Hepatoprotective effect of oral application of a silymarin extract in carbon tetrachloride-induced hepatotoxicity in rats

Abstract

Silymarin derived from the milk thistle plant “Silybum marianum” is composed of four major flavonolignans. Clinical as well as experimental studies indicate hepatoprotective effects of silymarin. However, the underlying mechanisms are only incompletely understood. The aim of this study was to assess the effect of oral administration of a defined silymarin extract in the model of acute carbon tetrachloride (CCl4) induced liver injury. A single dose of a silymarin extract (SE; 20 or 100 mg/kg body weight) was given to rats by oral gavage. Subsequently, rats were injected with a single dose of CCl4 (2 ml/kg body weight). After 24h, analysis of liver to body weight ratio, serum levels of transaminases and histological analysis revealed a marked liver damage which was inhibited by SE in a dose dependent manner. CCl4-induced expressions of pro-inflammatory and pro-fibrogenic genes were significantly reduced in SE treated rats. Molecular analysis revealed that SE reduced the expression of the pro-inflammatory chemokine MCP-1, the pro-fibrogenic cytokine TGF-beta as well as collagen I in isolated human hepatic stellate cells (HSC), which are the key effector cells of hepatic fibrosis. Oral administration of the tested silymarin extract inhibited hepatocellular damage in a model of acute liver injury. Moreover, we newly found that the silymarin extract had direct effects on pro-inflammatory and pro-fibrogenic gene expression in HSCs in vitro. This indicates that direct effects on HSC also contribute to the in vivo hepatoprotective effects of silymarin, and further promote its potential as anti-fibrogenic agent also in chronic liver disease.