Antifibrotic effects of tetrandrine on hepatic stellate cells and rats with liver fibrosis.

Abstract

BACKGROUND:

Anti-inflammation strategies are one of the proposed therapeutic approaches to hepatic fibrosis. Tetrandrine (C(38)H(42)O(8)N(2), molecular weight: 622; Tet), an alkaloid isolated from the Chinese medicinal herb Stephania tetrandra, has been shown to exert anti-inflammatory activity in pulmonary diseases. The purpose of the present study was to investigate the in vitro and in vivo effects of Tet on hepatic fibrosis.

METHODS:

A cell line of rat hepatic stellate cells (HSC-T6) was stimulated with transforming growth factor-beta1 (TGF-beta1) or tumor necrosis factor-alpha (TNF-alpha). The inhibitory effects of Tet on the nuclear factor kappaB (NFkappaB) signaling cascade and molecular markers including intercellular adhesion molecule-1 (ICAM-1) and alpha-smooth muscle actin (alpha-SMA) secretion were assessed. Fibrosis was induced by dimethylnitrosamine (DMN) administration in rats for 4 weeks. Fibrotic rats were randomly assigned to one of the four groups: vehicle (0.7% carboxyl methyl cellulose, CMC), Tet (1 mg/kg), Tet (5 mg/kg), or silymarin (50 mg/kg), each given by gavage twice daily for 3 weeks starting after 1 week of DMN administration. At the end of the study, liver tissues were scored for fibrosis and analyzed for molecular markers of fibrosis.

RESULTS:

Tetrandrine (0.5-5.0 micromol/L) concentration-dependently inhibited NFkappaB transcriptional activity induced by TNF-alpha, including IkappaBalpha phosphorylation and mRNA expressions of ICAM-1 in HSC-T6 cells. In addition, Tet also inhibited TGF-beta1-induced alpha-SMA secretion and collagen deposition in HSC-T6 cells. Fibrosis scores of livers from DMN-treated rats with high-dose Tet (1.3 +/- 0.3) were significantly reduced in comparison with DMN-treated rats receiving saline (2.0 +/- 0.2). Hepatic collagen content of DMN rats was significantly reduced by either Tet or silymarin treatment. Double-staining results showed that alpha-SMA- and NFkappaB-positive cells were decreased in the fibrotic livers by Tet and silymarin treatment. In addition, mRNA expression of ICAM-1, alpha-SMA, and TGF-beta1 was attenuated by Tet treatment. Moreover, levels of plasma aspartate aminotransferase and alanine aminotransferase activities were reduced by Tet and silymarin treatment.

CONCLUSION:

Tetrandrine exerts antifibrotic effects in both HSC-T6 cells and in rats with DMN-induced fibrosis.

• Authors: Yi-Chao Hsu, Yung-Tsung Chiu, Ching-Chang Cheng, Ching-Fen Wu, Yun-Lian Lin, Yi-Tsau Huang
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 22 Issue 1 Pg. 99-111 (Jan 2007) ISSN: 0815-9319 [Print] Australia
• PMID: 17201889 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Alkaloids
• Benzylisoquinolines
• Transforming Growth Factor beta1
• Tumor Necrosis Factor-alpha
• Intercellular Adhesion Molecule-1
• tetrandrine
• Dimethylnitrosamine

Topics

• Actins (metabolism)
• Alkaloids (pharmacology)
• Analysis of Variance
• Animals
• Benzylisoquinolines (pharmacology)
• Blotting, Western
• Cell Line
• Dimethylnitrosamine (pharmacology)
• Fibrosis (pathology)
• Intercellular Adhesion Molecule-1 (metabolism)
• Liver Cirrhosis, Experimental (drug therapy)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction
• Statistics, Nonparametric
• Transforming Growth Factor beta1 (pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)