“Silymarin”, a Promising Pharmacological Agent for Treatment of Diseases

Document Type: Review Article

Authors

1 Medical Toxicology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Widespread use of herbal drugs because of their protective effects on different organs toxicity has been shown in many studies. These protective effects have been illustrated in the fields of nephrotoxicity, hepatotoxicity, viral hepatitis, cancer, in vitro fertilization, neurotoxicity, depression, lung diseases, prostate diseases etc. Silymarin has cytoprotection activities due to its antioxidant activity and radical scavenging. The possible known mechanisms of action of silymarin protection are blockade and adjustment of cell transporters, p-glycoprotein, estrogenic and nuclear receptors. Moreover, silymarin anti-inflammatory effects through reduction of TNF-a, protective effects on erythrocyte lysis and cisplatin-induced acute nephrotoxicity have been indicated in some studies. Silymarin has also inhibited apoptosis and follicular development in patients undergoing IVF. Basis on such data, silymarin can be served as a novel medication in complementary medicine.

Keywords


1. Kren V, Walterova D. Silybin and Silymarin - New effects and applications. Biomed Papers 2005; 149:29-41.

2. Dermarderosin A. The review of natural products. 1st ed. United States of America: Facts and Comparisions; 2001.

3. Mayer KE, Mayer RP, Lee SS. Silymarin treatment of viral hepatitis: a systematic review. J Viral Hepatitis 2005; 12:559-567.

4. Saller R, Melzer J, Reichling J, Brignoli R, Meier R. An updated systematic review of the pharmacology of silymarin. Forsch Komp Klas Nat 2007; 14:70-80.

5. Cesanow N, Fleminh H, Kelly GA. PDR for nonprescription drugs, dietary supplements,and herbs. 27th ed. Montvale: Thomson PDR; 2006.

6. Kaur M, Agarwal R. Silymarin and epithelial cancer chemoprevention: How close we are to bedside? Toxicol Appl Pharm 2007; 224:350-359.

7. Karimi G, Ramezani M, Tahoonian Z. Cisplatin nephrotoxicity and protection by milk thistle extract in rats. Evid Based Complement Alternat Med 2005; 2:383-386.

8. Basiglio CL, Sanchez Pozzi EJ, Mottino AD, Roma MG. Differential effects of silymarin and its active component silybinin on plasma membrane stability and hepatocellular lysis. Chem Biol Interact 2009; 179:297-303.

9. Gazak R, Walterova D, Kren V. Silybin and silymarin - New and emerging applications in medicine. Curr Med Chem 2007; 14:315-338. 

10. WenWu J, Lin L, Tsai T. Drug-drug interactions of silymarin on the perspective of pharmacokinetics. J Ethnopharmacol 2009; 121:185-193.

11. Ramakrishnan G, Lo Muzio L, Elinos-Baez CM, Jagan S, Augustine TA, Kamaraj S, et al. Silymarin inhibited proliferation and induced apoptosis in hepatic cancer cells. Cell Prolif 2009; 42:229-40.

12. Toklu HZ, Tunali-Akbay T, Erkanli G, Yuksel M, Ercan F, Sener G. Silymarin, the antioxidant component of silybum marianum, protects against burn-induced oxidative skin injury. Burns 2007; 33:908-916.

13. Eminzade S, Uraz F, Izzettin FV. Silymarin protects liver against toxic effects of anti-tuberculosis drugs in experimental animals. Nutr Metab 2008; 5.

14. Katiyar SK, Roy AM, Baliga MS. Silymarin induces apoptosis primarily through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c release, and caspase activation. Mol Cancer Ther 2005; 4:207-216.

15. Shaker E, Mahmoud H, Mnaa S. Silymarin, the antioxidant component and Silybum marianum extracts prevent liver damage. Food Chem Toxicol 2010; 48:803-6.

16. Morishima C , Shuhart MC, Wang CC, Paschal DM, Apodaca MC, Liu Y, et al. Silymarin inhibits in vitro t- cell proliferation and cytokine production in hepatitis c virus infection. Gastroenterology 2010; 138:671-681.

17. Song Z, Song M, Lee DYW, Liu Y, Deaciuc IV, McClain CJ. Silymarin prevents palmitate-induced lipotoxicity in HepG2 cells: involvement of maintenance of Akt kinase activation. Basic Clin Pharmacol Toxicol 2007; 101:262-8.

18. Shaker E, Mahmoud H, Mnaa S. Silymarin, the antioxidant component and silybum marianum extracts prevent liver damage. Food Chem Toxicol 2010; 48:803-806.

