Effects of 2-acetylaminofluorene on liver cell proliferation after partial hepatectomy of female rats.

The effect of the hepatocarcinogen 2-acetylaminofluorene (AAF) on liver regeneration in female Sprague-Dawley rats was studied. While livers of normal female rats were highly resistant to this carcinogen, partial hepatectomy of female animals maintained on diet containing 0.04% AAF disclosed a marked hepatotoxicity which resulted in abnormal, nodular regeneration. The incorporation of thymidine-3H into DNA and the mitotic index were markedly inhibited in livers of AAF-treated animals following partial hepatectomy. Cell proliferation in control rats began to increase at 18 hr after partial hepatectomy, reached a maximum at 48 hr, and returned to normal by the 7th day. In contrast, cell proliferation in animals maintained on AAF for 3 weeks increased at a much lower rate at 18 hr after partial hepatectomy and continued to increase slowly for 2 weeks. Regeneration in AAF-treated rats was not uniform but occurred at discrete foci which led to a nodular regeneration. Sham operation had no effect on liver cell proliferation in animals maintained on AAF. Female rats were fed 0.02 or 0.04% AAF for 3 weeks, subjected to partial hepatectomy, and then maintained on AAF for an additional 28 weeks. These animals developed adenocarcinoma of the mammary gland and ear duct, but no hepatocellular carcinoma was observed. Thus, the failure of the hyperplastic liver nodules to progress to the stage of carcinoma indicates a requirement for some other factor in addition to cell division for tumor induction in livers of female rats.