Recapitulation of Evidence of Phytochemical, Pharmacokinetic and Biomedical Application of Silybin

Abstract

Silymarin is a standardized extract obtained from seeds of Silybum marianum (SM) belonging to the family Asteraceae. It is a flavonolignan complex and consists of various compounds like silybin A silybin B, isosilybin A, isosilybin B, silydianin, silychristin and isosilychristin. Silybin is the major active component present in 60–70% of the silymarin extract. It has been used traditionally for the treatment of various liver disorders like cirrhosis, jaundice, and hepatitis. Silymarin possesses antioxidant and anti-inflammatory properties and is responsible for its antitumor activity. Other than hepatoprotective effect SM also possesses renoprotective, anti-diabetic, neuroprotective, hypolipidemic, anti-atherosclerosis and cardioprotective effects. Rather antimicrobial property of silymarin was observed against specific microbes, fungi, and viruses. This manuscript covered recent preclinical and clinical evidence of specific components silybin, responsible for its efficacy and about clinical studies has been conducted so far, which proven it’s safety and offers mild effect like nausea, diarrhea and bloating. This review specifically focused on recent updates on its active components therapeutic applications against complicated ailments not covered in earlier reports.

Key words

Silybum marianum - Silybin - flavonolignan - therapeutic - clinical

Publication History

Received: 23 April 2021

Accepted: 08 June 2021

Article published online:
27 July 2021

• References

• 1 Raskin I, Ribnicky DM, Komarnytsky S. et al. Plants and human health in the twenty-first century. Trends Biotechnol 2002; 20: 522-531 DOI: 10.1016/S0167-7799(02)02080-2.
• 2 Khan MA, Blackshaw RE, Marwat KB. Biology of milk thistle (silybum marianum) and the management options for growers in north-western Pakistan. Weed Biol Manag 2009; 9: 99-105 DOI: 10.1111/j.1445-6664.2009.00326.x.
• 3 Ottai MES, Abdel-Moniem a SH.. Genetic parameter variations among milk thistle, Silybum marianum varieties and varietal sensitivity to infestation with seed-head weevil, Larinus latus Herbst. Int J Agric Biol 2006; 8: 862-866 Im Internet http://www.fspublishers.org/
• 4 Kren V, Walterová D. Silybin and silymarin--new effects and applications. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2005; 149: 29-41 DOI: 10.5507/bp.2005.002.
• 5 Gabr AMM, Ghareeb H, El Shabrawi HM. et al. Enhancement of silymarin and phenolic compound accumulation in tissue culture of Milk thistle using elicitor feeding and hairy root cultures. J Genet Eng Biotechnol 2016; 14: 327-333 DOI: 10.1016/j.jgeb.2016.10.003.
• 6 Saller R, Meier R, Brignoli R. The Use of Silymarin in the Treatment of Liver Diseases 2001; 61: 2035-2063
• 7 Abenavoli L, Capasso R, Milic N. et al. Milk thistle in liver diseases: Past, present, future. 2010; 1432: 1423-1432
• 8 Comoglio A, Tomasi A, Malandrino S. et al. Scavenging effect of silipide, a new silybin-phospholipid complex, on ethanol-derived free radicals. Biochem Pharmacol 1995; 50: 1313-1316 DOI: 10.1016/0006-2952(95)02001-S.
• 9 Cavaretta M. Therapeutic Review: Milk Thistle. J Exot Pet Med 2015; 24: 470-472 DOI: 10.1053/j.jepm.2015.09.001.
• 10 Ghosh A, Ghosh T, Jain S. Silymarin-a review on the pharmacodynamics and bioavailability enhancement approaches. Journal of Pharmaceutical Science and Technology 2010; 2: 348-355
• 11 Voinovich D. Solid State Mechanochemical Activation of Silybum marianum Dry Extract With Betacyclodextrins: Characterization and Bioavailability of the Coground Systems. J Pharm Sci 2009; 98: 4119-4129 DOI: 10.1002/jps.
