Hepatocellular glycogenosis and related pattern of enzymatic changes during hepatocarcinogenesis

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Systematic studies of the sequence of cellular changes during hepatocarcinogenesis induced predominantly in rats by stop experiments with N-nitrosomorphine (NNM) led to the following main results and conclusions: 1. 1.|The development of hepatocellular tumors is preceded by a multifocal hepatic glycogen storage disease (glycogenosis). 2. 2.|Cytomorphological and cytochemical findings suggest a sequence of focal changes leading from clear and acidophilic glycogen storage foci through mixed cell foci and neoplastic nodules to hepatocellular carcinomas. The clear and acidophilic glycogen storage cells persisting after withdrawal of the carcinogen apparently represent a preneoplastic cell population, the neoplastic transformation of which is accompanied by a gradual reduction of glycogen and a concomitant increase in ribosomes (basophilia). 3. 3.|The first appearance and frequency of the different liver lesions investigated was shown to depend on the dose of carcinogen administered. With increasing dose of NNM, the number of focal lesionsn considerably increased, and this was accompanied by an earlier development of mixed and basophilic cell populations. There was no indication of any reversibility of pronounced focal lesions under the experimental conditions chosen. On the contrary, the foci became larger and acquired phenotypic markers closer to neoplasia independent of further action of the carinogen. 4. 4.|Enzyme histochemically, the majority of the pronounced glycogen storage foci showed a reduction in the activities of glycogen phosphorylase and glucose-6-phosphatase while the activity of glucose-6-phosphate dehydrogenase, a key enzyme for the pentose phosphate pathway, was increased. The mixed cell foci, neoplastic nodules and carcinomas which emerged at later stages were characterized by a progressive shift away from glycogen metabolism towards glycolysis and the pentose phosphate pathway, as indicated by an increase in glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphate dehdyrogenase activities. These changes in enzyme pattern are in keeping with a developmental sequence leading fromm glycogen storage foci through mixed cell foci and neoplastic nodules to hepatocellular carcinomas. 5. 5.|Biochemical microanalysis of dissected glycogen storage foci and mixed cell foci revealed that the foci composed exclusively of storage cells contained on an average 100% more glycogen than the normal liver tissue. The overall glycogen content of the mixed cell foci, which were composed of both glycogenotic and glycogen-poor basophilic cells, was not distinguishable from that of normal tissue. The activity of the glucose-6-phosphate dehydrogenase showed a clear tendency to higher values in the majority of the small glycogen storage foci. However, in large glycogenetic foci and especially in mixed cell foci the activity of this enzyme was significantly higher than in the normal liver tissue. The data support the concept that hepatocarcinogens induce a focal glycogen storage disease of the liver. In consequence, adaptive enzymatic changes appear to be elicited which gradually redirect the disturbed carbohydrate metabolism towards alternative metabolic pathways.