Effect of Chronic Administration of Mestranol, Tamoxifen, and Toremifene on Hepatic Ploidy in Rats

• Published in: Toxicological sciences 1998-06, Vol.43 (2), p.129-138
• Main Authors: Dragan, Y.P., Shimel, R.J., Bahnub, N., Sattler, G., Vaughan, J.R., Jordan, V.C., Pitot, H.C.
• Format: Article
• Language: English
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1006/toxs.1998.2464

The nonsteroidal antiestrogen tamoxifen increases the incidence of rat liver cancer through a variety of mechanisms. Tocompare the effects of tamoxifen (TAM) and a structurallysimilar analog toremifene (TOR) on rat liver, we determinedthe ploidy distribution for hepatocytes isolated from rats treated for 18 months with these antiestrogens or the estrogenic compound mestranol (MS). Female Sprague-Dawley rats were subjected to a 70% partial hepatectomy and administered the solvent, trioctanoin, or diethylnitrosamine (10 mg DEN/kg). After a 2-week recovery from the surgery, the rats were administered a basal diet or one containing TAM (250 or 500 ppm), TOR (250, 500, or 750 ppm), or MS (0.2 ppm) for 18 months.Pathologic changes in the liver were examined in the 15–22 rats per treatment group at the 18-month time point. An increased incidence of hepatocellular carcinomas (HCC) was detected in the 500 ppm TAM group, but not with the other treatmentsthat did not include DEN. Both TOR and TAM promoted formation of DEN-initiated HCCs. At sacrifice, four to five rats per group were perfused and the hepatocytes isolated and cultured. Karyotypic analysis was performed on colcemid-blocked cells after 2 days in culture. The hepatic ploidy distribution was characterized in Giemsa-stained metaphase spreads. These studies indicated that chronic treatment with TAM alone resulted in a shift from tetraploid to diploid, as was also observed for rats treated once with DEN. TOR and MS alone did not cause this change in hepatic ploidy at the doses examined. A shift toward an increased content of diploid hepatocytes occurred in all rats treated once with DEN followed by TAM, TOR, or MS. These results indicate that tamoxifen administration results in a shift toward growth of diploid hepatocytes, thus contributing to its carcinogenic action in the rat liver.