Effect of 5-benzylacyclouridine, a potent inhibitor of uridine phosphorylase, on the metabolism of circulating uridine by the isolated rat liver.
5-Benzylacyclouridine (BAU) is a specific inhibitor of uridine phosphorylase, the first enzyme in the catabolism of uridine. It was found that 20 and 100 microM BAU dramatically reduced the rapid clearance of trace amounts of either [14C]uridine or hyperphysiologic concentrations of non-labeled uridine by the isolated rat liver perfused with an artificial oxygen carrier. In the absence of exogenously added uridine, non-treated livers maintained circulating concentrations of 1-2 microM uridine. In the presence of 20 microM BAU, these concentrations were increased 2- to 3-fold higher than physiologic levels (1.4 +/- 0.6 microM) and remained elevated for the duration of the experiment (120-160 min). In the presence of 100 microM BAU, uridine concentrations rose continuously at rates of between 80 and 150 nmoles per hr per g of liver, and the clearance of a single radioactive spike of uridine was reduced extensively. The half-life of a uridine spike was extended 2-fold in the presence of 20 microM BAU and 5- to 6-fold in the presence of 100 microM BAU. Exogenously added uridine (15 and 40 microM) was cleared rapidly by nontreated livers, with a half-life of approximately 10 min. However, BAU at a concentration of 20 microM increased the half-life of 15 or 40 microM uridine added to the perfusate by approximately 10-fold. A 100 microM concentration of BAU inhibited the removal of 40 microM circulating uridine, but with 15 microM uridine there was a continuous increase in the circulating concentration similar to that seen in the absence of added uridine. We conclude that extensive inhibition of uridine phosphorylase occurs at 100 microM BAU and partial inhibition at 20 microM BAU. These data indicate independent catabolic and excretory functions of the rat liver with respect to uridine.
D000818:Animals; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D014529:Uridine / Q000097:blood / Q000378:metabolism*; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors*
C034753:5-benzylacyclouridine; D014498:Uracil; D010430:Pentosyltransferases; D014543:Uridine Phosphorylase; D014529:Uridine