Synthetic pyrimidines as inhibitors of uracil and thymine degradation by rat-liver supernatant

We tested the ability of a number of synthetic pyrimidines to inhibit degradation of uracil and thymine by rat-tissue supernatants. Among nine tissues tested, only liver preparations showed significant pyrimidine-degrading activity, and among 46 compounds tested, only 5-substituted uracils, analogs of thymine, showed appreciable inhibition of pyrimidine degradation. Despite their structure, all active compounds were more effective inhibitors of uracil than of thymine degradation; similarly, uracil and thymine showed reciprocal inhibition, but thymine was considerably more effective. It was concluded that inhibition occurred only during the initial reductive step in pyrimidine degradation, that reduction of both uracil and thymine was catalyzed by the same enzyme (dihydrouracil dehydrogenase (4,5-dihydrouracil: NADP oxidoreductase, EC 1.3.1.2)), and that inhibition resulted from substrate competition for the active site on the enzyme.