Effects of 2-thiouracil and related compounds on pyrimidine metabolism

Abstract

The effects of 2-thiouracil and some related compounds on enzymatic reactions at the pyrimidine nucleotide level have been studied. Thiouracil and propylthiouracil depressed the incorporation of uracil-2- 14C into uridine, uridine nucleotides and RNA in rat liver slices without affecting uracil oxidation. Uridine-2- 14C degradation was also inhibited but incorporation into nucleotides and RNA was markedly enhanced. These alterations in the metabolism of uracil and uridine appeared to be due to an inhibition of uridine phosphorylase. Thiouracil, methylthiouracil, and propylthiouracil, but not methimazole, were potent inhibitors of uridine phosphorylase but were not utilized as substrates. Thiouracil inhibition of uridine phosphorylase appeared to be competitive. Thiouracil inhibition of uracil incorporation into nucleotides and RNA occurred only in those tissues in which uridine phosphorylase was rate limiting or was made rate limiting by inhibition. The thiourea derivatives had no effects on uridine kinase or OMP pyrophosphorylase and were not substrates for OMP pyrophosphorylase. Therefore none of these enzymes appear to serve as a site for thiouracil entrance into pathways leading to nucleotide and RNA synthesis. However, inhibition of uridine phosphorylase might explain the thiouracil produced inhibition of growth in some systems.