ISOENZYME SHIFT FROM GLUCOKINASE TO HEXOKINASE IS NOT AN EARLY BUT A LATE EVENT IN HEPATOCARCINOGENESIS

The appearance of hepatocellular adenomas and carcinomas induced in rat liver with N-nitrosomorpholine is preceded by different types of preneoplastic foci consisting of phenotypically altered hepatocytes. The altered cells show changes in the activities of various enzymes including those of carbohydrate metabolism. Glucokinase is a type of hexokinase that is specific for hepatocytes. The enzyme plays a key role in glucose homeostasis in normal liver parenchyma and is replaced in the dedifferentiated hepatocytes of carcinomas by a low K(m) hexokinase. To determine the time course of the shift from glucokinase to this isoenzyme in the development of carcinomas, focal hepatic lesions were dissected from freeze-dried serial tissue sections by the laser-dissection method and studied by microbiochemical tests. In early clear and acidophilic cell foci that excessively stored glycogen (glycogenotic foci) a nearly normal glucokinase activity comparable with that of the surrounding hepatocytes was observed, whereas in the later appearing mixed cell foci a reduction in the activity of this enzyme without a compensatory increase in the hexokinase activity was found. pronounced activity of hexokinase was only measurable in fully developed carcinomas. Since glucokinase is not modified at the post-transcriptional level, a gradual decrease in its mRNA during hepatocarcinogenesis can be assumed. A shift in gene expression from glucokinase to the isoenzyme hexokinase occurs only at the mixed cell foci/carcinoma transition step of the carcinogenic process.