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 experimental hepatocarcinogenesis. Groups of female Fisher F344 rats were initiated with a non-necrogenic, subcarcinogenic dose of diethylnitrosamine (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 compared with those animals which were initiated with DEN but not exposed to tamoxifen. This finding indicates that tamoxifen may have a carcinogenic potential in the rat liver. After 6 months of treatment, neoplastic nodules were observed in 3/8 rats in the DEN-initiated, tamoxifen-treated group. In the initiated group provided with tamoxifen for 15 months, neoplastic nodules were observed in 7/8 rats and hepatocellular carcinomas in 3/8 rats. The serum level of tamoxifen in these rats was 200-300 ng/ml. The ratio of tamoxifen, 4-hydroxy tamoxifen, and N-desmethyl 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 rat liver, the level of tamoxifen and its N-desmethyl metabolite was 10-29 micrograms/g liver after 6 or 15 months of chronic dietary administration. The ratio of tamoxifen:4-hydroxy tamoxifen:N-desmethyl tamoxifen was 1:0.1.3-3.3 in the liver. Therefore, the liver had 20- to 30-fold more tamoxifen and 4-hydroxy tamoxifen and at least 100-fold more N-desmethyl tamoxifen than the serum (assuming 1 gram of tissue is equivalent to 1 ml of serum). These results indicate that tamoxifen is a promoting 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 its known estrogenicity for liver could contribute to its promoting action. In addition, these results indicate that the pharmacodynamic differences in tamoxifen metabolism in rats and humans and at low versus high 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.
Dragan
Y P
YP
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison 53706.
Fahey
S
S
Street
K
K
Vaughan
J
J
Jordan
V C
VC
Pitot
H C
HC
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004032:Diet; D004052:Diethylnitrosamine / Q000633:toxicity*; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D013997:Time Factors
D002273:Carcinogens; D013629:Tamoxifen; C016601:afimoxifene; D004052:Diethylnitrosamine; C028787:N-desmethyltamoxifen