Phytomedicine Silybum marianum (Silymarin) as an Effective Hepato-protective source from nature
Background: Silybum marianum is the most commonly prescribed phytomedicine for multiple Hepatic disorders. The common name of this plant is milk thistle. It exhibit its effects by the presence of flavonolignans via numerous mechanism the noteworthy are its antioxidant, anti- inflammatory and anti-fibrotic actions which make it suitable applicant for treatment of Liver fibrosis, cirrhosis, Fatty liver disease, Hepatitis, Hepatocellular carcinoma and many more. The drug is available mostly with the name of Silymarin in the market
Objective: The aim of the present study is to unfold miracles of milk thistle to review its efficacy and safety for management in Hepatic disorders
Methodology: A thorough literature survey was carried out for the article. More than 50 articles were taken into consideration published between 2000 and 2018.
Result: The review exposed the main constituents of milk thistle and its properties to protect liver against various toxins, alcohol and viral attacks. Silymarin is capable to regenerate liver and bring the hepatic markers, AST, ALT and others, to normal levels and the reported toxicities of Silymarin are few.
Conclusion: Silybum marianum has proved its higher efficacy and safety in Hepatic disorders, as compare to other therapies and therefore is an agent of choice. Furthermore its cost effectiveness and ability to be developed as various dosage forms, like emulsion and nanoparticles, undoubtedly ensures its extensive use in future.
2. Pradhan SC, Girish C. Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian J Med Res.2006; 124: 491–504.
3. Abenavoli L, Bardazzi G, Cracolici F, Quaranta C, Santini G, Graziosi S. et al. Complementary therapies for treating alcoholism, First Annual meeting by Complementary Medicine Research Group of the Italian Society for Alcohol Studies-May 5, 2006, Florence, Italy. Fitoterapia. 2008; 79: 142–147.
4. Abenavoli L, Bellentani S.Milk thistle to treat non‐alcoholic fatty liver disease: Dream or reality? Expert Review of Gastroent & Hepat. 2013; 7: 677–79.
5. Wu JW, Lin LC, Tsai TH. Drug–drug interactions of silymarin on the perspective of pharmacokinetics. J Ethnopharmacol. 2009; 21: 185–193.
6. Abenavoli L, Capasso R, Milic N, Capasso F. Review Milk Thistle in Liver Diseases: Past, Present, Future Phytother. Res. 2010; 24: 1423–1432
7. Saller R, Brignoli R, Melzer J, Meier R. An updated systematic review with meta-analysis for the clinical evidence of silymarin. Forsch Komplement med. 2008; 15: 9–20.
8. Machicao F, Sonnenbichler J. Mechanism of the stimulation of RNA synthesis in rat liver nuclei by silybin, Physiol Chem. 1997; 358: 141-147.
9. Erlejman AG, Verstraeten SV, Fraga CG, Oteiza PI. The interaction of flavonoids with membranes: potential determinant of flavonoid antioxidant effects. Free Radic Res. 2004; 38: 1311-1320.
10. Dehmlow C. Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. Hepatol. 1996; 23: 749-54.
11. Upadhyay G, Tiwari MN, Praksh O, Jyoti A. Involvement of multiple molecular events in pyrogallol-induced hepatotoxicity and silymarin-mediated protection: Evidence from gene expression profiles. Food and Chem Toxicol. 2010; 48: 1660-1670.
12. Tsai JH, Liu JY, Wu TT,Ho PC, Huang CY, Shyu JC. et al. Effects of silymarin on the resolution of liver ﬁbrosis induced by carbon tetrachloride in rats. J Viral Hepat. 2008. 15: 508–14.
13. Shaker ME, Shiha GE, Ibrahim TM, Comparison of early treatment with low doses of nilotinib, imatinib and a clinically relevant dose of silymarin in thioacetamide–induced liver fibrosis. Eu J of Pharmacol. 2011; 670: 593-600.
14. Lieber CS, Leo MA, Cao Q Ren C, DeCarli LM. Silymarin retards the progression of alcohol-induced hepatic ﬁ brosis in baboons. J Clin Gastroenterol 2003; 37: 336–339.
15. Brandon-Warner E, Sugg JA, Schrum LW, Mckillop LH, Silibinin inhibits ethanol metabolism and ethanol dependent cell proliferation in an vitro model of hepatocellular carcinoma. Cancer Lett.2010; 291: 120-29.
16. Crocenzi FA Basiglio CL, Pérez LM, Portesio MS, Pozzi EJ, Roma MGSilibinin [Milk thistle] prevents cholestasis-associated retrieval of the bile salt export pump, Bsep, in isolated rat hepatocyte couplets: possible involvement of camp. Biochem Pharmacol. 2005; 69: 1113-20.
17. Mokdad AA, Lopez AD, Shahraz S, Lozano R, Mokdad AH, Stanaway J. et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC medicine. 2014; 12: 145.
18. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet (London, England). 2008; 371:838–51.
19. Jeong DH, Lee GP, Jeong WI, Do SH, Yang HJ, Yuan DW. et al. Alterations of mast cells and TGF-beta1 on the silymarin treatment for CCl(4)-induced hepatic fibrosis. World J Gastroenterol. 2005;11:1141–8.