• 12 Javed S, Kohli K, Ali M. Reassessing bioavailability of silymarin. Altern Med Rev 2011; 16: 239-249
• 13 Jančová P, Anzenbacherová E, Papoušková B. et al. Silybin is metabolized by cytochrome P450 2C8 in vitro. Drug Metab Dispos 2007; 35: 2035-2039 DOI: 10.1124/dmd.107.016410.
• 14 Wu JW, Lin LC, Hung SC. et al. Hepatobiliary excretion of silibinin in normal and liver cirrhotic rats. Drug Metab Dispos 2008; 36: 589-596 DOI: 10.1124/dmd.107.017004.
• 15 Corchete P. Silybum marianum (L.) Gaertn: the Source of Silymarin. Bioact Mol Med Plants 2008; 123-148 DOI: 10.1007/978-3-540-74603-4_6.
• 16 Abenavoli L, Izzo AA, Milić N. et al. Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phyther Res 2018; 32: 2202-2213 DOI: 10.1002/ptr.6171.
• 17 Ou Q, Weng Y, Wang S. et al. Silybin Alleviates Hepatic Steatosis and Fibrosis in NASH Mice by Inhibiting Oxidative Stress and Involvement with the Nf ‑ κB Pathway. Dig Dis Sci. 2018 DOI: 10.1007/s10620-018-5268-0
• 18 Haddad Y, Vallerand D, Brault A. et al. Antioxidant and Hepatoprotective Effects of Silibinin in a Rat Model of Nonalcoholic Steatohepatitis. 2011 2011. DOI: 10.1093/ecam/nep164
• 19 Kim SH, Oh DS, Oh JY. et al. Silymarin Prevents Restraint Stress-Induced Acute Liver Injury by Ameliorating Oxidative Stress and Reducing Inflammatory Response. Molecules 2016; 21 DOI: 10.3390/molecules21040443.
• 20 Karimi G, Ramezani M, Tahoonian Z. Cisplatin Nephrotoxicity and Protection by Milk Thistle Extract in Rats. 2005; 2: 383-386 DOI: 10.1093/ecam/neh103.
• 21 Akbas A, Akcay ÆA, Unal ÆD. Antioxidant and protective effects of silymarin on ischemia and reperfusion injury in the kidney tissues of rats. 2008; 453-460 DOI: 10.1007/s11255-008-9365-4.
• 22 Bektur NE, Sahin E, Baycu C. et al. Protective effects of silymarin against acetaminophen-induced hepatotoxicity and nephrotoxicity in mice. Toxicol Ind Health. 2013 DOI: 10.1177/0748233713502841
• 23 Dabak DO, Kocaman N. Effects of silymarin on methotrexate-induced nephrotoxicity in rats. Ren Fail 2015; 00: 1-6 DOI: 10.3109/0886022X.2015.1012984.
• 24 Soto CP, Perez BL, Favari LP. et al. Prevention of Alloxan-Induced Diabetes Mellitus in the Rat by Silymarin 1998; 119: 125-129
• 25 El-Far M, Negm A, Wahdan M. Promising biopharmaceutical use of silymarin and silibinin as antidiabetic natural agents in streptozotocin-induced diabetic rats: first comparative assessment. World J Pharm Pharm Sci 2014; 4: 7-28
• 26 Yao J, Zhi M, Gao X. et al. Effect and the probable mechanisms of silibinin in regulating insulin resistance in the liver of rats with non-alcoholic fatty liver. Brazilian J Med Biol Res 2013; 46: 270-277 DOI: 10.1590/1414-431X20122551.
• 27 Das S, Roy P, Pal R. et al. Engineered silybin nanoparticles educe efficient control in experimental diabetes. PLoS One 2014; 9 DOI: 10.1371/journal.pone.0101818.
• 28 Lu P, Mamiya T, Lu LL. et al. Silibinin prevents amyloid b peptide-induced memory impairment and oxidative stress in mice. Br J Pharmacol 2009; 157: 1270-1277 DOI: 10.1111/j.1476-5381.2009.00295.x.
• 29 Hou YC, Liou KT, Chern CM. et al. Preventive effect of silymarin in cerebral ischemia-reperfusion-induced brain injury in rats possibly through impairing NF-κB and STAT-1 activation. Phytomedicine 2010; 17: 963-973 DOI: 10.1016/j.phymed.2010.03.012.
