Direct 19F NMR spectroscopic observation of 5-fluorouracil metabolism in the isolated perfused mouse liver model

Abstract

A direct analysis of 5-fluorouracil (FUra) metabolism in the isolated perfused mouse liver was carried out using 19F NMR spectroscopy. In livers treated with low (30 mg/kg body weight (b.w.] or high (180 mg/kg b.w.) doses of FUra, with (180 mg/kg b.w.) or without thymidine (dThd), FUra was rapidly catabolized to alpha-fluoro-beta-ureidopropionic acid (FUPA) and alpha-fluoro-beta-alanine (FBAL), the latter usually becoming by far the major catabolite. The first catabolite of FUra, 5,6-dihydro-5-fluorouracil (5FUH2), was never detected both in the liver and in perchloric acid (PCA) extracts. In the latter, it was generally split into three signals, the major one being attributed to 5-fluorouridine-5'-monophosphate. Moreover, when the liver was treated with high doses of FUra and dThd, a signal for fluoronucleoside was observed in the liver, in PCA extracts and in perfusate where it was attributed to 5-fluoro-2'-deoxyuridine (FdUrd). The injection of concurrent dThd with the high dose of FUra led to a marked reduction of catabolism due to competitive inhibition of dihydrouracil dehydrogenase. Moreover, a significant formation of FdUrd was noticed whereas 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) was not detected. dThd therefore inhibits the conversion of FdUrd to FdUMP.