The effect of dietary protein depletion on hepatic 5-Fluorouracil metabolism

Abstract

Background. 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). Methods. 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. Results. The mean time of initial detection of fluoro‐β‐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. Conclusion. 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.

Indirect assessment of dihydropyrimidine dehydrogenase activity in cats

“…However, studies in mice and rats have reported a protective effect of high protein diets with reduced toxicity to 5-FU. 28,29 One significant difference we identified between cat populations was neuter status. Spayed females tended to have lower ratios than intact females.…”

“…The role of diet in DPD activity and uracil metabolism raises an interesting question, especially in light of the fact that cats are carnivores and therefore consume diets relatively high in protein. However, studies in mice and rats have reported a protective effect of high protein diets with reduced toxicity to 5‐FU , …”

Effects of Caloric Intake on Intestinal Mucosal Morphology and Immune Cells in Rats Treated with 5-Fluorouracil

“…Host toxicity such as leucopenia and diarrhea caused by 5-FU was increased by protein energy malnutrition [25]. With respect to the mechanism responsible for this phenomenon, the metabolism rate of 5-FU is implicated [26]. Protein depletion results in a decreased rate of hepatic metabolism and clearance of 5-FU, and decreased activity of hepatic dihydropyrimidine dehydrogenase (DPD) which deactivates 5-FU [27].…”

Monitoring fluoropyrimidine metabolism in solid tumors with in vivo 19F magnetic resonance spectroscopy

“…Therefore, clinical implementation of DPD modulation should be considered with caution. In fact, when rats on a low-protein diet (2.5%) were treated with FU, higher toxicity (diarrhea, weight loss, leukopenia) and mortality were observed compared with rats on a normal protein diet (21.5%), an effect attributed to lower DPD activity in the low-protein group [100]. By means of 19 F MRS it was observed that after i.p.…”