Silibinin and Related Compounds Are Direct Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase

Research Team Pathophysiology and Therapy of Chronic Viral Hepatitis, INSERM U955, Créteil, France.
Gastroenterology (Impact Factor: 16.72). 12/2009; 138(3):1112-22. DOI: 10.1053/j.gastro.2009.11.053
Source: PubMed


Silymarin is a mixture of flavonolignans extracted from the milk thistle. Silymarin contains several molecules, including silibinin A, silibinin B, isosilibinin A, isosilibinin B, silicristin, and silidianin. Intravenous infusion of silibinin induces dose-dependent reduction of hepatitis C virus (HCV) RNA levels. The aim of this study was to test the principal isomers contained in silymarin preparations for their ability to inhibit HCV enzymatic functions and replication in different models.
The inhibitory activity of silymarin components was tested in HCV RNA-dependent RNA polymerase and NS3/4A protease enzyme assays. Their ability to inhibit replication of an HCV genotype 1b replicon model and the JFH1 infectious HCV model in cell culture was also studied.
Silibinin A, silibinin B, their water-soluble dihydrogen succinate forms and Legalon SIL, a commercially available intravenous preparation of silibinin, inhibited HCV RNA-dependent RNA polymerase function, with inhibitory concentrations 50% of the order of 75-100 microM. Silibinin A and silibinin B also inhibited HCV genotype 1b replicon replication and HCV genotype 2a strain JFH1 replication in cell culture. None of these compounds inhibited HCV protease function.
Silibinin A and silibinin B, as well as Legalon SIL, inhibit HCV replicon and JFH1 replication in cell culture. This effect is at least partly explained by the ability of these compounds to inhibit HCV RNA-dependent RNA polymerase activity. Our results provide a basis for the optimization and subsequent development of members of the Flavonoid family as specific HCV antivirals.

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    • "Ferenci et al. [13] reported that daily intravenous administration of soluble silibinin in previous peginterferon nonresponders inhibits HCV viral loads by three to four logs within one to two weeks. Silibinin is the major compound of silymarin and consists of two flavonolignans silybin A and silybin B; their water-soluble dihydrogen succinate forms inhibited HCV polymerase function with IC50s ranging from 75 μM to 100 μM [37]. In contrast to phenyl-benzopyrone structure, silymarin is relatively hydrophobic; thus, silymarin may act by incorporating into lipid membranes of both viruses and target cells or may at least display partition into lipid bilayers similar to other plant flavonoids. "
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    ABSTRACT: Objective: This study aimed to evaluate the efficacy and safety of silymarin on chronic hepatitis C virus- (HCV-) infected patients. Methods: Randomized controlled trials (RCTs) of silymarin in chronic HCV-infected patients up to April 1, 2014 were systematically identified in PubMed, Ovid, Web of Science, and Cochrane Library databases. Results: A total of 222 and 167 patients in five RCTs were randomly treated with silymarin (or intravenous silibinin) and placebo, respectively. Serum HCV RNA relatively decreased in patients treated with silymarin compared with those administered with placebo, but no significance was found (P = 0.09). Meta-analysis of patients orally treated with silymarin indicated that the changes of HCV RNA are similar in the two groups (P = 0.19). The effect on alanine aminotransferase (ALT) of oral silymarin is not different from that of placebo (P = 0.45). Improvements in quality-of-life (Short Form-36) in both silymarin and placebo recipients were impressive but relatively identical (P = 0.09). Conclusion: Silymarin is well tolerated in chronic HCV-infected patients. However, no evidence of salutary effects of oral silymarin has yet been reported based on intermediate endpoints (ALT and HCV RNA) in this population. Moreover, intravenous administration of silymarin should be further studied.
    BioMed Research International 08/2014; 2014:941085. DOI:10.1155/2014/941085 · 2.71 Impact Factor
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    • "[137] Cell culture and ex vivo models. [129] Increased Akt Phosphorylation Isosilybin B — prostate cancer cell culture models. [118] Decreased Akt phosphorylation Isosilybin A — prostate cancer cell culture models. "
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    ABSTRACT: Silymarin, a standardised extract of Silybum marianum (milk thistle), comprises mainly of silybin, with dehydrosilybin (DHSB), quercetin, taxifolin, silychristin and a number of other compounds which are known to possess a range of salutary effects. Indeed, there is evidence for their role in reducing tumour growth, preventing liver toxicity, and protecting a number of organs against ischemic damage. The hepatoprotective effects of silymarin, especially in preventing amanita and alchohol intoxication induced damage to the liver, are a well established fact. Likewise, there is weighty evidence that silymarin possesses antimicrobial and anticancer activity. Additionally, it has emerged that in animal models, silymarin can protect the heart, brain, liver and kidneys against ischemia reperfusion injury, probably by preconditioning. The mechanisms of preconditioning are, in general, well studied, especially in the heart. On the other hand, the mechanism by which silymarin protects the heart from ischemia remains largely unexplored. This review, therefore, focuses on evaluating existing studies on silymarin induced cardioprotection in the context of the established mechanisms of preconditioning.
    Fitoterapia 05/2014; 97. DOI:10.1016/j.fitote.2014.05.016 · 2.35 Impact Factor
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    • "[137] Cell culture and ex vivo models. [129] Increased Akt Phosphorylation Isosilybin B — prostate cancer cell culture models. [118] Decreased Akt phosphorylation Isosilybin A — prostate cancer cell culture models. "
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    Fitoterapia 01/2014; · 2.35 Impact Factor
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