LIVER TUMOR PROMOTION IN SPARSE FUR MUTANT MICE

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The long term goal of the present proposal is to determine whether metabolic and genetic disorders that are associated with increased levels of orotic acid are at a higher risk of tumor promotion. The rationale for this stems from our observations: (i) orotic acid, a normal cellular constituent is a multi-organ tumor promoter, (ii) being a precursor of pyrimidine nucleotides, exposure to orotic acid results in increased levels of uridine nucleotides and creation of such an imbalance in nucleotide pools is essential for orotic acid to exert its tumor promoting effect; and (iii) feeding a diet deficient in arginine, a urea cycle amino acid induces disturbances in urea cycle, and such perturbations not only result in increased levels of orotic acid and hepatic uridine nucleotides but also exert tumor promoting effect in the livers of both rats and mice. Sparse fur mutant (spf/y) mice are 90% deficient in ornithine transcarbamylase (OTC) a urea cycle enzyme. This deficiency is associated with high levels of orotic acid and an imbalance in hepatic nucleotide pools. We propose to use these mutant mice as a model system to examine the question whether metabolic and genetic disorders associated with higher levels of orotic acid and uridine nucleotides post increased risk of tumor promotion. In the proposed study, both mutant male mice and the normal counterparts, Swiss ICR male mice will be exposed to liver carcinogens at doses which by themselves do not induce liver cell cancer in the normal mice unless promoted. It is anticipated that initiated sparse fur mutant mice which have higher levels of orotic acid will develop hepatocellular carcinoma even in the absence of any exogenous tumor promoter, while the initiated normal controls will not develop unless exposed to exogenous promoter. In the next series we will determine whether such cancer incidence can be decreased by administering phosphonylacetyl-L-aspartic acid and adenine which inhibit the synthesis of orotic acid and its conversion to uridine nucleotides respectively. This experiment should indicate whether the increased susceptibility of spf/y mice to carcinogen-induced tumorigenesis is because of high levels of orotic acid and the associated imbalance in nucleotide pools or due to some other abnormality associated with the mutant mice.