Silymarin Milk Thistle Extract May Inhibit Hepatitis C Virus Entry into Cells

SUMMARY: Silymarin, an extract from the milk thistle plant, has an inhibitory effect on the hepatitis C virus (HCV) polymerase in laboratory studies, but its anti-HCV action also appears to include blocking HCV from entering cells and preventing cell-to-cell transmission, according to research described in the June 2010 issue of Hepatology.

Milk thistle (Silybum marianum) has an extensive history of use as a remedy for liver problems in both Eastern and Western traditional medicine. Silymarin is a flavonoid comprised of a mix of milk thistle components including silibinin. Most silymarin studies have looked at its effect on liver fibrosis, but in recent years researchers have studied its direct activity against HCV in the laboratory and in vivo.

A survey of participants in the HALT-C trial -- which evaluated the benefits of long-term pegylated interferon for patients who did not respond to standard treatment with pegylated interferon plus ribavirin -- found that participants who said they used silymarin did not have lower HCV viral load on average than non-users. Another recent study, however, showed that silymarin inhibited activity of the HCV polymerase, which copies viral genetic material as part of replication.

In the present study, Jessica Wagoner from the University of Washington in Seattle and colleagues further characterized the antiviral action of silymarin in the laboratory.

Results

• Silymarin had antiviral effects against HCV in cell cultures, including inhibition of virus entry into cells, HCV RNA and protein expression, and production of infectious virus particles.
• Silymarin did not block HCV binding to cells, but did inhibit entry of viral pseudoparticles and fusion of HCV pseudoparticles with liposomes, or fat bubbles.
• Silymarin -- but not silibinin -- inhibited activity of the HCV genotype 2a NS5B RNA-dependent RNA polymerase at concentrations 5-10 times higher than required for an anti-HCV effect in cell culture.
• Silymarin had only minimal activity against genotype 1b isolate BK and 4 genotype 1b polymerases derived from HCV-infected patients, however.
• Silymarin did not inhibit HCV replication in 5 independent genotype 1a, 1b, and 2a replicon model cell lines that did not produce infectious virus.
• Silymarin inhibited microsomal triglyceride transfer protein activity, apolipoprotein B secretion, and infectious virion production in cell culture medium.
• Silymarin also blocked cell-to-cell spread of HCV. 

Based on these findings, the study authors concluded, "Although inhibition of in vitro NS5B polymerase activity is demonstrable, the mechanisms of silymarin's antiviral action appear to include blocking of virus entry and transmission, possibly by targeting the host cell."

Investigator affiliations: Departments of Laboratory Medicine, Microbiology, and Global Health, University of Washington, Seattle, WA; Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA; Department of Pediatrics, University of Texas Medical Branch, Galveston, TX; School of Medicine, University of Texas Southwestern Medical Center, Dallas, TX; Hepatitis C Virus Research Group, Institute of Biomedical Research, University of Birmingham, Birmingham, UK; Institut de Biologie et Chimie des Protéines, Université Lyon 1, IFR128 Lyon Biosciences Gerland, CNRS-Universite Claude Bernard, Lyon, France; Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC; Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO.

8/20/10

Reference
J Wagoner, A Negash, OJ Kane, and others. Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology 51(6): 1912-1921 (Abstract). June 2010.

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