COMPARISON OF THE EFFECTS OF TAMOXIFEN AND TOREMIFENE ON LIVER AND KIDNEY TUMOR PROMOTION IN FEMALE RATS

Female rats were subjected to a 70% partial hepatectomy and administer ed either diethylnitrosamine (10 mg/kg) or the solvent, trioctanoin, A fter a 2 day recovery from the surgery, the rats were placed on basal diet alone or containing phenobarbital (500 mg/kg diet), mestranol (0. 2 mg/kg diet), tamoxifen (250 or 500 mg/kg diet) or toremifene (250, 5 00 or 750 mg/kg diet) for 6 or 18 months prior to killing, The livers and kidneys were prepared for pathological diagnoses. In addition, sec tions of liver from the 6 month killing were frozen and serially secti oned, The sections were stained for expression of the placental isozym e of glutathione S-transferase (GST), gamma glutamyl transpeptidase (G GT), canalicular ATPase (ATP) and glucose 6-phosphatase (G6P) and scor ed by quantitative stereology for number and volume fraction of liver occupied by altered hepatic foci (AHF) with alterations in these marke rs individually and combined (ANY), Each of the agents increased the v olume fraction of liver occupied by AHF when the ANY category was used , Statistical increases in both the GGT-positive and G6P-deficient AHF populations were observed in the spontaneously as well as DEN-initiat ed groups treated with tamoxifen or toremifene, After 18 months of adm inistration, the highest concentration of tamoxifen increased the inci dence of malignant hepatic neoplasms in non-DEN-initiated rats, Toremi fene, at the highest tested dose, increased the incidence of hepatocel lular carcinomas in the DEN-initiated groups to a level one-third that observed with tamoxifen administration to DEN-initiated rats, Both ta moxifen and toremifene increased the incidence of hypernephromas in pr eviously DEN-initiated rats, While both tamoxifen and toremifene are e ffective promoting agents for DEN-initiated lesions, tamoxifen is more potent than toremifene in the induction of rat hepatocarcinogenesis.