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 X 10(-7) M and 3.6 X 10(-7) M, respectively.
D000818:Animals; D001463:Barbiturates / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D050744:Dihydrouracil Dehydrogenase (NAD+); D005472:Fluorouracil / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D012510:Sarcoma 180 / Q000378:metabolism; D013941:Thymine / Q000494:pharmacology; D014498:Uracil / Q000494:pharmacology
D001463:Barbiturates; D011725:Pyridines; D011743:Pyrimidines; D014498:Uracil; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050744:Dihydrouracil Dehydrogenase (NAD+); D013941:Thymine; D005472:Fluorouracil; C032232:barbituric acid