• 30 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 DOI: 10.1016/j.neulet.2010.06.038.
• 31 Geed M, Garabadu D, Ahmad A. et al. Silibinin pretreatment attenuates biochemical and behavioral changes induced by intrastriatal MPP+injection in rats. Pharmacol Biochem Behav 2014; 117: 92-103 DOI: 10.1016/j.pbb.2013.12.008.
• 32 Thakare VN, Patil RR, Oswal RJ. et al. Therapeutic potential of silymarin in chronic unpredictable mild stress induced depressive-like behavior in mice. J Psychopharmacol 2018; 32: 223-235 DOI: 10.1177/0269881117742666.
• 33 Salamone F, Galvano F, Marino A. et al. Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis. Dig Liver Dis 2012; 44: 334-342 DOI: 10.1016/j.dld.2011.11.010.
• 34 El-Shitany NA, El-Haggar S, El-desoky K. Silymarin prevents adriamycin-induced cardiotoxicity and nephrotoxicity in rats. Food Chem Toxicol 2008; 46: 2422-2428 DOI: 10.1016/j.fct.2008.03.033.
• 35 Nabavi SM, Nabavi SF, Moghaddam AH. et al. Effect of silymarin on sodium fluoride-induced toxicity and oxidative stress in rat cardiac tissues. An Acad Bras Cienc 2012; 84: 1121-1126 DOI: 10.1590/S0001-37652012005000056.
• 36 Rao PR, Viswanath RK. Cardioprotective activity of silymarin in ischemia-reperfusion-induced myocardial infarction in albino rats. Exp Clin Cardiol 2007; 12: 179-187
• 37 Taghiabadi E, Imenshahidi M, Abnous K. et al. Protective effect of silymarin against acrolein-induced cardiotoxicity in mice. Evidence-based Complement Altern Med 2012; 2012 DOI: 10.1155/2012/352091.
• 38 Sharma B, Chaube U, Patel BM. Beneficial effect of silymarin in pressure overload induced experimental cardiac hypertrophy. Cardiovasc Toxicol 2019; 19: 23-35 DOI: 10.1007/s12012-018-9470-2.
• 39 De La Puerta R, Martinez E, Bravo L. et al. Effect of silymarin on different acute inflammation models and on leukocyte migration. J Pharm Pharmacol 1996; 48: 968-970 DOI: 10.1111/j.2042-7158.1996.tb06014.x.
• 40 Juma’a KM, Ahmed ZA, Numan IT. et al. Dose-dependent anti-inflammatory effect of silymarin in experimental animal model of chronic inflammation. African J Pharm Pharmacol 2009; 3: 242-247
• 41 Choi YH, Jin GY, Guo HS. et al. Silibinin attenuates allergic airway inflammation in mice. Biochem Biophys Res Commun 2012; 427: 450-455 DOI: 10.1016/j.bbrc.2012.07.112.
• 42 Won DH, Kim LH, Jang B. et al. In vitro and in vivo anti-cancer activity of silymarin on oral cancer. Tumor Biol 2018; 40: 1-11 DOI: 10.1177/1010428318776170.
• 43 Oufi HG. The cytogenetic effects of silibinin alone and in combination with methotrexate in mouse bone marrow. Eur J Pharmacol 2018; 824: 179-184 DOI: 10.1016/j.ejphar.2018.02.018.
• 44 El-Far M, Salah N, Essam A. et al. Silymarin nanoformulation as potential anticancer agent in experimental Ehrlich ascites carcinoma-bearing animals. Nanomedicine 2018; 13: 1865-1888 DOI: 10.2217/nnm-2017-0394.
• 45 Wu T, Liu W, Guo W. et al. Silymarin suppressed lung cancer growth in mice via inhibiting myeloid-derived suppressor cells. Biomed Pharmacother 2016; 81: 460-467 DOI: 10.1016/j.biopha.2016.04.039.
• 46 Iqbal B, Ali J, Ganguli M. et al. Silymarin-loaded nanostructured lipid carrier gel for the treatment of skin cancer. Nanomedicine 2019; 14: 1077-1093 DOI: 10.2217/nnm-2018-0235.
