Effect of 5-diazouracil on the catabolism of circulating pyrimidines in rat liver and kidneys.
The inhibitory effect of 5-diazouracil on the catabolism of circulating uracil and 5-fluorouracil was examined in the rat in vivo. Measurements of the activity of the entire enzymatic pathway of uracil catabolism in the cytosolic supernatant of different rat organs as well as the determination of the total amount of 5-fluorouracil catabolites, accumulated in these tissues, served to clarify their role in the complete systemic breakdown of uracil or 5-fluorouracil. The activity of the enzymatic pathway involved in uracil catabolism was estimated from the 14CO2 produced from [2-14C]uracil in the cytosolic supernatants. Complete degradation of uracil was detected only in the liver and, at a much lower rate, in the kidneys. Fifteen min after the i.p. injection of a tracer dose of 5-fluoro[6-14C]-uracil, more than 90% of the total radioactivity in blood plasma was associated with 5-fluorouracil catabolites. The relative amount of the major catabolite alpha-fluoro-beta-alanine and of dihydrofluorouracil in blood plasma was considerably suppressed after a pretreatment with 5-diazouracil inversely correlated with a 27-fold increase in the absolute amount of unchanged 5-fluorouracil. Control animals accumulated by far the highest amount of total acid-soluble radioactivity from 5-fluoro[6-14C]uracil in liver and kidneys. Total radioactivity in all other organs was much lower and was comparable to the amount of label in blood plasma. In liver and kidneys, the sum of total acid-soluble catabolites including dihydrofluorouracil, alpha-fluoro-beta-ureidopropionic acid, and alpha-fluoro-beta-alanine made up more than 98% of the label correlating with minimal salvage utilization of the base analogue in both organs. Injection of 5-diazouracil 2 h before a tracer dose of 5-fluoro[6-14C]uracil strongly inhibited the accumulation of labeled catabolites in liver and kidneys causing a fall in total acid-soluble radioactivity in both tissues by 75 and 66%, respectively. In blood plasma and all other organs, however, pretreatment with 5-diazouracil was followed by a 2-fold enhancement of the radioactivity contents, mostly due to the appearance of unchanged 5-fluorouracil. Under these conditions, there was a 2.6- to 4-fold increase in the relative proportion of cis-diol group-containing anabolites of 5-fluorouracil in liver and in kidneys. Within 2 h, 12.7% of the administered radioactivity from 5-fluorouracil was excreted into bile. 5-Diazouracil lowered the biliary excretion of radioactivity to 2% of the injected dose.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D001646:Bile / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051381:Rats; D014018:Tissue Distribution / Q000187:drug effects; D014498:Uracil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
C004758:5-diazouracil; D014498:Uracil; D005472:Fluorouracil