Inhibitory Effects of Pyrimidine, Barbituric Acid and Pyridine Derivatives on 5-Fluorouracil Degradation in Rat Liver Extracts

The inhibitory effects of about 30 compounds, mainly pyrimidine and pyridine derivatives, on 5-fluorouracil degradation catalyzed by dihydrouracil dehydrogenase (DHU dehydrogenase) were investigated. The inhibitory activities of 5-substituted uracil derivatives decreased time-dependently during preincubation with liver extracts, indicating that these compounds are substrates of DHU dehydrogenase. During preincubation, 4, 6-dihydroxypyrimidine derivatives were found to be converted to barbituric acid derivatives, which have stronger activities. The inhibitory activity of 2, 4-dihydroxypyridine (3-deazauracil), which was stronger than that of uracil, did not change during preincubation, indicating that this compound is not a substrate but is an inhibitor of DHU dehydrogenase, and suggesting that 2, 6-dihydroxypyridine (1-deazauracil) could be a potent inhibitor. In the light of these findings, we examined various derivatives of barbituric acid, 2, 4-dihydroxypyridine and 2, 6-dihydroxypyridine. Among these compounds, 3-cyano-2, 6-dihydroxypyridine and 5-chloro-2, 4-dihydroxypyridine were the strongest inhibitors with Ki values for DHU dehydrogenase of 2.3×10-7M and 3.6×10-7M, respectively.