• 47 Choi ES, Oh S, Jang B. et al. Silymarin and its active component silibinin act as novel therapeutic alternatives for salivary gland cancer by targeting the ERK1/2-Bim signaling cascade. Cell Oncol 2017; 40: 235-246 DOI: 10.1007/s13402-017-0318-8.
• 48 Eo HJ, Park GH, Song HM. et al. Silymarin induces cyclin D1 proteasomal degradation via its phosphorylation of threonine-286 in human colorectal cancer cells. Int Immunopharmacol 2015; 24: 1-6 DOI: 10.1016/j.intimp.2014.11.009.
• 49 Faezizadeh Z, Mesbah-Namin SAR, Allameh A. The effect of silymarin on telomerase activity in the human leukemia cell line K562. Planta Med 2012; 78: 899-902 DOI: 10.1055/s-0031-1298464.
• 50 Gioti K, Papachristodoulou A, Benaki D. et al. Silymarin Enriched Extract (Silybum marianum) Additive Effect on Doxorubicin-Mediated Cytotoxicity in PC-3 Prostate Cancer Cells. Planta Med 2019; 85: 997-1007 DOI: 10.1055/a-0954-6704.
• 51 Hajighasemlou S, Farajollahi M, Alebouyeh M. et al. Study of the effect of silymarin on viability of breast cancer cell lines. Adv Breast Cancer Res 2014; 03: 100-105 DOI: 10.4236/abcr.2014.33015.
• 52 Kim SH, Choo GS, Yoo ES. et al. Silymarin induces inhibition of growth and apoptosis through modulation of the MAPK signaling pathway in AGS human gastric cancer cells. Oncol Rep 2019; 42: 1904-1914 DOI: 10.3892/or.2019.7295.
• 53 Li W, Mu D, Song L. et al. Molecular mechanism of silymarin-induced apoptosis in a highly metastatic lung cancer cell line Anip973. Cancer Biother Radiopharm 2011; 26: 317-324 DOI: 10.1089/cbr.2010.0892.
• 54 Mombeini M, Saki G, Khorsandi L. et al. Effects of silymarin-loaded nanoparticles on HT-29 human colon cancer cells. Med 2018; 54: 1-9 DOI: 10.3390/medicina54010001.
• 55 Snima KS, Arunkumar P, Jayakumar R. et al. Silymarin encapsulated Poly(D,L-lactic-co-glycolic acid) nanoparticles: A prospective candidate for prostate cancer therapy. J Biomed Nanotechnol 2014; 10: 559-570 DOI: 10.1166/jbn.2014.1735.
• 56 Vaid M, Prasad R, Sun Q. et al. Silymarin targets β-Catenin signaling in blocking migration/invasion of human melanoma cells. PLoS One 2011; 6 DOI: 10.1371/journal.pone.0023000.
• 57 Yu HC, Chen LJ, Cheng KC. et al. Silymarin inhibits cervical cancer cell through an increase of phosphatase and tensin homolog. Phyther Res 2012; 26: 709-715 DOI: 10.1002/ptr.3618.
• 58 Fan L, Ma Y, Liu Y. et al. Silymarin induces cell cycle arrest and apoptosis in ovarian cancer cells. Eur J Pharmacol 2014; 743: 79-88 DOI: 10.1016/j.ejphar.2014.09.019.
• 59 Janeczko M, Kochanowicz E. Silymarin, a popular dietary supplement shows anti–Candida activity. Antibiotics 2019; 8 DOI: 10.3390/antibiotics8040206.
• 60 Yun DG, Lee DG. Silymarin exerts antifungal effects via membrane-targeted mode of action by increasing permeability and inducing oxidative stress. Biochim Biophys Acta - Biomembr 2017; 1859: 467-474 DOI: 10.1016/j.bbamem.2017.01.009.
• 61 Mina PR, Kumar Y, Verma AK. et al. Silymarin, a polyphenolic flavonoid impede Plasmodium falciparum growth through interaction with heme. Nat Prod Res 2020; 34: 2647-2651 DOI: 10.1080/14786419.2018.1548449.
