Studies on Metabolic Perturbations and Tumor Promotion: Glycine Induces the Synthesis of Orotic Acid, a Tumor Promoter and the Expression of Certain Cell Cycle Dependent Genes
Recently we have demonstrated that orotic acid (OA), a normal cellular constituent is an efficient promoter of liver carcinogenesis in the rat1–4. Being a precursor of pyrimidine nucleotides, feeding OA results in an increased synthesis of uridine nucleotides in the liver. This increase in uridine nucleotides is associated with a decrease in adenine nucleotides thereby creating an imbalance in the nucleotide pool. It was hypothesized that creation of such an imbalance in the nucleotide pool is an important factor in the mechanism by which OA exerts its promoting effect4,5. One of the significant aspects of this hypothesis is that since each cell has its own nucleotide pool pattern geared to its needs, disruption of this pattern could be one mechanism to achieve promotion in a variety of organs. Indeed OA has been shown to promote carcinogenesis in the duodenum initiated by azoxymethane6.
KeywordsRibonucleotide Reductase Orotic Acid Nucleotide Pool Liver Carcinogenesis Ornithine Transcarbamylase
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- 5.P. M. Rao, S. Vasudevan, E. Laconi, S. Rajalakshmi and D. S. R. Sarma, Imbalances of pyrimidine and purine nucleotides and their implications in liver carcinogenesis, in: “Nutritional Diseases: Research Directions in Comparative Pathobiology”, D. Scarpeli and G. Migaki, eds., Alan R. Liss. Inc., New York (1986).Google Scholar
- 6.P. M. Rao, E. Laconi, S. Rajalakshmi and D. S. R. Sarma, Orotic acid, a liver tumor promoter also promotes carcinogenesis in the intestine, Proc. Am. Assoc. Cancer Res. 27:142 (1986).Google Scholar
- 10.C. L. Krumdieck, Role of folate deficiency in carcinogenesis, in: “Nutrition Factors in the Induction and Maintenance of Malignancy”, C. S. Butteworth and M. L. Hutchinson, eds., Bristol Myers Nutrition Symposium 2, Academic Press, New York (1983).Google Scholar
- 11.S. Vasudevan, E. Laconi, S. E. Abanobi, P. M. Rao, S. Rajalakshmi and D. S. R. Sarma, Regulation of synthesis of orotic acid (OA), a liver tumor promoter, induced by amino acids, Fed. Proc. 44:1339 (1985).Google Scholar
- 12.S. Vasudevan, E. Laconi, P. M. Rao, S. Rajalakshmi and D. S. R. Sarma, Interrelationship between ornithine decarboxylase (ODC) and orotic acid (OA) synthesis induced by amino acids, Fed. Proc. 46:753 (1987).Google Scholar
- 17.R. Baserga, “The Biology of Cell Reproduction”, Harvard University Press, Cambridge, MA, (1985).Google Scholar
- 18.J. Short, N. B. Armstrong, M. A. Kolitsky, R. A. Mitchell, R. Zemel and I. Liberman, Amino acids and the control of nuclear DNA replication in the liver, in: “Control of Proliferation in Animal Cells”, B. Clarkson and R. Baserga, eds., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1974).Google Scholar
- 25.T. Maniatis, E. F. Fritisch and J. Sambrook, “Molecular Cloning: A Laboratory Manual”, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1982).Google Scholar
- 28.New England Nuclear, Boston. “Gene Screen Instruction Manual”, Catalogue No. NEF-972.Google Scholar