pharm Bull 1994;17(3):443-445. 8019514
  27. Vinh, P. Q., Sugie, S., Tanaka, T., Hara, A., Yamada, Y., Katayama, M., Deguchi, T., and Mori, H. Chemopreventive Effects of a Flavonoid Antioxidant Silymarin on N-Butyl- N-(4-hydroxybutyl)nitrosamine-induced Urinary Bladder Carcinogenesis in Male ICR Mice. Jpn J Cancer Res 2002;93(1):42-49. 11802807
  28. Bhatia, N. and Agarwal, R. Detrimental effect of cancer preventive phytochemicals silymarin, genistein and epigallocatechin 3-gallate on epigenetic events in human prostate carcinoma DU145 cells. Prostate 2-1-2001;46(2):98-107. 11170137
  29. Zhu, W., Zhang, J. S., and Young, C. Y. Silymarin inhibits function of the androgen receptor by reducing nuclear localization of the receptor in the human prostate cancer cell line LNCaP. Carcinogenesis 2001;22(9):1399-1403. 11532861
  30. Hannay, J. A. and Yu, D. Silibinin: a thorny therapeutic for EGF-R expressing tumors? Cancer Biol Ther 2003;2(5):532-533. 14614321
  31. Thelen, P., Jarry, H., Ringert, R. H., and Wuttke, W. Silibinin down-regulates prostate epithelium-derived Ets transcription factor in LNCaP prostate cancer cells. Planta Med 2004;70(5):397-400. 15124082
  32. Yoo, H. G., Jung, S. N., Hwang, Y. S., Park, J. S., Kim, M. H., Jeong, M., Ahn, S. J., Ahn, B. W., Shin, B. A., Park, R. K., and Jung, Y. D. Involvement of NF-kappaB and caspases in silibinin-induced apoptosis of endothelial cells. Int J Mol Med 2004;13(1):81-86. 15124082
  33. Hikino, H., Kiso, Y., Wagner, H., and Fiebig, M. Antihepatotoxic actions of flavonolignans from Silybum marianum fruits. Planta Med 1984;50(3):248-250. 6091165
  34. Mira ML, Azevedo MS, and Manso C. The neutralization of hydroxyl radical by silibin, sorbinil and bendazac. Free Radical Res Commun 1987;4(125):129.
  35. Muzes G, Deak G, and Lang I. Silymarin (Legalon) kezeles hatasa idult alkoholos majbetegek antioxidans vedorendszerere es a lipid peroxidaciora (kettos vak protokoll). Orvosi Hetilap 1990;131:863-866.
  36. Altorjay, I., Dalmi, L., Sari, B., Imre, S., and Balla, G. The effect of silibinin (Legalon) on the the free radical scavenger mechanisms of human erythrocytes in vitro. Acta Physiol Hung 1992;80(1-4):375-380. 1345204
  37. Comoglio, A., Tomasi, A., Malandrino, S., Poli, G., and Albano, E. Scavenging effect of silipide, a new silybin-phospholipid complex, on ethanol-derived free radicals. Biochem Pharmacol 10-12-1995;50(8):1313-1316. 7488251
  38. Dehmlow, C., Murawski, N., and de Groot, H. Scavenging of reactive oxygen species and inhibition of arachidonic acid metabolism by silibinin in human cells. Life Sci 1996;58(18):1591-1600. 8649189
  39. Batakov, E. A. [Effect of Silybum marianum oil and legalon on lipid peroxidation and liver antioxidant systems in rats intoxicated with carbon tetrachloride]. Eksp Klin Farmakol 2001;64(4):53-55. 11589112
