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The Resistance of Putative Premalignant Liver Cell Populations, Hyperplastic Nodules, to the Acute Cytotoxic Effects of Some Hepatocarcinogens¹

Fels Research Institute [E. F., S. P., M. G.], and the Departments of Biochemistry and Pathology [E. F.], Temple University School of Medicine, Philadelphia, Pennsylvania 19140

The hypothesis that liver carcinogenesis may have as an important facet the early selection of carcinogen-resistant cells was tested in animals in which putative premalignant hepatocyte populations, hyperplastic nodules, were induced by 2-acetylaminofluorene or by ethionine. Hyperplastic nodules were observed to be resistant to the acute necrogenic effects of 2 hepatotoxins, CCI₄ and dimethylnitrosamine, under conditions in which liver cell necrosis occurred in the liver surrounding the nodules. In addition, although [methyl-³H]dimethylnitrosamine was taken up to an equal degree in nodules and normal liver, the interactions with DNA, RNA, and protein in hyperplastic nodules were found to be about 50% less than in control liver. Hyperplastic nodules showed a marked decrease in uptake of [9-¹⁴C]-2-acetylaminofluorene, a finding that could account for the large decrease in labeling of DNA, RNA, and protein by [9-¹⁴C]-2-acetylaminofluorene observed in the nodules. The results are consistent with and support the hypothesis that new hepatocyte populations that appear prior to cancer, during liver carcinogenesis, have as an important biological property a resistance to the cytotoxic effect of hepatocarcinogens. The basis for this resistance might be a decrease in uptake and/or a reduction in the level of activation of carcinogens.

¹ This research was supported in part by Grants CA-12218, CA-12227, and AM-14882 from the NIH, Grant BC-7N from the American Cancer Society, and by Contract N01-CP-33262 from the National Cancer Institute.

² American Cancer Society Research Professor (1970–1974). Present address: Department of Pathology, University of Toronto, 100 College Street, Toronto, Ontario, Canada. To whom requests for reprints should be addressed.

Received 5/10/76. Accepted 7/14/76.