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Enzymes Related to Glutamine Metabolism in Tumor-bearing Rats¹

( Department of Internal Medicine, The University of Michigan, Ann Arbor, Michigan)

Glutamine synthetase, glutaminyl- and glutamyl-RNA (ribonucleic acid) synthetase, and -glutamyltranspeptidase activities have been studied in rats bearing minimal deviation hepatomas and other transplantable tumors. The activity of glutamine synthetase remained undiminished in the liver of rats bearing most hepatomas, but it declined in the liver of rats bearing the Murphy-Sturm, Jensen, and Guerin tumors. The enzyme activity in brain of these animals, however, showed no change. With the exception of Morris hepatoma 7800, none of the tumors examined contained significant glutamine synthetase activity. Morris hepatoma 7800 possessed an activity equal to that of normal rat liver. Further investigations showed that the enzyme in this hepatoma resembled that in normal liver.

The reduction of both glutamyl- and glutaminyl-RNA synthetase activities in the liver of rats bearing Morris hepatoma 7800 was less than that in the liver of rats bearing other tumors. Morris hepatoma 7800 also had a glutamyl-RNA synthetase activity approaching that of normal rat liver. No correlation between the activities of these two enzymes in tumors and the rates of growth of the tumors has been observed, however.

-Glutamyltranspeptidase activity declined in kidney, but not in liver and serum, of rats bearing Morris hepatomas. The activity of this enzyme in Morris hepatoma 7800 was like that in normal liver, but that of Morris hepatoma 7316 was lower and that of Novikoff hepatoma was higher. Possession of "normal" glutamine synthetase, glutamyl-RNA synthetase, and -glutamyltranspeptidase activities by Morris hepatoma 7800 marks this hepatoma as the one least deviating from normal liver of any thus far studied.

Determination of free glutamine levels in serum, liver, and tumor shows that the decrease usually occurring in rats bearing fast growing tumors did not take place in rats bearing slow growing hepatomas. Although this observation lends support to the hypothesis that the high glycolytic rate of a tumor causes an exodus of glutamine from normal tissue into the tumor, other factors, such as tumor size, growth rate, and inability of the host's liver to maintain normal glutamine synthetase activity, may contribute equally to the fall of glutamine levels in tissues of the host.

¹ This work was supported in part by a research grant (CA-01719) from the National Cancer Institute, USPHS, and by a grant from the University of Michigan Cancer Research Institute.

Received 12/ 7/64.