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Isotope Studies on the Pathways of Glucose-6-phosphate Metabolism in the Novikoff Hepatoma^*

James Ashmore, George Weber and Bernard R. Landau

( Department of Biological Chemistry, Harvard Medical School, Boston, Mass., and the Montreal Cancer Institute, Research Laboratories, Notre Dame Hospital, Montreal, Canada)

The metabolism of glucose-6-phosphate in normal rat liver and Novikoff hepatoma slices was studied by utilization of glucose-1-C¹⁴ and glucose-6-C¹⁴. The tissue slices were incubated in two different media: a high-sodium and a high-potassium medium. Glucose uptake was determined, and balance sheets were drawn up by determining glycogen, lactic acid, fatty acid, and CO₂. Results were expressed on wet weight basis and per average cell.

1. Liver and hepatoma were similar in ionic response in two respects: (a) Liver and hepatoma slices exhibited less glycogen breakdown in the high-potassium medium than in the highsodium medium. (b) Both liver and hepatoma slices showed a greater lactic acid production in the sodium medium. On the other hand, hepatoma slices exhibited greater glucose uptake in the high-sodium medium than in the high-potassium medium, which was the opposite of what was seen in the liver.

2. When glucose metabolism of the hepatoma slices was expressed on a per cell basis, it was noted that the glucose uptake was 58 per cent and the incorporation of glucose-C¹⁴ into glycogen was only 6 per cent of that of the liver. Glucose oxidation in the hepatoma was unchanged relative to glucose uptake but represented only 58 per cent of the amount oxidized by the liver. The incorporation of C¹⁴ from glucose into fatty acids was reduced to 11 per cent, while conversion of glucose to lactic acid was increased to fourfold of the liver values.

3. The review of the four pathways of glucose-6-phosphate utilization in the hepatoma showed complete absence (glucose release) or nearly complete abolition (glycogen synthesis) of two pathways. On the other hand, the hexose monophosphate shunt (as calculated on the basis of CO₂, lactate, and fatty acid data) appeared to be present, and the lactic acid production was markedly increased. These data are essentially in line with the previously obtained enzymatic indications of the alterations of glucose-6-phosphate metabolism in the neoplastic liver.

^* Supported in part by the United States Atomic Energy Commission and Swift & Co. This work was performed at Harvard Medical School. Preliminary reports on this study were given at the meeting of the Canad. Physiol. Soc., Oct. 10–12, 1957 (Rev. Can. Biol., 16:524, 1957) and at the meeting of the Am. Assoc. for Cancer Research, April 11–13, 1958 (Proc. Am. Assoc. Cancer Research, 2:277, 1958).

U. S. Public Health Service Postdoctorate Fellow in Biological Chemistry.

The following abbreviations are employed in this paper: G-6-P = glucose-6-phosphate; G-6-Pase = glucose-6-phosphatase; FDPase = fructose-1,6-diphosphatase; TCA = trichloroacetic acid.

Received 5/13/58.