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

L. E. Davis, R. E. Lenkinski, M. A. Shinkwin, H. Y. Kressel, J. M. Daly

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3715-3722
Number of pages8
JournalCancer
Volume72
Issue number12
DOIs
StatePublished - 1993

Fingerprint

Dietary Proteins
Fluorouracil
Liver
Dihydrouracil Dehydrogenase (NADP)
Leukopenia
Proteins
Weight Loss
Diarrhea
Protein-Energy Malnutrition
Protein-Restricted Diet
Fluorine
Mortality
Alanine
Magnetic Resonance Spectroscopy
Pharmacokinetics
High Pressure Liquid Chromatography
Diet
Drug Therapy

Keywords

  • 5-fluorouracil
  • F-nuclear magnetic resonance spectroscopy
  • high-performance liquid chromatography
  • metabolism
  • protein-calorie malnutrition

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The effect of dietary protein depletion on hepatic 5-fluorouracil metabolism. / Davis, L. E.; Lenkinski, R. E.; Shinkwin, M. A.; Kressel, H. Y.; Daly, J. M.

In: Cancer, Vol. 72, No. 12, 1993, p. 3715-3722.

Research output: Contribution to journalArticle

Davis, L. E. ; Lenkinski, R. E. ; Shinkwin, M. A. ; Kressel, H. Y. ; Daly, J. M. / The effect of dietary protein depletion on hepatic 5-fluorouracil metabolism. In: Cancer. 1993 ; Vol. 72, No. 12. pp. 3715-3722.
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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.",
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AU - Daly, J. M.

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N2 - 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.

AB - 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.

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