Inhibitory effects of idoxifene on hepatic fibrosis in rats.

ABSTRACT

AIM: To investigate the effects of a tissue-specific selective estrogen receptor modulator, idoxifene, on hepatic fibrosis in rats. METHODS: Hepatic fibrosis was induced by dimethylnitrosamine (DMN) in male rats. The DMN model of hepatic fibrosis and the hepatocytes undergoing oxidative stress were treated with idoxifene respectively. The effect of idoxifene on hepatic fibrosis in the DMN model was examined by immunohistochemistry. Effects of idoxifene on antioxidant enzyme levels of copper, zinc-dependent superoxide dismutase (CuZn-SOD), and cellular glutathione peroxidase (GSHPx) were measured by ELISA. Effects of idoxifene on activation, proliferation, and apoptosis of culture-activated hepatic stellate cells (HSC) were analysed by immunohistochemistry, bromodeoxyuridine (BrdU) uptake, and flow cytometry, respectively. RESULTS: Idoxifene could markedly suppress DMN-induced hepatic fibrosis in male rats. A treatment of 0.4 mg x kg(-1) x d(-1) of idoxifene reduced the protein levels of collagen in the DMN model by 41.19% (P<0.05). Protein level of CuZn-SOD and activitiy of GSHPx in liver treated with DMN plus 0.4 mg/kg/d of idoxifene were 2.65 times (P<0.05) and 2.08 times greater (P<0.05) than that of liver treated with DMN alone respectively. The protein level of CuZn-SOD and activity of GSHPx in cultured rat hepatocytes treated with ferric nitrilotriacetate (FeNTA) plus 1 multiply 10(-7) mol/L of idoxifene were 3.43 times (P<0.05) and 2.52 times (P<0.05) greater than that treated with FeNTA alone. Idoxifene could inhibit HSC activation. Compared with the control, the uptake of BrdU in HSC cultured with 1 multiply 10(-7) mol/L of idoxifene was reduced by 51.87 % (P<0.05), and the number of apoptotic HSCs cultured with 1 multiply 10(-7) mol/L of idoxifene increased by 94.52% (P<0.05). CONCLUSION: Idoxifene showed inhibitory action on hepatic fibrosis in male rats.