  40. Mullen K and Dasarathy S. Potential new therapies for alcoholic liver disease. Clin Liver Dis 1998;2(4):853-874.
  41. Gonzalez-Correa, J. A., de la Cruz, J. P., Gordillo, J., Urena, I., Redondo, L., and Sanchez, de la Cuesta. Effects of silymarin MZ-80 on hepatic oxidative stress in rats with biliary obstruction. Pharmacology 2002;64(1):18-27. 11731718
  42. Bass, N. M. Is there any use for nontraditional or alternative therapies in patients with chronic liver disease? Curr Gastroenterol Rep 1999;1(1):50-56. 10980927
  43. Lahiri-Chatterjee, M., Katiyar, S. K., Mohan, R. R., and Agarwal, R. A flavonoid antioxidant, silymarin, affords exceptionally high protection against tumor promotion in the SENCAR mouse skin tumorigenesis model. Cancer Res 2-1-1999;59(3):622-632. 9973210
  44. Tsai, J. H., Liu, J. Y., Wu, T. T., Ho, P. C., Huang, C. Y., Shyu, J. C., Hsieh, Y. S., Tsai, C. C., and Liu, Y. C. Effects of silymarin on the resolution of liver fibrosis induced by carbon tetrachloride in rats. J Viral Hepat 2008;15(7):508-514. 18397225
  45. Fintelmann, V. Modern phytotherapy and its uses in gastrointestinal conditions. Planta Med 1991;57(7):S48-S52. 1956958
  46. Ramasamy, K. and Agarwal, R. Multitargeted therapy of cancer by silymarin. Cancer Lett 10-8-2008;269(2):352-362. 18472213
  47. Asghar, Z. and Masood, Z. Evaluation of antioxidant properties of silymarin and its potential to inhibit peroxyl radicals in vitro. Pak J Pharm Sci 2008;21(3):249-254. 18614420
  48. Verschoyle, R. D., Greaves, P., Patel, K., Marsden, D. A., Brown, K., Steward, W. P., and Gescher, A. J. Evaluation of the cancer chemopreventive efficacy of silibinin in genetic mouse models of prostate and intestinal carcinogenesis: relationship with silibinin levels. Eur J Cancer 2008;44(6):898-906. 18343654
  49. Raina, K., Rajamanickam, S., Singh, R. P., Deep, G., Chittezhath, M., and Agarwal, R. Stage-specific inhibitory effects and associated mechanisms of silibinin on tumor progression and metastasis in transgenic adenocarcinoma of the mouse prostate model. Cancer Res 8-15-2008;68(16):6822-6830. 18701508
  50. Mokhtari, M. J., Motamed, N., and Shokrgozar, M. A. Evaluation of silibinin on the viability, migration and adhesion of the human prostate adenocarcinoma (PC-3) cell line. Cell Biol Int 2008;32(8):888-892. 18538589
  51. Ramakrishnan, G., Jagan, S., Kamaraj, S., Anandakumar, P., and Devaki, T. Silymarin attenuated mast cell recruitment thereby decreased the expressions of matrix metalloproteinases-2 and 9 in rat liver carcinogenesis. Invest New Drugs 7-30-2008;18665326
  52. Wallace, S., Vaughn, K., Stewart, B. W., Viswanathan, T., Clausen, E., Nagarajan, S., and Carrier, D. J. Milk thistle extracts inhibit the oxidation of low-density lipoprotein (LDL) and subsequent scavenger receptor-dependent monocyte adhesion. J Agric Food Chem 6-11-2008;56(11):3966-3972. 18476698
  53. Bialecka, M. [The effect of bioflavonoids and lecithin on the course of experimental atherosclerosis in rabbits]. Ann Acad Med Stetin 1997;43:41-56. 9471922
  54. Soto, C. P., Perez, B. L., Favari, L. P., and Reyes, J. L. Prevention of alloxan-induced diabetes mellitus in the rat by silymarin. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1998;119(2):125-129. 9669080
  55. von Schonfeld, J., Weisbrod, B., and Muller, M. K. Silibinin, a plant extract with antioxidant and membrane stabilizing properties, protects exocrine pancreas from cyclosporin A toxicity. Cell Mol Life Sci 1997;53(11-12):917-920. 9447243