• 62 Evren E, Yurtcu E. In vitro effects on biofilm viability and antibacterial and antiadherent activities of silymarin. Folia Microbiol (Praha) 2015; 60: 351-356 DOI: 10.1007/s12223-015-0399-6.
• 63 Camini FC, da Silva TF, da Silva Caetano CC. et al. Antiviral activity of silymarin against Mayaro virus and protective effect in virus-induced oxidative stress. Antiviral Res 2018; 158: 8-12 DOI: 10.1016/j.antiviral.2018.07.023.
• 64 de Oliveira akell DR, Tintino eliso SR, Braga MF. et al. In vitro antimicrobial and modulatory activity of the natural products silymarin and silibinin. Biomed Res Int 2015; 2015: 292797 DOI: 10.1155/2015/292797.
• 65 Di Pierro F, Callegari A, Carotenuto D. et al. Clinical efficacy, safety and tolerability of BIO-C® (micronized Silymarin) as a galactagogue. Acta Biomed l’Ateneo Parm 2008; 79: 205-210
• 66 Fallahzadeh MK, Dormanesh B, Sagheb MM. et al. Effect of addition of silymarin to renin-angiotensin system inhibitors on proteinuria in type 2 diabetic patients with overt nephropathy: A randomized, double-blind, placebo-controlled trial. Am J Kidney Dis 2012; 60: 896-903 DOI: 10.1053/j.ajkd.2012.06.005.
• 67 Hawke RL, Schrieber SJ, Soule TA. et al. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol 2010; 50: 434-449 DOI: 10.1177/0091270009347475.
• 68 Luangchosiri C, Thakkinstian A, Chitphuk S. et al. A double-blinded randomized controlled trial of silymarin for the prevention of antituberculosis drug-induced liver injury. BMC Complement Altern Med 2015; 15: 1-7 DOI: 10.1186/s12906-015-0861-7.
• 69 Momeni A, Hajigholami A, Geshnizjani S. et al. Effect of silymarin in the prevention of cisplatin nephrotoxicity, a clinical trial study. J Clin Diagnostic Res 2015; 9: OC11-OC13 DOI: 10.7860/JCDR/2015/12776.5789.
• 70 Valentová K, Vidlář A, Zatloukalová M. et al. Biosafety and antioxidant effects of a beverage containing silymarin and arginine. A pilot, human intervention cross-over trial. Food Chem Toxicol 2013; 56: 178-183 DOI: 10.1016/j.fct.2013.02.023.
• 71 Rastegarpanah M, Malekzadeh R, Vahedi H. et al. A randomized, double blinded, placebo-controlled clinical trial of silymarin in ulcerative colitis. Chin J Integr Med 2015; 21: 902-906 DOI: 10.1007/s11655-012-1026-x.
• 72 Chan W, Raihan N, Mustapha N. et al. AC. Clin Gastroenterol Hepatol. 2017 DOI: 10.1016/j.cgh.2017.04.016
• 73 El-Kamary SS, Shardell MD, Abdel-Hamid M. et al. A randomized controlled trial to assess the safety and efficacy of silymarin on symptoms, signs and biomarkers of acute hepatitis. Phytomedicine 2009; 16: 391-400 DOI: 10.1016/j.phymed.2009.02.002.
• 74 Hosseini S, Elyasi S, Niazi Moghadam MR. et al. 371P Effect of oral silymarin administration on prevention of radiotherapy induced mucositis: A randomized, double-blinded, placebo-controlled clinical trial. Ann Oncol 2016; 27 DOI: 10.1093/annonc/mdw587.013.
• 75 Karbasforooshan H, Hosseini S, Elyasi S. et al. Topical silymarin administration for prevention of acute radiodermatitis in breast cancer patients: A randomized, double-blind, placebo-controlled clinical trial. Phyther Res 2019; 33: 379-386 DOI: 10.1002/ptr.6231.
• 76 Elyasi S, Shojaee FSR, Allahyari A. et al. Topical Silymarin Administration for Prevention of Capecitabine-Induced Hand–Foot Syndrome: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. Phyther Res 2017; 31: 1323-1329 DOI: 10.1002/ptr.5857.
