Induction of resistant hepatocytes as a new principle for a possible short-term in vivo test for carcinogens.

The induction of resistant hepatocytes in vivo in the rat has been observed with 21 different chemical carcinogens. The resistance was measured by the ability of the cells to proliferate as focal lesions in the presence of an environment that inhibits the original or surrounding hepatocytes from proliferation. This was created by a dietary 2-acetylaminofluorene plus a stimulus for cell proliferation, a single necrogenic dose of CCl4. The foci were readily visualized by staining for gamma-glutamyl transpeptidase activity. With most of the chemicals, a single administration at an appropriate time after partial hepatectomy is efficacious. However, with safrole and dieldrin, three doses over a 36-hr period were required to induce a significant number of foci of resistant hepatocytes. The presumptive preneoplastic nature of the resistant hepatocytes and the possible usefulness of this approach for the development of a new in vivo short-term test system for carcinogens are discussed.