Silymarin, an extract of milk thistle seeds, and silymarin-derived compounds have been considered hepatoprotective since the plant was first described in ancient times. Hepatoprotection is defined as several non-mutually exclusive biological activities including antiviral, antioxidant, anti-inflammatory and immunomodulatory functions. Despite clear evidence for silymarin-induced hepatoprotection in cell culture and animal models, evidence for benefcial effects in humans has been equivocal. This review will summarize the current state of knowledge on silymarin in the context of HCV infection. The information was collated from a recent workshop on silibinin in Germany.
References
1.
RamasamyK., AgarwalR.Multitargeted therapy of cancer by silymarin. Cancer Lett2008; 269: 352–362.
2.
PolyakS.J., MorishimaC., ShuhartM.C., WangC.C., LiuY., LeeD.Y.Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin. Gastroenterology2007; 132: 1925–1936.
3.
WagonerJ., NegashA., KaneO.J.Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology2010; 51: 1912–1921.
4.
FerenciP., ScherzerT.M., KerschnerH.Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology2008; 135: 1561–1567.
5.
BeinhardtS., Rasoul-RockenschaubS., ScherzerT.M., FerenciP.Silibinin monotherapy prevents graft infection after orthotopic liver transplantation in a patient with chronic hepatitis C. J Hepatol2011; 54: 591–592.
6.
EurichD., BahraM., BergT.Treatment of hepatitis C-virus-reinfection after liver transplant with silibinin in nonresponders to pegylated interferon-based therapy. Exp Clin Transplant2011; 9: 1–6.
7.
NeumannU.P., BiermerM., EurichD., NeuhausP., BergT.Successful prevention of hepatitis C virus (HCV) liver graft reinfection by silibinin mono-therapy. J Hepatol2010; 52: 951–952.
8.
HawkeR.L., SchrieberS.J., SouleT.A.Silymarin ascending multiple oral dosing Phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol2010; 50: 434–449.
9.
GrafT.N., WaniM.C., AgarwalR., KrollD.J., OberliesN.H.Gram-scale purification of flavonolignan diastereoisomers from Silybum marianum (milk thistle) extract in support of preclinical in vivo studies for prostate cancer chemoprevention. Planta Med2007; 73: 1495–1501.
10.
KrollD.J., ShawH.S., OberliesN.H.Milk thistle nomenclature: why it matters in cancer research and pharmacokinetic studies. Integr Cancer Ther2007; 6: 110–119.
11.
KiesewetterE., LeodolterI., ThalerH.[Results of two double-blind studies on the effect of silymarine in chronic hepatitis]. Leber Magen Darm1977; 7: 318–323. German.
12.
MarcelliR., BizzoniP., ConteD.Randomized controlled study of the efficacy and tolerability of a short course of IdB 1016 in the treatment of chronic persistent hepatitis. European Bulletin of Drug Research1992; 1: 131–135.
13.
BuzzelliG., MoscarellaS., GiustiA., DuchiniA., MarenaC., LamperticoM.A pilot study on the liver protective effect of silybin-phosphatidylcholine complex (IdB1016) in chronic active hepatitis. Int J Clin Pharmacol Ther Toxicol1993; 31: 456–460.
14.
TanamlyM.D., TadrosF., LabeebS.Randomised double-blinded trial evaluating silymarin for chronic hepatitis C in an Egyptian village: study description and 12-month results. Dig Liver Dis2004; 36: 752–759.
15.
HuberR., FutterI., LudtkeR.Oral silymarin for chronic hepatitis C - a retrospective analysis comparing three dose regimens. Eur J Med Res2005; 10: 68–70.
16.
MelhemA., SternM., ShiboletO.Treatment of chronic hepatitis C virus infection via antioxidants: results of a Phase I clinical trial. J Clin Gastroenterol2005; 39: 737–742.
17.
GordonA., HobbsD.A., BowdenD.S.Effects of Silybum marianum on serum hepatitis C virus RNA, alanine aminotransferase levels and well-being in patients with chronic hepatitis C. J Gastroenterol Hepatol2006; 21: 275–280.
18.
SeeffL.B., CurtoT.M., SzaboG.Herbal product use by persons enrolled in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial. Hepatology2008; 47: 605–612.
19.
FreedmanN.D., CurtoT.M., MorishimaC.Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial. Aliment Pharmacol Ther2011; 33: 127–137.
20.
RutterK., ScherzerT.M., BeinhardtS.Intravenous silibinin as ‘rescue treatment’ for on-treatment non-responders to pegylated interferon/ribavirin combination therapy. Antivir Ther2011; 16: 1327–1333.
21.
BiermerM., SchlosserB., FulopF.High-dose silibinin rescue treatment for HCV-infected patients showing suboptimal virologic response to standard combination therapy. J Viral Hepat2012; 19: 547–553.
22.
Ahmed-BelkacemA., AhnouN., BarbotteL.Silibinin and related compounds are direct inhibitors of hepatitis C virus RNA-dependent RNA polymerase. Gastroenterology2010; 138: 1112–1122.
