toremifene and Alcoholism

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.. 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.. 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) alpha mRNA and also the production of TNF-alpha 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.. The partial protection by toremifene against ethanol-induced liver lesions suggests a pathogenic contribution of estrogens, possibly associated with an oxygen radical mediated mechanism.

Topics: Alcoholism; Animals; Cells, Cultured; Cytochrome P-450 CYP2E1; Enzymes; Ethanol; Female; Glutathione Peroxidase; Interleukin-10; Kupffer Cells; Lipopolysaccharide Receptors; Liver; Liver Diseases, Alcoholic; Rats; Rats, Wistar; RNA, Messenger; Selective Estrogen Receptor Modulators; Sex Characteristics; Toremifene; Tumor Necrosis Factor-alpha