Cell proliferation and tumour promotion by ethinyl estradiol in rat hepatocarcinogenesis

A two-stage model of hepatocarcinogenesis is used to study the effect of exposure time to ethinyl estradiol (EE) on promotion of preneoplastic lesions in rat liver induced by diethylnitrosamine (DEN). Young male and female Sprague-Dawley rats initiated by a single dose of DEN (100 mg/kg) were subjected to different times of EE administration incorporated into the diet at 10 p.p.m. (0.5 mg/kg x day). Animals were killed 1 year after initiation. Whereas macroscopic tumours were rarely seen in animals with short exposure (3 or 4 months) or in only-initiated controls, all the animals under a long period of administration (8 months) showed macroscopic tumours. Morphometric studies on glutathione-S-transferase (GST) positive preneoplastic lesions revealed an increase in the mean size of foci and nodules corresponding to 8 months of treatment, whereas no changes were observed between animals with short exposure and only-initiated controls. No differences were seen in the incidence of these lesions between any of the protocols. In addition to an acute hyperplastic effect on non-initiated liver described earlier, our preliminary results suggest cytotoxicity and an enhancement of the liver cell turnover after several months of continuous EE administration. These results taken together suggest that promotion of hepatocarcinogenesis by EE largely depends on the time of exposure to the compound and that chronic effects on the liver cell turnover may play an important role in its ability to promote hepatocarcinogenesis.