20. Chen IS, Chen YC, Chou CH, Chuang RF, Sheen LY, Chiu CH. Hepatoprotection of silymarin against thioacetamide-induced chronic liver fibrosis. J Sci Food Agric. 2012; 92:1441–7.
21. Shaker ME, Zalata KR, Mehal WZ, Shiha GE, Ibrahim TM. Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachlorideinduced hepatic oxidative stress, injury and fibrosis. Toxicol Appl Pharmacol. 2011;252:165–75.
22. Ezhilarasan D, Karthikeyan S, Vivekanandan P. Ameliorative effect of silibinin against N-nitrosodimethylamine-induced hepatic fibrosis in rats. Environ Toxicol Pharmacol. 2012;34: 1004–13.
23. Li CC, Hsiang CY, Wu SL, Ho TY. Identification of novel mechanisms of silymarin on the carbon tetrachloride-induced liver fibrosis in mice by nuclear factor-kappaB bioluminescent imaging-guided transcriptomic analysis. Food and chemical toxicol. 2012;50: 1568–75.
24. Mahli A, Koch A, Czech B, Peterburs P, Lechner A, Haunschild J, et al. Hepatoprotective effect of oral application of a silymarin extract in carbon tetrachloride-induced hepatotoxicity in rats. Clinical Phytoscience. 2015;1: 5.
25. Alaca N, Özbeyli D, Uslu S, Şahin HH, Yiğittürk G, Kurtel, H,Treatment with milk thistle extract (Silybum marianum), ursodeoxycholic acid, or their combination attenuates cholestatic liver injury in rats: Role of the hepatic stem cells. The Turk J of Gastroent. 2017; 28: 476–84.
26. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterol. 2011;141: 1249–53.
27. Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterol. 2015;148: 547–55.
28. Kim M, Yang SG, Kim JM, Lee JW, Kim YS, Lee JI. Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: analysis of isolated hepatic stellate cells. International journal of molecular medicine. 2012; 30: 473–9.
29. Salamone F, Galvano F, Cappello F, Mangiameli A, Barbagallo I, Li VG. Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis. Translational research: the journal of Lab. and Cl. med. 2012; 159: 477– 86.
30. Pais P, D’Amato M. In vivo efficacy study of milk thistle extract (ETHIS-094) in STAM model of nonalcoholic steatohepatitis. Drugs in R&D. 2014; 14: 291–9.
31. Hajiani EHSJ. Comparison of therapeutic effects of silymarin and vitamin E in nonalcoholic fatty liver disease: results of an open labele, prospective, randomized study Jundishapur. J of Nat Ph. Prod. 2009;4: 8–14
32. Hashemi SJHE, Sardabi EH. A placebo-controlled trial of silymarin in patients with nonalcoholic fatty liver disease. Hepat Mon. 2009; 9:265–70.
33. Masoodi MRA, Panahian M, Vojdanian M. Effects of silymarin on reducing liver aminotransferases in patients with nonalcoholic fatty liver diseases. GOVARESH. 2013; 18: 181–5.
34. Solhi H, Ghahremani R, Kazemifar AM, Hoseini YZ. Silymarin in treatment of non-alcoholic steatohepatitis: a randomized clinical trial. Cas J of Int Med. 2014; 5: 9–12.
35. Hajiaghamohammadi AA, Ziaee A, Oveisi S, Masroor H. Effects of metformin, pioglitazone, and silymarin treatment on non-alcoholic fatty liver disease: a randomized controlled pilot study. Hepat Mon. 2012; 12: e6099.
36. Zhang B, Xu D, She L, Wang Z, Yang N, Sun R, Xie Y, Silybin inhibits NLRP3 inflammasome assembly through the NAD(+)/SIRT2 pathway in mice with nonalcoholic fatty liver disease. The FASEB J. 2018; 32: 757–67.
37. Wah Kheong C, Nik Mustapha NR, Mahadeva S. A randomized trial of silymarin for the treatment of nonalcoholic steatohepatitis. Clinical Gastroenterology and Hepat. 2017; 15: 1940–49.
38. Stanaway JD, Flaxman AD, Naghavi M, Fitzmaurice C, Vos T, Abubakar I. et al. The global burden of viral hepatitis from 1990 to 2013: Findings from the Global Burden of Disease Study 2013. Lanc. 2016; 388: 1081–88.
39. Wei F, Liu SK, Liu XY, Li ZJ, Li B, Zhou YL. et al. Meta-analysis: Silymarin and its combination therapy for the treatment of chronic hepatitis B. Eur J Clin Microbiol Infect Dis. 2013; 32: 657–69
40. Petruzziello A, Marigliano S, Loquercio G, Cacciapuoti C. Hepatitis C virus (HCV) genotypes distribution: An epidemiological up-date in Europe. Infect. Agents Canc. 2016; 11: 53-66
41. Ghany MG, Strader DB, Thomas DL, Seeff LB. American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: An update. Hepatology 2009; 49: 1335–74.
