Distribution and inhibition of dihydrouracil dehydrogenase activities in human tissues using 5-fluorouracil as a substrate.
Dihydrouracil dehydrogenase activity, with 5-fluorouracil used as the substrate, was measured in human tissues and leukemic cells. The liver had the highest enzyme activity (mean, 705 nmoles/g tissue/hr) with minimal activity found in the kidneys, spleen, lung, colon, colon tumors, pancreas, breast tissue, breast tumors, bone marrow cells, and peripheral leukemic cells. Wide variations in the enzyme activities were noted in samples collected from different subjects. 5-diazouracil inhibits the enzyme activity with the concentration required for inhibiting 50% (IC50) of the liver enzyme being 3 microM. Other compounds, thymine, thymidine, 6-methoxydiazouracil, and cyclo-5-diazouridine were also tested for their effect on this enzyme. With the exception of cyclo-5-diazouridine, all others produced inhibitory effect. The inhibitory effect of 6-methoxydiazouracil is similar to that of diazouracil. Thymidine and thymine are less active with identical values for IC50 of 80 microM.
D050744:Dihydrouracil Dehydrogenase (NAD+); D005472:Fluorouracil / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000201:enzymology; D010088:Oxidoreductases / Q000032:analysis* / Q000037:antagonists & inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; D013936:Thymidine / Q000494:pharmacology; D013941:Thymine / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology
C004758:5-diazouracil; D014498:Uracil; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050744:Dihydrouracil Dehydrogenase (NAD+); D013941:Thymine; D005472:Fluorouracil; D013936:Thymidine