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.


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.


CONCLUSIONS
PN decreases hepatic DPD activity, which may lead to increased toxicity of 5-FU.
Taniguchi
Masaaki
M
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2-E2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Yano
Masahiko
M
Tsujinaka
Toshimasa
T
Ogawa
Atsuhiro
A
Morita
Shunji
S
Kaneko
Katsuhiko
K
Akiyama
Yosuke
Y
Miki
Hirofumi
H
Monden
Morito
M
D000818:Animals; D001711:Biotransformation; D002940:Circadian Rhythm; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism*; D004435:Eating; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics*; D007583:Jejunum / Q000201:enzymology; D008099:Liver / Q000378:metabolism*; D008297:Male; D010288:Parenteral Nutrition; D051381:Rats; D011919:Rats, Inbred Strains; D013940:Thymidylate Synthase / Q000378:metabolism
D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil