The effect of dietary protein depletion on hepatic 5-fluorouracil metabolism.

Abstract

Protein calorie malnutrition, which is highly prevalent in tumor-bearing hosts, increases toxicity to 5-fluorouracil (5-FU), but the mechanisms are unclear. This study investigated the effects of protein depletion on 5-FU in vivo hepatic metabolism using F19-nuclear magnetic resonance spectroscopy (19F-NMRS). Rats received normal (21.5%) or low (2.5%) protein diet for 25 days. 5-FU was injected intraperitoneally, and hepatic fluorine spectra were obtained. Parallel experiments were conducted to determine serum 5-FU pharmacokinetics using high-performance liquid chromatography (HPLC) and to measure hepatic dihydropyrimidine dehydrogenase (DPD) activity. The mean time of initial detection of fluoro-beta-alanine and the mean duration of the 5-FU signal in the liver were significantly prolonged in the low-protein group. 5-FU clearance and hepatic DPD activity were significantly lower in the low-protein group. Low-protein animals demonstrated increased toxicity, with diarrhea, weight loss, leukopenia (P < 0.001), and an 85% mortality, compared with regular diet animals, who had mild diarrhea and weight loss but no leukopenia and a 12% mortality. Protein depletion results in increased toxicity to 5-FU, which is associated with a significantly decreased rate of hepatic metabolism and clearance of 5-FU and a significant decrease in hepatic DPD activity. 19F-NMRS can noninvasively identify these alterations of 5-FU metabolism in vivo and may serve as a useful guide to determining chemotherapy dosage adjustments to reduce toxicity.