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 andadministered either diethylnitrosamine (10 mg/kg) or the solvent,trioctanoin. After a 2 day recovery from the surgery, the ratswere placed on basal diet alone or containing phenobarbital(500 mg/kg diet), mestranol (0.2 mg/kg diet), tamoxifen (250or 500 mg/kg diet) or toremifene (250, 500 or 750 mg/kg diet)for 6 or 18 months prior to killing. The livers and kidneyswere prepared for pathological diagnoses. In addition, sectionsof liver from the 6 month killing were frozen and serially sectioned.The sections were stained for expression of the placental isozymeof glutathione S-transferase (GST), gamma glutamyl transpeptidase(GGT), canalicular ATPase (ATP) and glucose 6-phosphatase (G6P)and scored by quantitative stereology for number and volumefraction of liver occupied by altered hepatic foci (AHF) withalterations in these markers individually and combined (ANY).Each of the agents increased the volume fraction of liver occupiedby AHF when the ANY category was used. Statistical increasesin both the GGT-positive and G6P-deficient AHF populations wereobserved in the spontaneously as well as DEN-initiated groupstreated with tamoxifen or toremifene. After 18 months of administration,the highest concentration of tamoxifen increased the incidenceof malignant hepatic neoplasms in non-DEN-initiated rats. Toremifene,at the highest tested dose, increased the incidence of hepatocellularcarcinomas in the DEN-initiated groups to a level one-thirdthat observed with tamoxifen administration to DEN-initiatedrats. Both tamoxifen and toremifene increased the incidenceof hypernephromas in previously DEN-initiated rats. While bothtamoxifen and toremifene are effective promoting agents forDEN-initiated lesions, tamoxifen is more potent than toremifenein the induction of rat hepatocarcinogenesis.