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Inability of Mitogen-induced Liver Hyperplasia to Support the Induction of Enzyme-altered Islands Induced by Liver Carcinogens¹

Istituto di Farmacologia e Patologia Biochimica, Universita di Cagliari, 09100 Cagliari, Italy [A. C., G. M. L-C.] and Department of Pathology, Medical Sciences Building, University of Toronto, Toronto, Ontario M5S 1A8, Canada [G. L., S. R., D. S. R. S.]

Experiments were designed to determine whether liver cell proliferation induced by direct mitogens is as effective as compensatory cell proliferation consequent to previous cell loss, in supporting the growth of enzyme-altered islands in the liver induced by chemical carcinogens. Male Wistar rats were given injections of a single nonnecrogenic dose of N-methyl-N-nitrosourea or benzo(a)pyrene during the S phase following the administration of four different liver mitogens, namely, lead nitrate, ethylene dibromide, nafenopin, and cyproterone acetate, or during compensatory cell proliferation following partial hepatectomy or a necrogenic dose of CCl₄. The carcinogen-altered hepatocytes were monitored as -glutamyltransferase- or placental glutathione S-transferase-positive foci using a 2-wk promoting regimen consisting of 0.03% 2-acetylaminofluorene coupled with a necrogenic dose of CCl₄. The results indicate that, unlike compensatory cell proliferation induced by partial hepatectomy or CCl₄, the mitogen-induced cell proliferation did not result in a significant number of enzyme-altered islands, despite the fact that the extent of cell proliferation at the time of carcinogen administration, as monitored by the examination of labeled cells, is similar with both types of proliferative stimuli.

¹ This investigation was supported by funds from USPHS Research Grants CA 23958 from the National Cancer Institute, C.N.R. (Medicina Preventiva e Riabilitativa No. 85.00509.56), Italy, and NATO (85/0184).

² To whom requests for reprints should be addressed, at Istituto di Farmacologia e Patologia Biochimica, Universita di Cagliari, Via Porcell 4, 09100 Cagliari, Italy.

Received 12/ 1/86. Revised 3/31/87. Revised 7/17/87. Accepted 7/22/87.

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