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Role of Acute Hepatic Necrosis in the Induction of Early Steps in Liver Carcinogenesis by Diethylnitrosamine¹

Department of Pathology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Experiments were performed to assess the role of liver cell necrosis in the induction of early steps in liver carcinogenesis with diethylnitrosamine, as measured by the appearance of foci of resistant hepatocytes that stain for -glutamyl transpeptidase and that are presumptive preneoplastic lesions in the rat. With the use of a necrogenic dose of diethylnitrosamine and an assay for the carcinogen-induced early stages or resistant hepatocytes, the number of enzyme-altered foci was decreased to a major extent (up to 62%) by posttreatment with diethyldithiocarbamate, a derivative of disulfiram. Such posttreatment decreased to a large degree (78%) the cumulative labeling index of hepatocytes following an initial exposure to diethylnitrosamine. The performance of partial hepatectomy up to 68 hr after such posttreatment restored the level of the induction of the resistant hepatocytes. Nonnecrogenic doses of diethylnitrosamine or dimethylnitrosamine induced virtually no foci of resistant hepatocytes but did so when coupled with cell proliferation. These results establish clearly an important role for liver cell necrosis in the production of early steps in liver carcinogenesis in one model. The mechanism for this effect appears to be by the induction of compensatory liver cell proliferation.

¹ This research was supported by research grants from the Medical Research Council of Canada (MT-5994), the National Cancer Institute of Canada, and the National Cancer Institute, USPHS United States Department of Health, Education, and Welfare (CA-21157 and CA-23958).

² Recipient of a studentship from the Medical Research Council of Canada. To whom requests for reprints should be addressed.

Received 12/12/79. Accepted 2/13/81.

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