• 77 Ghosh A, Biswas S, Ghosh T. Preparation and evaluation of silymarin β-cyclodextrin molecular inclusion complexes. J Young Pharm 2011; 3: 205-210 DOI: 10.4103/0975-1483.83759.
• 78 Nagi A, Iqbal B, Kumar S. et al. Quality by design based silymarin nanoemulsion for enhancement of oral bioavailability. Elsevier Ltd; 2017. DOI: 10.1016/j.jddst.2017.05.019
• 79 Mady FM, Essa H, El-ammawi T. Formulation and clinical evaluation of silymarin pluronic-lecithin organogels for treatment of atopic dermatitis. 2016; 1101-1110
• 80 Singh P, Singh M, Kanoujia J. et al. Process optimization and photostability of silymarin nanostructured lipid carriers : effect on UV-irradiated rat skin and SK-MEL 2 cell line. Drug Deliv Transl Res 2016; DOI: 10.1007/s13346-016-0317-8.
• 81 Yang KY, Hwang DH, Yousaf AM. et al. Silymarin-loaded solid nanoparticles provide excellent hepatic protection: Physicochemical characterization and in vivo evaluation. Int J Nanomedicine 2013; 8: 3333-3343 DOI: 10.2147/IJN.S50683.
• 82 Sharma A, Puri V, Kakkar V. et al. Formulation and Evaluation of Silymarin-Loaded Chitosan-Montmorilloite Microbeads for the Potential Treatment of Gastric Ulcers. 2018 DOI: 10.3390/jfb9030052
• 83 Elmowafy M, Viitala T, Ibrahim HM. et al. European Journal of Pharmaceutical Sciences Silymarin loaded liposomes for hepatic targeting : In vitro evaluation and HepG2 drug uptake. Eur J Pharm Sci 2013; 50: 161-171 DOI: 10.1016/j.ejps.2013.06.012.
• 84 El-Nahas AE, Allam AN, El-Kamel AH. Mucoadhesive buccal tablets containing silymarin Eudragit-loaded nanoparticles: formulation, characterisation and ex vivo permeation. J Microencapsul 2017; 34: 463-474 DOI: 10.1080/02652048.2017.1345996.
• 85 Kumar N, Rai A, Reddy ND. et al. Pharmacological Reports Improved in vitro and in vivo hepatoprotective effects of liposomal silymarin in alcohol-induced hepatotoxicity in Wistar rats. Pharmacol Reports 2019; 71: 703-712 DOI: 10.1016/j.pharep.2019.03.013.
• 86 Mohsen AM, Asfour MH, Salama AAA. Improved hepatoprotective activity of silymarin via encapsulation in the novel vesicular nanosystem bilosomes. Drug Dev Ind Pharm 2017; 43: 2043-2054 DOI: 10.1080/03639045.2017.1361968.
• 87 Singh A, Kumar A, Verma RK. et al. Silymarin encapsulated nanoliquid crystals for improved activity against beta amyloid induced cytotoxicity. Int J Biol Macromol 2020; 149: 1198-1206 DOI: 10.1016/j.ijbiomac.2020.02.041.
• 88 Ramadan AA, Elbakry AM, Sarhan HA. et al. Silymarin loaded floating polymer(s) microspheres: Characterization, in-vitro/in-vivo evaluation. Pharm Dev Technol 2020; 25: 1081-1089 DOI: 10.1080/10837450.2020.1795192.
• 89 Faezizadeh Z, Gharib A, Godarzee M. In-vitroand in-vivo evaluation of silymarin nanoliposomes against isolated methicillin-resistant Staphylococcus aureus. Iran J Pharm Res 2015; 14: 627-633 DOI: 10.22037/ijpr.2015.1660.
• 90 Chang L, Hou M, Tsai T. Silymarin in liposome and ethosome on pharmacokinetics and tissue distribution in free-moving rats by HPLC-MS/MS. 2014 DOI: 10.1021/jf504139g
• 91 El-Ridy MS, Badawi AA, Safar MM. et al. Niosomes as a novel pharmaceutical formulation encapsulating the hepatoprotective drug silymarin. Int J Pharm Pharm Sci 2012; 4: 549-559