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Intracellular Distribution of Radioactivity in Nucleic Acid Nucleotides and Proteins Following Simultaneous Administration of P³² and Glycine-2-C^{14* ,}

( McArdle Memorial Laboratory, The Medical School, University of Wisconsin, Madison 6. Wis.)

1. Glycine-2-C¹⁴ and P³² were simultaneously injected intraperitoneally into normal rats and others bearing multiple Flexner-Jobling carcinoma transplants. The animals were sacrificed after various time intervals, and the livers and tumors were fractionated by differential centrifugation into nuclear, mitochondrial, microsomal, and supernatant fractions. From each fraction the nucleic acids were isolated, hydrolyzed, and the nucleotides were separated by ion-exchange chromatography. The specific activity of the nucleotides with respect to P³² was determined, the purine nucleotides were hydrolyzed, and the C¹⁴ specific activity of the purines was measured.

2. From the data on the acid-soluble phosphorus and uncombined glycine, it was concluded that the metabolic pool sizes of these are similar.

3. At early time intervals the order of decreasing specific activity of both isotopes in the RNA of cell fractions was nuclei, supernatant, microsomes, and mitochondria.

4. At early times the C¹⁴ specific activity of the proteins was highest in the microsomal fraction. The relationship of this finding to those for the RNA has been discussed.

5. The specific activity of the DNA and RNA nucleotides in tumors was higher at all times than in the corresponding liver nucleotides.

6. The specific activities of the P³² and C¹⁴ in the purine nucleotides from DNA were similar, indicating that both precursors are incorporated into some intermediate at the same time.

7. The specific activity of the P³² in the RNA purine nucleotides of normal liver was considerably higher than that of the C¹⁴. This indicates that the phosphorus is incorporated into an intermediate at an earlier time than is the glycine.

8. The total radioactivities in the RNA nucleotides of all cell fractions are directly proportional to the total quantity of the nucleotides present. This suggests that the composition of the nucleic acid determines the amount of synthesis and, further, that the RNA molecule is synthesized as a whole from the component nucleotide precursors.

9. The nucleic acid metabolism of tumors appears to be qualitatively similar, but quantitatively more rapid than that of liver.

10. The systemic effect of a tumor on the metabolism of liver is manifested in an increased specific and total radioactivity of the DNA nucleotides in the livers of tumor-bearing animals as compared to those of normal liver.

11. A tentative scheme of nucleic acid biosynthesis with respect to adenylic acid has been proposed in order to account for these findings. The significance of this tentative scheme has been discussed.

^* This work was supported by a grant from the Wisconsin Section of the American Cancer Society, and by the Alexander and Margaret Stewart Trust Fund.

An abstract of part of this work has been published in Fed. Proc., 11:300, 1952.

Received 11/ 5/52.