The antiestrogen toremifene protects against alcoholic liver injury in female rats

Background/Aims: Females are generally considered to be more susceptible to alcohol-induced liver injury than males. To elucidate whether gonadal hormones are involved, female rats were chronically treated with ethanol and with an antiestrogen. Methods: Ethanol was administered in a low-carbohydrate liquid diet. Estrogen action was blocked by daily intubation of toremifene, a non-hepatotoxic second generation estrogen receptor antagonist. Results: The female rats consuming intoxicating amounts of ethanol diet for 6 weeks developed massive microvesicular/macrovesicular steatosis, frequent inflammatory foci and spotty necrosis. Serum alanine aminotransferase increased 7-fold. Toremifene treatment did not affect steatosis, but significantly reduced inflammation and necrosis. Ethanol increased the expression of CD14 and tumor necrosis factor- (TNF) α mRNA and also the production of TNF-α by isolated Kupffer cells, but toremifene had no significant counteracting effect. However, toremifene significantly alleviated both ethanol induction of the pro-oxidant enzyme CYP2E1 and ethanol reduction of the oxidant-protective enzyme Se-glutathione peroxidase. Conclusions: The partial protection by toremifene against ethanol-induced liver lesions suggests a pathogenic contribution of estrogens, possibly associated with an oxygen radical mediated mechanism.