23.
MorishimaC., ShuhartM.C., WangC.C.Silymarin inhibits in vitro T-cell proliferation and cytokine production in hepatitis C virus infection. Gastroenterology2010; 138: 671–681.
24.
WagonerJ., MorishimaC., GrafT.N.Differential in vitro effects of intravenous versus oral formulations of silibinin on the HCV life cycle and inflammation. PLoS ONE2011; 6: e16464.
25.
GyörgyI., AntusS., BlazovicsA., FoldiakG.Substituent effects in the free radical reactions of silybin: radiation-induced oxidation of the flavonoid at neutral pH. Int J Radiat Biol1992; 61: 603–609.
26.
NeumannA.U., LamN.P., DahariH.Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science1998; 282: 103–107.
27.
DahariH., GuedjJ., PerelsonA.S., LaydenT.J.Hepatitis C viral kinetics in the era of direct acting antiviral agents and IL28B. Curr Hepat Rep2011; 10: 214–227.
28.
GuedjJ., DahariH., PohlR.T., FerenciP., PerelsonA.S.Understanding silibinin's modes of action against HCV using viral kinetic modeling. J Hepatol2012; 56: 1019–1024.
29.
PolyakS.J., MorishimaC., LohmannV.Identification of hepatoprotective flavonolignans from silymarin. Proc Natl Acad Sci U S A2010; 107: 5995–5999.
30.
DahariH., GuedjJ., PerelsonA.S.Silibinin mode of action against hepatitis C virus: a controversy yet to be resolved. Hepatology2011; 54: 749.
31.
SchrieberS.J., HawkeR.L., WenZ.Differences in the disposition of silymarin between patients with nonalcoholic fatty liver disease and chronic hepatitis C. Drug Metab Dispos2011; 39: 2182–2190.
32.
SchrieberS.J., WenZ., VourvahisM.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 Dispos2008; 36: 1909–1916.
33.
WenZ., DumasT.E., SchrieberS.J., HawkeR.L., FriedM.W., SmithP.C.Pharmacokinetics and metabolic profile of free, conjugated, and total silymarin flavonolignans in human plasma after oral administration of milk thistle extract. Drug Metab Dispos2008; 36: 65–72.
34.
WeyhenmeyerR., MascherH., BirkmayerJ.Study on dose-linearity of the pharmacokinetics of silibinin diastereomers using a new stereospecific assay. Int J Clin Pharmacol Ther Toxicol1992; 30: 134–138.
35.
RicklingB., HansB., KramarczykR., KrumbiegelG., WeyhenmeyerR.Two high-performance liquid chromatographic assays for the determination of free and total silibinin diastereomers in plasma using column switching with electrochemical detection and reversed-phase chromatography with ultraviolet detection. J Chromatogr B Biomed Appl1995; 670: 267–277.
36.
GattiG., PeruccaE.Plasma concentrations of free and conjugated silybin after oral intake of a silybin-phosphatidylcholine complex (silipide) in healthy volunteers. Int J Clin Pharmacol Ther1994; 32: 614–617.
37.
LorenzD., LuckerP.W., MennickeW.H., WetzelsbergerN.studies with silymarin in human serum and bile. Methods Find Exp Clin Pharmacol1984; 6: 655–661.
38.
SchrieberS.J., WenZ., VourvahisM.Silymarin pharmacokinetics (PK) is altered in patients with chronic hepatitis C virus (HCV) and nonalcoholic fatty liver disease (NAFLD) and correlates with caspase-3/7 activity. Hepatology2007; 46: 807A.
39.
FlaigT.W., GustafsonD.L., SuL.J.A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients. Invest New Drugs2007; 25: 139–146.
40.
FriedM.W., NavarroV.J., AfdhalN.Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. JAMA2012; 308: 274–282.
41.
ReddyK.R., BelleS.H., FriedM.W.Rationale, challenges, and participants in a Phase II trial of a botanical product for chronic hepatitis C. Clin Trials2012; 9: 102–112.
42.
WuJ.W., LinL.C., TsaiT.H.Drug-drug interactions of silymarin on the perspective of pharmacokinetics. J Ethnopharmacol2009; 121: 185–193.
43.
Esser-NobisK., Romero-BreyI., GantenT.Analysis of hepatitis C virus resistance to Silibinin in vitro and in vivo points to a novel mechanism involving nonstructural protein 4B. Hepatology2013; doi: 10.1002/hep.26260.
44.
McClureJ., LovelaceE.S., ElahiS.Silibinin inhibits HIV-1 infection by reducing cellular activation and proliferation. PLoS ONE2012; 7: e41832.
ComelliM.C., MengsU., SchneiderC., ProsdocimiM.Toward the definition of the mechanism of action of silymarin: activities related to cellular protection from toxic damage induced by chemotherapy. Integr Cancer Ther2007; 6: 120–129.
