The antiestrogen toremifene protects against alcoholic liver injury in female rats.
OBJECTIVE
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) 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.


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.
Järveläinen
H A
HA
National Public Health Institute, Alcohol Research Center, Helsinki, Finland.
Lukkari
T A
TA
Heinaro
S
S
Sippel
H
H
Lindros
K O
KO
D000437:Alcoholism / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004798:Enzymes / Q000097:blood; D000431:Ethanol / Q000378:metabolism; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics; D007728:Kupffer Cells / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D012727:Sex Characteristics; D017312:Toremifene / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D004798:Enzymes; D018950:Lipopolysaccharide Receptors; D012333:RNA, Messenger; D020845:Selective Estrogen Receptor Modulators; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000431:Ethanol; D017312:Toremifene; D005979:Glutathione Peroxidase; D019392:Cytochrome P-450 CYP2E1