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Carbamyl Phosphate Synthetases in Rat Liver Neoplasms¹

The Fels Research Institute and Department of Biochemistry, Temple University School of Medicine, Philadelphia, 19140 [D.L., W.K.P., S.W.], and the Department of Biochemistry, Howard University, Washington, D. C. 20001 [H. P. M.]

Isozymes of carbamyl phosphate synthetase (CPS), CPS I, a mitochondrial enzyme found exclusively in liver and involved in urea synthesis, and of CPS II, a soluble cytoplasmic enzyme widely distributed in animal tissues, were assayed in rat liver and in a series of rat liver neoplasms ranging widely in growth rate and degree of differentiation. CPS I was absent from fast-growing, poorly differentiated hepatomas, such as the Novikoff hepatoma and Morris hepatomas 3924A and 9098F, but was present in slow-growing, well- and highly differentiated Morris hepatomas. However, there was no close correlation between the growth rate or degree of differentiation and the CPS I activity. Activity was very high, at levels comparable with normal liver at about 9 units/g, in slow-growing hepatomas 21, 47C, and 28A but was very low in other slow-growing, highly differentiated hepatomas 9618A, 66, and 16. CPS II activity was present in normal liver and all hepatomas examined, but with very low activity, of the order of 1% or less of that of CPS I activity, with maximal values at 5 to 70 milliunits/g. Again, there was no clear correlation with growth rate; the activity was lowest in fast-growing, poorly differentiated hepatomas.

A striking observation was a marked lowering of CPS I activity in livers of rats bearing large, slow-growing tumors that have high CPS I activity. As the tumors grew larger and the liver CPS I decreased, a relatively constant total CPS I activity was maintained, suggesting the existence of a homeostatic mechanism. The effect was not observed in rats bearing either fast-growing hepatomas or slow-growing hepatomas with low CPS I activity and was not due to some specific nutritional effects of the tumor on the host.

¹ This work was supported by Grants AM-09603, HD-05874, CA-10439, CA-12227, CA-10729, and CA-10916 from the NIH and Grant 74-BC from the American Cancer Society. Additional aid was received from an Institutional Grant from the American Cancer Society (IN-88). This work will be included in a thesis to be presented by Daniel Lawson to the Graduate Council of Temple University in partial fulfillment of the requirements of the Ph.D. degree.

Received 7/ 8/74. Accepted 10/ 8/74.