Inhibitory Effect of Tamoxifen on Diethylstilbestrol‐promoted Hepatic Tumorigenesis in Male Rats and Its Possible Mechanism of Action

Male Sprague‐Dawley rats were given a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg body weight). Two weeks later the rats were divided into 4 groups; DEN‐C group rats were given no further treatment; DEN‐DES group rats were fed diethylstilbestrol (DES, 0.5 mg/day); DEN‐TMX group rats were given tamoxifen (TMX, 1.0 mg/ day) orally; DEN‐DES TMX group rats were fed both DES and TMX for 8 months. Rats of the DEN‐DES group developed grossly visible hepatic tumors. On the other hand, tumor development was significantly inhibited in rats of the DEN‐DES TMX group. Total area of γ‐glutamyl transpeptidase‐positive lesions and the mean area per lesion were significantly larger in rats of the DEN‐DES group than those of the DEN‐C, DEN‐TMX or DEN‐DES TMX group. Estrogen receptor (ER) content of liver cytosol assayed by enzyme immunoassay (EIA) was significantly greater in rats of the DEN‐DES group than in those of the DEN‐C group and smaller in rats of the DEN‐TMX and DEN‐DES TMX group than in the DEN‐C group. On the contrary, ER content of liver nuclei was significantly greater in rats of the DEN‐TMX and DEN‐DES TMX group than in those of the DEN‐C or DEN‐DES group. These results suggest that the promotive action of DES and the inhibitory action of TMX on DES‐promoted hepatic tumorigenesis are, at least in part, mediated by ER in the rat.