19. Upadhyay G, Tiwari MN, Prakash O, Jyoti A, Shanker R, Singh MP. Involvement of multiple molecular events in pyrogallol-induced hepatotoxicity and silymarin-mediated protection: Evidence from gene expression profiles. Food Chem Toxicol 2010; 48:1660-1670.

20. Polyak SJ, Morishima C, Shuhart MC. Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized silymarin. Gastroenterology 2007; 132:1925-1936.

21. Ahmed-Belkacem A, Ahnou N, Barbotte L, Wychowski C, Pallier C, Brillet R, et al. Silybinin and related compounds are direct inhibitors of hepatitis c virus rna-dependent rna polymerase. Gastroenterology 2010; 138:1112-1122.

22. Miranda SR, Jin KL, Brouwer KLR, Wen Z, Smith PC, Hawke RL. Hepatic metabolism and biliary excretion of silymarin flavonolignans in isolated perfused rat livers: Role of multidrug resistance-associated protein 2 (Abcc2). Drug Metab Dispos 2008; 36:2219-2226.

23. Pradeep K, Mohan CVR, Gobianand K, Karthikeyan S. Silymarin: An effective hepatoprotective agent against diethylnitrosamine- induced hepatotoxicity in rats. Pharm Biol 2007; 45:707-714.

24. Stickel F, Schuppan D. Herbal medicine in the treatment of liver diseases. Digest Liver Dis 2007; 39:293-304.

25. Polyak SJ, Morishima C, Shuhart MC, Wang CC, Liu Y, Lee DYW. Inhibition of T-cell inflammatory cytokines, hepatocyte NF-B signaling, and HCV infection by standardized silymarin. Gastroenterol 2007; 132:1925-1936.

26. Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs 2001; 61:2035-2063.

27. Tyagi AK , Agarwal C, Chan DC, Agarwal R. Synergistic anti- cancer effects of silybinin with conventional cytotoxic agents doxorubicin, cisplatin and carboplatin against human breast carcinomaMCF-7 and MDA- MB468 cells. Oncol Rep 2004a; 11:493-499.

28. Tyagi A, Agarwal C, Harrison G, Glode L M, Agarwal R. Silybinin causes cell cycle arrest and apoptosis in human bladder transitional cell carcinoma cells by regulating CDKI-CDK-cyclin cascade, and caspase 3 and PARP cleavages. Carcinogenesis 2004b; 25:1711-1720.

29. Chu SC, Chiou HL, Chen PN, Yang SF, Hsieh YS. Silybinin inhibits the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2. Mol Carcinog 2004; 40:143-149.

30. Lahiri-Chatterjee M, Katiyar SK, Mohan RR, Agarwal R. A flavonoid antioxidant, silymarin, affords exceptionally high protection against tumor promotion in the SENCAR mouse skin tumorigenesis model. Cancer Res 1999; 59:622-632.

31. Deep G, Singh RP, Agarwal C, Kroll DJ , Agarwal R. Silymarin and silybinin cause G1 and G2-M cell cycle arrest via distinct circuitries in human prostate cancer PC3 cells: a comparison of flavanone silybinin with flavanolignan mixture silymarin. Oncogene 2006; 25:1053-1069.

32. Thelen P, Jarry H, Ringert RH, Wuttke W. Silybinin down-regulates prostate epithelium-derived Ets transcription factor in LNCaP prostate cancer cells. Planta Med 2004; 70:397-400.

33. Rana P, Agarwal S, Agarwal R. Prostate cancer chemoprevention by silybinin: bench to bedside. Mol Carcinog 2006; 45:436-442

34. Varghese L, Agarwal C, Tyagi A, Singh RP, Agarwal R. Silybinin efficacy against human hepatocellular. Carcinoma Clin Cancer Res 2005; 11:8441-8448. 

35. Agarwal C, Singh RP, Dhanalakshmi S, Tyagi AK, Tecklenburg M , Sclafani RA, et al. Silybinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells. Oncogene 2003; 22: 8271-8282.

36. Li LH, Wu LJ, Jiang YY, Tashiro S, Onodera S, Uchiumi F, et al. Silymarin enhanced cytotoxic effect of anti- Fas agonistic antibody CH11 on A375-S2 cells. J Asian Nat Prod Res 2007; 9:593-602.

37. Ramasamy K, Agarwal R. Multitargeted therapy of cancer by silymarin. Cancer Lett 2008; 352-362

38. Ramakrishnan G, Augustine TA, Jagan S, Vinodhkumar R, Devaki T. Effect of silymarin on N- nitrsodiethylamine induced hepatocarcinogenesis in rats. Exp Oncol 2007; 29:39-44.

39. Szkudelski T. The mechanism of alloxan and streptozocin action in B cells of the rat pancreas. Phyiol Res 2001; 50:536-546.

