Mechanism of inhibition of phosphoribosylation of 5-fluorouracil by purines.

The mechanism of the abolishment of the cytotoxicity of 5-flurouracil by purines in L5178Y cells was determined by using phosphoribosylation enzymes for both 5-fluorouracil and hypoxanthine. Hypoxanthine inhibited the phosphoribosylation of 5-fluorouracil in the presence of both enzymes, but no inhibition by hypoxanthine was found without hypoxanthine phosphoribosyltransferase or at a high concentration of 5-phosphoribosyl 1-pyrophosphate (PRPP). Hypoxanthine, adenine and inosine decreased the intracellular concentration of PRPP to less than one-tenth of that of the control. These results suggest that 5-fluorouracil is activated directly to its nucleotide, 5-fluorouridine 5'-monophosphate, by the phosphoribosylation enzyme and that the inhibition of activation by purines is due to depletion of PRPP.