This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Holstege, A. Articles by Gerok, W. Search for Related Content PubMed PubMed Citation Articles by Holstege, A. Articles by Gerok, W.

Effect of 5-Diazouracil on the Catabolism of Circulating Pyrimidines in Rat Liver and Kidneys¹

Medizinische Klinik der Universität Freiburg, Hugstetter Strasse 55, D-7800 Freiburg, Federal Republic of Germany

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 -fluoro-ß-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 acidsoluble 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, -fluoro-ß-ureidopropionic acid, and -fluoro-ß-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.

Our studies indicate a strong inhibition of the catabolism of 5-fluorouracil and uracil by 5-diazouracil in the rat in vivo. Complete degradation of circulating pyrimidine bases was restricted to rat liver and kidneys, with the major part occurring in liver. Inhibition of the catabolic pathway by 5-diazouracil considerably increased the bioavailability of 5-fluorouracil

¹ Supported by Deutsche Forschungsgemeinschaft, SFB 154, "Klinische und experimentelle Hepatologie."

² To whom requests for reprints should be addressed.

Received 6/11/85. Revised 3/24/86. Revised 7/14/86. Accepted 7/16/86.