Prolonged ornithine decarboxylase induction in regenerating carcinogen-treated liver

A cascade of events leading to hypertrophy has been proposed and implicated in growth regulation in a variety of normal and neoplastic cells and tissues. There is a tightly coupled temporal sequence: (a) cyclic adenosine 3':5'-monophosphate-dependent protein kinase (cAPK) activation; (b) ornithine decarboxylase (ODC) induction; and (c) the accumulation of the organic cation, spermidine, resulting in an increased spermidine/spermine ratio characteristic of both normal and neoplastic growth. The specific activation of type I cAPK has been implicated to ODC induction, and the amounts of type I and type II cAPK alter as a function of growth and transformation. Therefore, we wished to study the alterations in these biochemical parameters as well as that of a putative marker of preneoplastic hepatocytes, gamma-glutamyltranspeptidase, in a rapid multistep hepatocarcinogenesis system. We found a marked and prolonged increase in the cAPK ratio followed by a similar pattern of ODC induction after a single carcinogenic dose of diethylnitrosamine and again in response to partial hepatectomy. Liver foci were detectable within four days of partial hepatectomy in animals that received the entire carcinogen regimen, and the foci contained significant and increasing amounts of gamma-glutamyltranspeptidase activity. The increase in ODC activity was followed closely by an increased spermidine/spermine ratio. Total type I activity in the cytosol decreased most dramatically at the time of foci formation, suggestive of selective activation and turnover. These data suggest that the prolonged activation of cAPK and elevation of ODC may be necessary for hepatocarcinogenesis.