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 ra t liver with N-nitrosomorpholine is preceded by different types of pre neoplastic foci consisting of phenotypically altered hepatocytes. The altered cells show changes in the activities of various enzymes includ ing those of carbohydrate metabolism. Glucokinase is a type of hexokin ase that is specific for hepatocytes. The enzyme plays a key role in g lucose homeostasis in normal liver parenchyma and is replaced in the d edifferentiated hepatocytes of carcinomas by a low K(m) hexokinase. To determine the time course of the shift from glucokinase to this isoen zyme in the development of carcinomas, focal hepatic lesions were diss ected from freeze-dried serial tissue sections by the laser-dissection method and studied by microbiochemical tests. In early clear and acid ophilic cell foci that excessively stored glycogen (glycogenotic foci) a nearly normal glucokinase activity comparable with that of the surr ounding hepatocytes was observed, whereas in the later appearing mixed cell foci a reduction in the activity of this enzyme without a compen satory increase in the hexokinase activity was found. pronounced activ ity of hexokinase was only measurable in fully developed carcinomas. S ince glucokinase is not modified at the post-transcriptional level, a gradual decrease in its mRNA during hepatocarcinogenesis can be assume d. A shift in gene expression from glucokinase to the isoenzyme hexoki nase occurs only at the mixed cell foci/carcinoma transition step of t he carcinogenic process.