STUDIES OF TAMOXIFEN AS A PROMOTER OF HEPATOCARCINOGENESIS IN FEMALE FISCHER F344 RATS

Tamoxifen, an antiestrogen used in the treatment of breast cancer, was assessed for carcinogenic potential in the two-stage model of experim ental hepatocarcinogenesis. Groups of female Fischer F344 rats were in itiated with a non-necrogenic, subcarcinogenic dose of diethylnitrosam ine (DEN;10 mg/kg, po) and fed tamoxifen at a concentration of 250 mg per kg of AIN-76A diet for 6 or 15 months. The livers of these animals exhibited an increase in size and number of altered hepatic foci comp ared with those animals which were initiated with DEN but not exposed to tamoxifen. This finding indicates that tamoxifen may have a carcino genic potential in the rat liver. After 6 months of treatment, neoplas tic nodules were observed in 3/8 rats in the DEN-initiated, tamoxifen- treated group. In the initiated group provided with tamoxifen for 15 m onths, neoplastic nodules were observed in 7/8 rats and hepatocellular carcinomas in 3/8 rats. The serum level of tamoxifen in these rats wa s 200-300 ng/ml. The ratio of tamoxifen, 4-hydroxy tamoxifen, and N-de smethyl tamoxifen was 1:0.1:0.5-1 in the serum. When adjusted for age- related weight increases, the serum and liver levels of tamoxifen and its N-desmethyl metabolite did not change over the 15 months. In the r at liver, the level of tamoxifen and its N-desmethyl metabolite was 10 -29 mu g/g liver after 6 or 15 months of chronic dietary administratio n. The ratio of tamoxifen:4-hydroxy tamoxifen:N-desmethyl tamoxifen wa s 1:0.1:1.3-2.3 in the liver. Therefore, the liver had 20- to 30-fold more tamoxifen and 4-hydroxy tamoxifen and at least 100-fold more N-de smethyl tamoxifen than the serum (assuming 1 gram of tissue is equival ent to 1 ml of serum). These results indicate that tamoxifen is a prom oting agent for the rat liver at serum levels found in patients given the usual therapeutic course of tamoxifen. The high concentrations of tamoxifen attained in the rat liver indicate that actions other than i ts known estrogenicity for liver could contribute to its promoting act ion. In addition, these results indicate that the pharmacodynamic diff erences in tamoxifen metabolism in rats and humans and at low versus h igh doses should be determined. Thus, the therapeutic indications for tamoxifen should be balanced by the potential risk it may present as a promoting agent in mammalian liver.