40. Sha S, Baliga R, Rajapurkar M, Fonseca V. Oxidants in chronic kidney disease. J Am Soc Nephrol 2007; 18:16-28.

41.  Soto C, Mena R, Luna J, Cerbon M, Larrieta E, Vital P, et al. Silymarin induces recovery of pancreatic function after alloxan damage in rats. Life Sci 2004; 75:2167-2180.

42. Soto C, Perez J, Garcia V, Uria E, Vadillo M, Raya L. Effect of silymarin on kidneys of rats suffering from alloxan-induced diabetes mellitus. Phytomedicine 2010; 17:1090-1094.

43. Varzi HN, Esmailzadeh S, Morovvati H, Avizeh R, Shahriari A, Givi ME .Effect of silymarin and vitamin E on gentamicin-induced nephrotoxicity in dogs. J Vet Pharmacol Ther 2007; 30:477-481.

44. Karimi G, Ramezani M, Tahoonian Z. Cisplatin nephrotoxicity and protection by milk thistle extract in rats. Evid Based Complment Alternat 2005; 2:383-386.

45. Karimi G, Fallah Huseini H, Ramezani M, Tahoonian Z. Protective effect of silybum marianum (l.) gaertn. seeds extract and silymarin against cisplatin-induced acute nephrotoxicity in rats. J Med Plants 2005; 4:42-45.

46. Kaur G, Athar M, Alam MS. Dietary supplementation of silymarin protects against chemically induced nephrotoxicity, inflammation and renal tumor promotion response. Invest New Drugs 2010; 28:703-13.

47. Nazemian F, Karimi GH, Moatamedi M, Charkazi S, Shamsara J, Moohammadpour AH. Effect of Silymarin administration on TNF-a serum concentration in peritoneal dialysis patients. Phytother Res 2010; 24:1654-1657.

48. Galhardi F, Mesquita K, Monserrat JM, Barros DM. Effect of silymarin on biochemical parameters of oxidative stress in aged and young rat brain. Food Chem Toxicol 2009; 47:2655-60.

49. Nencini C, Giorgi G, Micheli L. Protective effect of silymarin on oxidative stress in rat brain. Phytomedicine 2007; 14:129-135.

50. Davies K J. Oxidative stress, antioxidant defenses, and damage removal, repair, and replacement systems. IUBMB Life 2000; 50:279-289.

51. Metodiewa D, Koska C. Reactive oxygen species and reactive nitrogen species: relevance to cyto(neuro)toxicity events and neurological disorders. Neurotox Res 2000; 1:197-233.

52. Baluchnejadmojarad T, Roghani M, Mafakheri M. Neuroprotective effect of silymarin in 6-hydroxydopamine hemi-parkinsonian rat: involvement of estrogen receptors and oxidative stress. Neurosci Lett 2010; 480:206-210.

53. Karimi G, Saradeghi Keisari M. Evaluation of antidepressant effect of ethanolic and aqueous extracts of Silybum marianum L. seed in mice. J Med Plants 2007; 6:38-43.

54. Gharagozloo M, Velardi E, Bruscoli S, Agostini M, Di Sante M, Donato V, et al. Silymarin suppress CD4+ T cell activation and proliferation: Effects on NFk-B activity and IL-2 production. Pharmacol Res 2010; 61:405-409.

55. Soto PC, Sanchez RM, Uria CE, Favari PL. Silymarin effect in the pancreas of alloxan-induced diabetes mellitus in the rat. Rev Mex Cien Farm 2002; 33:5-10.

56. Soto C, Recoba R, Barron H, Alvarez C, Favari L. Silymarin increases antioxidant enzymes in alloxan-induced diabetes in rat pancreas. Comp Biochem Physiol C Toxicol Pharmacol 2003; 136:205-12.

57. Karimi GH, Hassanzadeh M, Mehri S. Protective effects of Silymarin against free radical-induced erythrocyte lysis. J Alternat Complement Med 2006; 3.

58.  Psotova J, Chlopcikova S, Miketova P, Hrbac J, Simanek V. Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. part III. apigenin, baicalelin, kaempherol, luteolin and quercetin. Phytother Res 2004; 18:516-521.

59. El-Shitany NA, Hegazy S, El-desoky K. Evidences for antiosteoporotic and selective estrogen receptor modulator activity of silymarin compared with ethinylestradiol in ovariectomized rats. Phytomedicine 2010; 17:116-125.

60. Kiruthiga PV, Pandian SK, Devi KP. Silymarin protects PBMC against B(a)P induced toxicity by replenishing redox status and modulating glutathione metabolizing enzymes—an in vitro study. Toxicol Appl Pharmacol 2010; 247:116-128.