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Glucose-ATP Phosphotransferases During Hepatocarcinogenesis¹

(The Fels Research Institute and the Department of Chemistry, Temple University School of Medicine; The Institute for Cancer Research, Philadelphia, Pennsylvania; and the Laboratory of Biochemistry, The National Cancer Institute, Bethesda, Maryland)

The 2 glucose-ATP phosphotransferases normally present in rat liver were assayed in the "preneoplastic" liver of azo dye-fed rats, in regenerated liver, in primary cholangio- and hepatocarcinomas resulting from azo dye feeding, and in a series of transplantable rat hepatomas. In the "preneoplastic" liver there was a progressive rise in hexokinase, the low glucose K_m enzyme, to levels 5 to 6 times higher than normal and to a 5-fold lowering of glucokinase, the high glucose K_m enzyme, during an 11-week period of feeding 3'-methyl-dimethylaminoazobenzene (3'-Me-DAB) in an otherwise normal diet. These changes were correlated with bile duct cell proliferation and marked decreases in parenchymal cells. No marked changes were found in regenerated rat liver after partial hepatectomy, except for an early small increase in hexokinase and lowering of glucokinase during the first 4 days after hepatectomy.

All but one of 4 cholangiocarcinomas that developed after dimethylaminoazobenzene (DAB) feeding had no glucokinase and all had high hexokinase activities, whereas 3 out of 5 hepatocarcinomas had moderate glucokinase and all had moderate hexokinase activities. Of 8 hepatocarcinomas or mixed hepatocholangiocarcinomas that developed on 3'-Me-DAB feeding, 4 had zero or borderline glucokinase activity, and 4 had moderate glucokinase activity. All 8 had moderate to high hexokinase activity.

Of 10 transplantable liver tumors ranging widely in transplant generation and in growth rate, 8 had zero or borderline glucokinase and low to high hexokinase activities. Two tumors had low but significant glucokinase activity. One of these, the Morris 3683 hepatoma, had a very high hexokinase activity and a rapid growth rate; the other, the 7794A, grew slowly and had a moderate hexokinase activity. One tumor, studied in the 3d and 4th transplant generations, a highly differentiated and extremely slow-growing hepatocarcinoma, the Morris 7787, had a low hexokinase and a moderate-to-high glucokinase activity; this is the only tumor found thus far that has a phosphotransferase pattern similar to that of normal rat liver. The presence or absence of the two hepatic glucose-ATP phosphotransferases cannot be correlated with the histologic type of either primary or transplantable liver tumors, though cholangiocarcinomas are likely to contain no glucokinase.

¹ This work was supported by grants AM-05487 and CA-07174 from the National Institutes of Health; and Grants P119 and P202 from the American Cancer Society.

² Part of a thesis to be submitted by Rajani Manjeshwar Sharma to the Graduate Council of Temple University in partial fulfillment of the requirements for the M.A. Degree.

Received 8/19/64.