Comparison of the effects of tamoxifen and toremifene on liver and kidney tumor promotion in female rats

Abstract

Female rats were subjected to a 70% partial hepatectomy and administered either diethylnitrosamine (10 mg/kg) or the solvent, trioctanoin. After 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, 500 or 750 mg/kg diet) for 6 or 18 months prior to killing. The liver and kidneys were prepared for pathological diagnoses. In addition, sections of liver from the 6 month killing were frozen and serially sectioned. The sections were stained for expression of the placental isozyme of glutathione S-transferase (GST), gamma glutamyl transpeptidase (GGT), canalicular ATPase (ATP) and glucose 6-phosphatase (G6P) and scored by quantitative stereology for number and volume fraction of liver occupied by altered hepatic foci (AHF) with alterations in these markers individually and combined (ANY). Each of the agents increased the volume 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-initiated groups treated with tamoxifen or toremifene. After 18 months of administration, the highest concentration of tamoxifen increased the incidence of malignant hepatic neoplasms in non-DEN-initiated rats. Toremifene, at the highest tested dose, increased the incidence of hepatocellular carcinomas in the DEN-initiated groups to a level one-third that observed with tamoxifen administration to DEN-initiated rats. Both tamoxifen and toremifene increased the incidence of hypernephromas in previously DEN-initiated rats. While both tamoxifen and toremifene are effective promoting agents for DEN-initiated lesions, tamoxifen is more potent than toremifene in the induction of rat hepatocarcinogenesis.

Tamoxifen inhibits acidification in cells independent of the estrogen receptor

“…Other studies suggest that tamoxifen may enhance the effects of the carcinogen diethylnitrosamine (57). Many environmental toxins are weak bases.…”

Hepatocellular Alterations after Intraportal Transplantation of Ovarian Tissue in Ovariectomized Rats

“…However, this interpretation is limited by the finding that the antiestrogen tamoxifen, which has been used in these experiments, has genotoxic potential and exerts hepatocarcinogenic effects in rats. 11,15 We wanted to investigate the long-term effects of natural Supported by the Deutsche Forschungsgemeinschaft (grants DO 622/1-1 and DO 622/1-3). …”

Hepatocellular neoplasms after intrahepatic transplantation of ovarian fragments into ovariectomized rats†

“…Like tamoxifen, toremifene acts predominantly antiestrogenically, mainly by blocking the estrogen receptor (normally expressed in the FAH; data not shown), but toremifene, in contrast to tamoxifen, has no tumorigenic potential on the liver. [30][31][32][33][34] Toremifene-induced tumor prevention not only highlights the contribution of the estrogen receptor, but clarifies that other secretory products of the ovarian grafts, such as progesterone or ␣-inhibin, although possibly modulating estrogen effects, are not the primary triggers of carcinogenesis. The molecular events that are important for carcinogenesis in the complex intracellular network related to estradiol action have yet to be investigated.…”