42. Ahmed-Belkacem A, Ahnou N, Barbotte L, Wychowski C, Pallier C, Brillet R. et al. Silibinin and related compounds are direct inhibitors of hepatitis C virus RNA-dependent RNA polymerase. Gastroentern. 2010; 138: 1112–22.
43. Ferenci P, Scherzer TM, Kerschner H, Rutter K, Beinhardt S, Hofer H. et al. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroent. 2008; 135: 1561–67.
44. Dahari H, Shteingart S, Gafanovich I, Cotler SJ, D’Amato M, Pohl R.T. et al. Sustained virological response with intravenous silibinin: Individualized IFNfree therapy via real-time modelling of HCV kinetics. Liver Int. 2015, 35, 289–94.
45. Liu CH, Lin CC, Hsu WC, Chung CY, Lin CC, Jassey A. Highly bioavailable silibinin nanoparticles inhibit HCV infection. Gut. 2017; 66: 1853–61.
46. Fathalah WF, Abdel Aziz MA, Abou El, Soud NH, El Raziky MES. High dose of silymarin in patients with decompensated liver disease: A randomized controlled trial. Journal of Interferon & Cytokine Res.2017; 37: 480–87.
47. Dimitroulis D, Damaskos C, Valsami S, Davakis S, Garmpis N, Spartalis E. et al. From diagnosis to treatment of hepatocellular carcinoma: An epidemic problem for both developed and developing world. World J of Gastroent. 2017; 23: 5282–94.
48. Prasad V, Goldstein JA. US news and world report cancer hospital rankings: Do they reflect measures of research productivity? PLoS ONE 2014; 9: e107803.
49. Ghouri YA, Mian I, Rowe JH. Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis. J of Carcino. 2017; 16: 1.
50. Bae K, Park JH, Kim J, Cho CK, Oh B, Costa D. et al. Traditional oriental herbal medicine and natural killer cells for cancer patients: A systematic review and meta‐analysis. Phyto. Res. 2017; 31: 519–32.
51. Chen SR, Qiu HC, Hu Y, Wang Y, Wang YT. Herbal medicine offered as an initiative therapeutic option for the management of hepatocellular carcinoma. Phyto Res. 2016; 30: 863–77.
52. Safe S, Kasiappan R.Natural products as mechanism‐based anticancer agents: Sp transcription factors as targets. Phyto Res. 2016; 30: 1723–32.
53. Tariq A, Sadia S, Pan K, Ullah I, Mussarat S, Sun F, et al. A systematic review on ethnomedicines of anti‐cancer plants. Phyto Res. 2017; 31: 202–64.
54. Mastron JK, Siveen KS, Sethi G, Bishayee A.Silymarin and hepatocellular carcinoma: A systematic, comprehensive, and critical review. Anti‐Canc Dru. 2015; 26: 475–86.
55. Bosch‐Barrera J, Queral B, Menendez JA. Targeting STAT3 with silibinin to improve cancer therapeutics. Canc Treat Rev. 2017; 58: 61–69
56. Ramakrishnan G,Augustine TA,Jagan S,Vinodhkumar R,Devaki T. Effect of silymarin on N-nitrosodiethylamine induced hepatocarcinogenesis in rats Exp Onco. 2007; 1: 43-50
57. Mesallamy HOE, Metwally NS,Soliman MS, Ahmed KA, Moaty MMA. The chemopreventive effect of Ginkgo biloba and Silybum marianum extracts on hepatocarcinogenesis in rats. Can Cell Int. 2011; 11:38 (1-12)
58. Ahmed U, Akhtar J, Singh SP, Badruddeen, Ahmed FJ, Siddiqui S. Silymarin nanoemulsion against human hepatocellular carcinoma: development and optimization Art Cells, Nanomedicine, and Biotech. 2018; 46: 231-41
59. Ghosh AGT, Jain S. Silymarin-a review on pharmacodynamics and bioavailability enhancement. J of Pharm Sci and Tech. 2010; 2: 348–55.
60. Dunnick JK, Nyska A, Bishop JB, Bucher JR, Chhabra RS, Foster PM. et al. Toxicology and carcinogenesis studies of milk thistle extract (CAS No. 84604-20-6) in F344/N rats and B6C3F1 mice (Feed Studies). National Toxicology Program technical report series. 2011;565:1–177.
61. Dunnick JK, Nyska A. The toxicity and pathology of selected dietary herbal medicines. Toxicol Pathol. 2013; 41: 374–86.
62. Polyak SJ, Ferenci P, Pawlotsky JM. Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection. Hepat. (Baltimore, Md). 2013; 57:1262–71.
63. Han Y, Guo D, Chen Y, Tan ZR, Zhou HH. Effect of continuous silymarin administration on oral Talinolol pharmacokinetics in healthy volunteers. Xenobiotica; the fate of foreign compounds in biological systems. 2009; 39: 694–9.
64. Brantley SJ, Gufford BT, Dua R, Fediuk DJ, Graf TN, Scarlett YV. et al. Physiologically based pharmacokinetic modeling framework for quantitative prediction of an herb-drug interaction. CPT Pharmacomet. and systems pharma. 2014; 3: e107.