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Responsiveness of Glutamine-metabolizing Enzymes in Morris Hepatomas to Metabolic Modulations¹

Departments of Biological Chemistry and Internal Medicine, The University of Michigan Medical School, Ann Arbor, Michigan 48104, and Department of Biochemistry, College of Medicine, Howard University, Washington, D. C. 20001

The activities of glutamine synthetase, glutamine aminotransferase, and transglutaminase have been assayed in a number of hepatomas. No correlation exists between any of the enzyme activities and the growth rate, the chromosome number, or the degree of differentiation of the hepatomas. Glutamine synthetase activity declined with successive transplantations in some hepatoma lines. Adrenalectomy lowered the enzyme activity in young rat liver, and cortisol administration raised it. In adult rat liver, such manipulations had little effect on the enzyme activity. Moreover, the responsiveness of glutamine synthetase in several hepatoma lines to adrenalectomy and cortisol treatment far exceeded that in young rat liver. Cortisol elevated glutamine synthetase activity 14-fold in Hepatoma 7800 grown in intact rats and 20-fold in the same hepatoma grown in adrenalectomized rats. The hormone, however, did not affect the enzyme activity in the host livers of either group. Similar differences in response to cortisol between the enzyme in other hepatomas and that in the host livers have been observed. The induction of glutamine synthetase by cortisol does not appear to arise from an increase in tissue amino acid concentration following the hormonal treatment. In addition, thyroxine enhanced glutamine aminotransferase activity in the 2 hepatoma lines studied but not in the host livers. The action of both cortisol and thyroxine was blocked by actinomycin D when given together with the hormone. However, actinomycin D was devoid of its blocking effect when given after glutamine synthetase had been fully induced by cortisol. Under none of the conditions did the antibiotic affect the enzyme in the host livers. Furthermore, glutamine synthetase in Hepatomas 9618A, 8999, and 7800 also showed a greater sensitivity to protein or amino acid content of the diet than did the enzyme in the host livers.

Thus, a series of metabolic modulations (adrenalectomy, administration of cortisol and thyroxine, treatment with actinomycin D, and ingestion of low- and high-protein diets) has demonstrated the responsiveness of the enzymes in several hepatomas and the lack of it in the host livers. We suggest that overresponsiveness by some enzymes in these hepatomas is a manifestation of deranged control mechanisms for synthesis of the enzymes in cells that have reacquired the type of regulation prevailing in liver of the animal during the early period of life.

¹ This study was supported in part by Grant AM-07319 from the National Institute of Arthritis and Metabolic Diseases, and by Grant CA-10729 from the National Cancer Institute, USPHS.

Received 3/ 5/70. Accepted 7/14/70.