Effect of 5-Diazouracil on the Synthetic and Catabolic Utilization of Thymine in Rat Liver 1

Abstract

Summary

Injection of 5-diazouracil increased in 2 hr the incorporation of thymine-2-¹⁴C into DNA of rat liver over 4-fold and it elevated the level of the acid-soluble pool 7-fold. Continued treatment with 5-diazouracil over a 4-day period did not increase the incorporation of labeled thymine above the level achieved at 2 hr after administration. Treatment with 5-diazouracil decreased the degradation of thymine to CO₂ to 13% of the values observed in control rats. Addition of 5-diazouracil to liver slices caused a dose-dependent progressive decrease in the degradation of thymine to CO₂ yielding a 50% inhibition at 0.02 mM. Actinomycin D or cycloheximide, whether injected 1 hr before or simultaneously with 5-diazouracil, did not inhibit the stimulation of the incorporation of thymine into DNA produced by the diazouracil treatment. Thus, 5-diazouracil, which irreversibly inhibits hepatic dihydrouracil dehydrogenase, can rapidly cause a marked imbalance in pyrimidine metabolism leading to a rise in the synthetic utilization and a decrease in the catabolism of thymine.