Parenteral nutrition decreases hepatic dihydropyrimidine dehydrogenase activity and modulates catabolism of 5-fluorouracil in rats

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). The effect of parenteral nutrition (PN) on hepatic DPD activity and metabolism of 5-FU remains unknown. MATERIALS AND METHODS: Rats were divided into two groups: a sham-operated oral feeding group (FED) and a PN group. After 7-day PN infusion, hepatic DPD activity, serum 5-FU levels and thymidylate synthase (TS) levels in the jejunum and tumor were measured. RESULTS: PN administration significantly decreased hepatic DPD activities. After infusion of 5-FU (40 mg/kg body), the serum 5-FU concentration and 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP)-bound TS levels in the jejunum were significantly higher in the PN group than the FED group (156.8 +/- 51.9 vs 100.5 +/- 51.9 ng/ml, p < 0.001 and 38.55 +/- 7.61 vs 22.89 +/- 4.46 pmol/g of tissue, p < 0.01, respectively). In Yoshida sarcoma-bearing rats, the FdUMP-bound TS level in the tumor did not differ significantly between the PN and FED rats. CONCLUSION: PN decreases hepatic DPD activity, which may lead to increased toxicity of 5-FU.