  56. Detaille, D., Sanchez, C., Sanz, N., Lopez-Novoa, J. M., Leverve, X., and El Mir, M. Y. Interrelation between the inhibition of glycolytic flux by silibinin and the lowering of mitochondrial ROS production in perifused rat hepatocytes. Life Sci 5-23-2008;82(21-22):1070-1076. 18448125
  57. Mereish, K. A., Bunner, D. L., Ragland, D. R., and Creasia, D. A. Protection against microcystin-LR-induced hepatotoxicity by Silymarin: biochemistry, histopathology, and lethality. Pharm Res 1991;8(2):273-277. 1902564
  58. Pietrangelo, A., Borella, F., Casalgrandi, G., Montosi, G., Ceccarelli, D., Gallesi, D., Giovannini, F., Gasparetto, A., and Masini, A. Antioxidant activity of silybin in vivo during long-term iron overload in rats. Gastroenterology 1995;109(6):1941-1949. 7498660
  59. Feher, J., Lang, I., Nekam, K., Muzes, G., and Deak, G. Effect of free radical scavengers on superoxide dismutase (SOD) enzyme in patients with alcoholic cirrhosis. Acta Med Hung 1988;45(3-4):265-276. 3249654
  60. Tuchweber, B., Trost, W., Salas, M., and Sieck, R. Prevention of praseodymium-induced hepatotoxicity by silybin. Toxicol Appl Pharmacol 1976;38(3):559-570. 1014013
  61. Tuchweber, B., Sieck, R., and Trost, W. Prevention of silybin of phalloidin-induced acute hepatoxicity. Toxicol Appl Pharmacol 1979;51(2):265-275. 531892
  62. Campos R, Garrido A, Guerra R, and et al. Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 1989;55:417-419.
  63. Skakun N and Moseichuk I. [Clinical pharmacology of Legalon]. Vrach Delo 1988;5:5-10.
  64. Mourelle, M., Favari, L., and Amezcua, J. L. Protection against thallium hepatotoxicity by silymarin. J Appl Toxicol 1988;8(5):351-354. 3230245
  65. Mourelle, M., Muriel, P., Favari, L., and Franco, T. Prevention of CCL4-induced liver cirrhosis by silymarin. Fundam Clin Pharmacol 1989;3(3):183-191. 2548940
  66. Muriel, P. and Mourelle, M. Prevention by silymarin of membrane alterations in acute CCl4 liver damage. J Appl Toxicol 1990;10(4):275-279. 1975258
  67. Muriel, P., Garciapina, T., Perez-Alvarez, V., and Mourelle, M. Silymarin protects against paracetamol-induced lipid peroxidation and liver damage. J Appl Toxicol 1992;12(6):439-442. 1360480
  68. Shear, N. H., Malkiewicz, I. M., Klein, D., Koren, G., Randor, S., and Neuman, M. G. Acetaminophen-induced toxicity to human epidermoid cell line A431 and hepatoblastoma cell line Hep G2, in vitro, is diminished by silymarin. Skin Pharmacol 1995;8(6):279-291. 8688194
  69. Vogel, G. and Temme, I. [Curative antagonism of phalloidin induced liver damage with silymarin as a model of an antihepatotoxic therapy]. Arzneimittelforschung 1969;19(4):613-615. 5819161
  70. Floersheim, G. L., Eberhard, M., Tschumi, P., and Duckert, F. Effects of penicillin and silymarin on liver enzymes and blood clotting factors in dogs given a boiled preparation of Amanita phalloides. Toxicol Appl Pharmacol 1978;46(2):455-462. 569913
  71. Trost, W. and Halbach, G. Anti-phalloidine and anti-alpha-amanitine action of silybin in comparison with compounds similar to structural parts of silybin. Experientia 8-15-1978;34(8):1051-1052. 700023
  72. Vogel, G., Tuchweber, B., Trost, W., and Mengs, U. Protection by silibinin against Amanita phalloides intoxication in beagles. Toxicol Appl Pharmacol 1984;73(3):355-362. 6719456
  73. Ramellini, G. and Meldolesi, J. Liver protection by silymarin: in vitro effect on dissociated rat hepatocytes. Arzneimittelforschung 1976;26(1):69-73. 947182
