Gastroenterology

Gastroenterology

Volume 132, Issue 5, May 2007, Pages 1925-1936
Gastroenterology

Basic–liver, pancreas, and biliary tract
Inhibition of T-Cell Inflammatory Cytokines, Hepatocyte NF-κB Signaling, and HCV Infection by Standardized Silymarin

https://doi.org/10.1053/j.gastro.2007.02.038Get rights and content

Background & Aims: Chronic hepatitis C is a serious global medical problem necessitating effective treatment. Because standard of care with pegylated interferon plus ribavirin therapy is costly, has significant side effects, and fails to cure about half of all infections, many patients seek complementary and alternative medicine to improve their health, such as Silymarin, derived from milk thistle (Silybum marianum). Milk thistle’s clinical benefits for chronic hepatitis C are unsettled due to variability in standardization of the herbal product. Methods: In the current study, we focused on the anti-inflammatory and antiviral properties of a standardized Silymarin extract (MK-001). Results: MK-001 inhibited expression of tumor necrosis factor-alpha in anti-CD3 stimulated human peripheral blood mononuclear cells and nuclear factor kappa B-dependent transcription in human hepatoma Huh7 cells. Moreover, MK-001 dose dependently inhibited infection of Huh7 and Huh7.5.1 cells by JFH-1 virus. MK-001 displayed both prophylactic and therapeutic effects against HCV infection, and when combined with interferon-α, inhibited HCV replication more than interferon-α alone. Commercial preparations of Silymarin also displayed antiviral activity, although the effects were not as potent as MK-001. Antiviral effects of the extract were attributable in part to induction of Stat1 phosphorylation, while interferon-independent mechanisms were suggested when the extract was biochemically fractionated by high-performance liquid chromatography. Silybin A, silybin B, and isosilybin A, isosilybin B elicited the strongest anti-NF-κB and anti-HCV actions. These effects were independent of MK-001-induced cytotoxicity. Conclusions: The data indicate that Silymarin exerts anti-inflammatory and antiviral effects, and suggest that complementary and alternative medicine-based approaches may assist in the management of patients with chronic hepatitis C.

Section snippets

Patients

Overall, 3 of the 6 subjects were male, and the median age was 42.5 years (range, 37–52). Four of 6 subjects were HCV-infected (all genotype 1, median HCV RNA level 11,891,922 IU/mL (range, 402,708–46,573,010). Liver biopsy data were available on 3 HCV-infected subjects. The necroinflammatory activity (grade) and degree of fibrosis (stage) of the liver disease were scored semiquantitatively, each on a scale of 0–4, using the Batts and Ludwig method.42 All had at least grade 1 inflammation.

MK-001: A Standardized Extract of Silymarin

Biologic authentication of milk thistle is based on macroscopic and microscopic examinations of the plant by light and electronic microscopy, followed by chemical authentication by high-performance liquid chromatograph and/or liquid chromatograph-mass spectrometry fingerprinting. Using these methods, a standardized preparation of Silymarin, called MK-001, was recently developed.22 MK-001 contains the highest content (92%) of flavonolignans and every component (>2%) in MK-001 has been completely

Discussion

Despite global use, the detailed molecular mechanisms of Silymarin-induced hepatoprotection are not known. In the current report, we show for the first time that a rigorously standardized Silymarin (MK-001) displayed anti-inflammatory actions via inhibition of NF-κB induced transcription in human liver cell cultures, inhibition of inflammatory cytokine induction in human PBMC, and direct antiviral effects against HCV infection. Thus, our data are in accord with the view that Silymarin is

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    The authors of this study have no conflicts of interest to disclose.

    1

    D. Y. W.–L. is supported in part by NIH-STTR grant (R42-AT-00766) to Natural Pharmacia International Inc.

    2

    S. J. P. is partially supported by NIH Grants R01 DK 62187 and U19 AI 66328 from NIDDK and NIAID, respectively.

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