Antioxidant and Antiapoptotic Activities of a Tissue-Specific Selective Estrogen Receptor Modulator, Idoxifene, in Rat Fibrotic Liver and Cultured Rat Hepatocytes

Idoxifene is a tissue-specific selective estrogen receptor modulator. Oxidative stress has a causative role in the development of hepatic fibrosis and apoptosis, and the Bcl-2 protein suppresses lipid peroxidation and prevents apoptosis. Although estradiol is a potent endogenous antioxidant, little information is available relative to the beneficial role of idoxifene in the liver. The antioxidant and antiapoptotic activities of idoxifene have been examined using experimental rat fibrotic livers and cultured rat hepatocytes undergoing oxidative stress. Hepatic levels of collagen and malondialdehyde were decreased and hepatic levels of Superoxide dismutase and glutathione peroxidase were increased by the presence of idoxifene and estradiol in the experimental fibrosis model. The antioxidant enzyme response of cultured hepatocytes to oxidative stress was significantly improved by idoxifene in a dose-dependent manner. Idoxifene was also observed to induce Bcl-2 expression in the injured livers and hepatocytes, to have no adverse effects, and to act as an inhibitor early in the apoptotic pathway. In addition, treatment with idoxifene inhibited IκB-α degradation and NF-κB activation with attenuation of hepatocyte oxidative bursts. The hepatoprotective effect of idoxifene was somewhat greater than that observed for the same dose of estradiol. These findings suggest that idoxifene may enhance biological defense activities against oxidative stress and function as a potent antifibrosuppressant by inhibiting lipid peroxidation and preventing early apoptosis in the liver.