  74. Tyutyulkova, N., Tuneva, S., Gorantcheva, U., Tanev, G., Zhivkov, V., Chelibonova-Lorer, H., and Bozhkov, S. Hepatoprotective effect of silymarin (carsil) on liver of D- galactosamine treated rats. Biochemical and morphological investigations. Methods Find Exp Clin Pharmacol 1981;3(2):71-77. 7230979
  75. Sonnenbichler, J. and Zetl, I. Biochemical effects of the flavonolignane silibinin on RNA, protein and DNA synthesis in rat livers. Prog Clin Biol Res 1986;213:319-331. 2424029
  76. Sonnenbichler, J., Goldberg, M., Hane, L., Madubunyi, I., Vogl, S., and Zetl, I. Stimulatory effect of Silibinin on the DNA synthesis in partially hepatectomized rat livers: non-response in hepatoma and other malign cell lines. Biochem Pharmacol 2-1-1986;35(3):538-541. 3004503
  77. Sonnenbichler J and Zetl I. Stimulating influence of a flavonolignane derivative on proliferation, RNA synthesis and protein synthesis in liver cells. In: Okoliczanyi L, Csomos G, Crepaldi G, and et al. Assessment and Management of Hepatobiliary Disease. Berlin: Springer-Verlag;1987.
  78. Sonnenbichler, J., Scalera, F., Sonnenbichler, I., and Weyhenmeyer, R. Stimulatory effects of silibinin and silicristin from the milk thistle Silybum marianum on kidney cells. J Pharmacol Exp Ther 1999;290(3):1375-1383. 10454517
  79. Fiebrich, F. and Koch, H. Silymarin, an inhibitor of prostaglandin synthetase. Experientia 12-15-1979;35(12):1550-1552. 118049
  80. Fiebrich, F. and Koch, H. Silymarin, an inhibitor of lipoxygenase. Experientia 12-15-1979;35(12):1548-1560. 118048
  81. Valenzuela, A., Aspillaga, M., Vial, S., and Guerra, R. Selectivity of silymarin on the increase of the glutathione content in different tissues of the rat. Planta Med 1989;55(5):420-422. 2813578
  82. Wenzel, S., Stolte, H., and Soose, M. Effects of silibinin and antioxidants on high glucose-induced alterations of fibronectin turnover in human mesangial cell cultures. J Pharmacol Exp Ther 1996;279(3):1520-1526. 8968378
  83. Locher, R., Suter, P. M., Weyhenmeyer, R., and Vetter, W. Inhibitory action of silibinin on low density lipoprotein oxidation. Arzneimittelforschung 1998;48(3):236-239. 9553679
  84. Zima, T., Kamenikova, L., Janebova, M., Buchar, E., Crkovska, J., and Tesar, V. The effect of silibinin on experimental cyclosporine nephrotoxicity. Ren Fail 1998;20(3):471-479. 9606735
  85. Basaga, H., Poli, G., Tekkaya, C., and Aras, I. Free radical scavenging and antioxidative properties of 'silibin' complexes on microsomal lipid peroxidation. Cell Biochem Funct 1997;15(1):27-33. 9075334
  86. Carini, R., Comoglio, A., Albano, E., and Poli, G. Lipid peroxidation and irreversible damage in the rat hepatocyte model. Protection by the silybin-phospholipid complex IdB 1016. Biochem Pharmacol 5-28-1992;43(10):2111-2115. 1599497
  87. Bosisio, E., Benelli, C., and Pirola, O. Effect of the flavanolignans of Silybum marianum L. on lipid peroxidation in rat liver microsomes and freshly isolated hepatocytes. Pharmacol Res 1992;25(2):147-154. 1635893
  88. Minonzio, F., Venegoni, E., Ongari, A. M., Ciani, D., and Capsoni, F. Modulation of human polymorphonuclear leukocyte function by the flavonoid silybin. Int J Tissue React 1988;10(4):223-231. 2855072
  89. Kalmar, L., Kadar, J., Somogyi, A., Gergely, P., Csomos, G., and Feher, J. Silibinin (Legalon-70) enhances the motility of human neutrophils immobilized by formyl-tripeptide, calcium ionophore, lymphokine and by normal human serum. Agents Actions 1990;29(3-4):239-246. 2111081
  90. Leng-Peschlow E and Strenge-Hesse A. [The milk thistle (Silybum marianum) and silymarin in liver therapy]. Z Phytother 1991;12:162-174.
