The objective of the research program is to establish the extent to which dietary modification can result in a nucleotide imbalance which might result in the misincorporation of uracil into DNA and thereby initiate or promote carcinogenesis. Increased synthesis of pyrimidine ribonucleotides and decreased synthesis of purine ribonucleotides has been observed in rat liver on a diet high in orotate or deficient in arginine. The tissue specificity of this effect is being studied in rats and mice. The extent to which deoxyribonucleotide levels are changed will be investigated with particular emphasis on the metabolism of dUTP. Dietary influence on the activity of hydrolases for dUTP and on uracil- DNA glycosylase will be examined to determine if there is an adaptive response in these enzymes. The influence of a high orotate diet and an arginine-deficient diet on the misincorporation of uracil into DNA and the appearance of strand breaks during excision repair will be investigated. The studies should throw some light on the question of whether a high orotate diet is promotional for hepatocarcinogenesis through formation of lipid oxidation products or through creation of a nucleotide imbalance.