  91. Bokemeyer, C., Fels, L. M., Dunn, T., Voigt, W., Gaedeke, J., Schmoll, H. J., Stolte, H., and Lentzen, H. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity. Br J Cancer 1996;74(12):2036-2041. 8980410
  92. Gaedeke, J., Fels, L. M., Bokemeyer, C., Mengs, U., Stolte, H., and Lentzen, H. Cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant 1996;11(1):55-62. 8649653
  93. Petry, J. J. and Hadley, S. K. Medicinal herbs: answers and advice, part 1. Hosp Pract (Minneap) 7-15-2001;36(7):57-60. 11446601
  94. Pade, D. and Stavchansky, S. Selection of bioavailability markers for herbal extracts based on in silico descriptors and their correlation to in vitro permeability. Mol Pharm 2008;5(4):665-671. 18481869
  95. Schandalik, R., Gatti, G., and Perucca, E. Pharmacokinetics of silybin in bile following administration of silipide and silymarin in cholecystectomy patients. Arzneimittelforschung 1992;42(7):964-968. 1329780
  96. Gatti, G. and Perucca, E. Plasma concentrations of free and conjugated silybin after oral intake of a silybin-phosphatidylcholine complex (silipide) in healthy volunteers. Int J Clin Pharmacol Ther 1994;32(11):614-617. 7874377
  97. Savio, D., Harrasser, P. C., and Basso, G. Softgel capsule technology as an enhancer device for the absorption of natural principles in humans. A bioavailability cross-over randomised study on silybin. Arzneimittelforschung 1998;48(11):1104-1106. 9850434
  98. Leber, H. W. and Knauff, S. Influence of silymarin on drug metabolizing enzymes in rat and man. Arzneimittelforschung 1976;26(8):1603-1605. 1036961
  99. Flory, P. J., Krug, G., Lorenz, D., and Mennicke, W. H. [Studies on elimination of silymarin in cholecystectomized patients. I. Biliary and renal elimination after a single oral dose]. Planta Med 1980;38(3):227-237. 7367491
  100. Weyhenmeyer, R., Mascher, H., and Birkmayer, J. Study on dose-linearity of the pharmacokinetics of silibinin diastereomers using a new stereospecific assay. Int J Clin Pharmacol Ther Toxicol 1992;30(4):134-138. 1572758
  101. Singh, R. P. and Agarwal, R. A cancer chemopreventive agent silibinin, targets mitogenic and survival signaling in prostate cancer. Mutat Res 11-2-2004;555(1-2):21-32. 15476849
  102. Varga, Z., Ujhelyi, L., Kiss, A., Balla, J., Czompa, A., and Antus, S. Effect of silybin on phorbol myristate actetate-induced protein kinase C translocation, NADPH oxidase activity and apoptosis in human neutrophils. Phytomedicine 2004;11(2-3):206-212. 15070174
  103. Schrieber, S. J., Wen, Z., Vourvahis, M., Smith, P. C., Fried, M. W., Kashuba, A. D., and Hawke, R. L. The pharmacokinetics of silymarin is altered in patients with hepatitis C virus and nonalcoholic Fatty liver disease and correlates with plasma caspase-3/7 activity. Drug Metab Dispos 2008;36(9):1909-1916. 18566043




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