Formation of conjugates of 2-fluoro-β-alanine and bile acids during the metabolism of 5-fluorouracil and 5-fluoro-2-deoxyuridine in the isolated perfused rat liver

D. J. Sweeny, S. Barnes, Robert B Diasio

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19 Citations (Scopus)

Abstract

We have recently demonstrated that the major biliary metabolite of 5-fluorouracil (FUra) in cancer patients is a conjugate of the FUra catabolite 2-fluoro-β-alanine (FBAL) and cholic acid (D.J. Sweeny, S. Barnes, G. Heggie, and R.B. Diasio. Proc. Natl. Acad. Sci. USA, 84: 5439-5443, 1987). This finding prompted us to further examine the metabolism and biliary excretion of clinically relevant concentrations of the fluoropyrimidines FUra and 5-fluoro-2'-deoxyuridine (FdUrd) using the isolated perfused rat liver. During infusion of fluoropyrimidines, rates of appearance of metabolites in bile were similar with both 1 μM FUra and 1 μM FdUrd but were 9-fold higher with 25 μM FUra. Analysis by high performance liquid chromatography demonstrated that unmetabolized fluoropyrimidines and known catabolites (i.e., FBAL) accounted for less than 15% of the total metabolites in bile and that the majority of the biliary metabolites were eluted as three distinct nonpolar compounds. Fast atom bombardment-mass spectrometry demonstrated that these unique metabolites had molecular weights of 497 (peak 1), 497 (peak 2), and 481 (peak 3). These metabolites were hydrolyzed by cholylglycine hydrolase to FBAL and unconjugated bile acids that were identified by gas chromatography-mass spectrometry to be α-muricholic acid (peak 1), cholic acid (peak 2), and chenodeoxycholic acid (peak 3). Thus, the major biliary metabolites of FUra and FdUrd were identified as N-(bile acid)-FBAL conjugates. While the N-(bile acid)-FBAL conjugates were the major metabolites in bile, dihydroFUra was the major (>70%) metabolite eliminated into perfusate. In summary, these results demonstrate that FUra and FdUrd undergo similar metabolism in the isolated perfused rat liver and, as was observed in humans, the major biliary fluoropyrimidine metabolites are conjugates of FBAL and bile acids.

Original languageEnglish (US)
Pages (from-to)2010-2014
Number of pages5
JournalCancer Research
Volume48
Issue number8
StatePublished - 1988
Externally publishedYes

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Bile Acids and Salts
Fluorouracil
Alanine
Liver
Bile
Cholic Acid
choloylglycine hydrolase
Fast Atom Bombardment Mass Spectrometry
Chenodeoxycholic Acid
5-fluoro-2'-deoxyuridine
Gas Chromatography-Mass Spectrometry
alpha-fluoro-beta-alanine
Molecular Weight
High Pressure Liquid Chromatography
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{0a6cdb27ced04862a8bbd897ea334ded,
title = "Formation of conjugates of 2-fluoro-β-alanine and bile acids during the metabolism of 5-fluorouracil and 5-fluoro-2-deoxyuridine in the isolated perfused rat liver",
abstract = "We have recently demonstrated that the major biliary metabolite of 5-fluorouracil (FUra) in cancer patients is a conjugate of the FUra catabolite 2-fluoro-β-alanine (FBAL) and cholic acid (D.J. Sweeny, S. Barnes, G. Heggie, and R.B. Diasio. Proc. Natl. Acad. Sci. USA, 84: 5439-5443, 1987). This finding prompted us to further examine the metabolism and biliary excretion of clinically relevant concentrations of the fluoropyrimidines FUra and 5-fluoro-2'-deoxyuridine (FdUrd) using the isolated perfused rat liver. During infusion of fluoropyrimidines, rates of appearance of metabolites in bile were similar with both 1 μM FUra and 1 μM FdUrd but were 9-fold higher with 25 μM FUra. Analysis by high performance liquid chromatography demonstrated that unmetabolized fluoropyrimidines and known catabolites (i.e., FBAL) accounted for less than 15{\%} of the total metabolites in bile and that the majority of the biliary metabolites were eluted as three distinct nonpolar compounds. Fast atom bombardment-mass spectrometry demonstrated that these unique metabolites had molecular weights of 497 (peak 1), 497 (peak 2), and 481 (peak 3). These metabolites were hydrolyzed by cholylglycine hydrolase to FBAL and unconjugated bile acids that were identified by gas chromatography-mass spectrometry to be α-muricholic acid (peak 1), cholic acid (peak 2), and chenodeoxycholic acid (peak 3). Thus, the major biliary metabolites of FUra and FdUrd were identified as N-(bile acid)-FBAL conjugates. While the N-(bile acid)-FBAL conjugates were the major metabolites in bile, dihydroFUra was the major (>70{\%}) metabolite eliminated into perfusate. In summary, these results demonstrate that FUra and FdUrd undergo similar metabolism in the isolated perfused rat liver and, as was observed in humans, the major biliary fluoropyrimidine metabolites are conjugates of FBAL and bile acids.",
author = "Sweeny, {D. J.} and S. Barnes and Diasio, {Robert B}",
year = "1988",
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journal = "Journal of Cancer Research",
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T1 - Formation of conjugates of 2-fluoro-β-alanine and bile acids during the metabolism of 5-fluorouracil and 5-fluoro-2-deoxyuridine in the isolated perfused rat liver

AU - Sweeny, D. J.

AU - Barnes, S.

AU - Diasio, Robert B

PY - 1988

Y1 - 1988

N2 - We have recently demonstrated that the major biliary metabolite of 5-fluorouracil (FUra) in cancer patients is a conjugate of the FUra catabolite 2-fluoro-β-alanine (FBAL) and cholic acid (D.J. Sweeny, S. Barnes, G. Heggie, and R.B. Diasio. Proc. Natl. Acad. Sci. USA, 84: 5439-5443, 1987). This finding prompted us to further examine the metabolism and biliary excretion of clinically relevant concentrations of the fluoropyrimidines FUra and 5-fluoro-2'-deoxyuridine (FdUrd) using the isolated perfused rat liver. During infusion of fluoropyrimidines, rates of appearance of metabolites in bile were similar with both 1 μM FUra and 1 μM FdUrd but were 9-fold higher with 25 μM FUra. Analysis by high performance liquid chromatography demonstrated that unmetabolized fluoropyrimidines and known catabolites (i.e., FBAL) accounted for less than 15% of the total metabolites in bile and that the majority of the biliary metabolites were eluted as three distinct nonpolar compounds. Fast atom bombardment-mass spectrometry demonstrated that these unique metabolites had molecular weights of 497 (peak 1), 497 (peak 2), and 481 (peak 3). These metabolites were hydrolyzed by cholylglycine hydrolase to FBAL and unconjugated bile acids that were identified by gas chromatography-mass spectrometry to be α-muricholic acid (peak 1), cholic acid (peak 2), and chenodeoxycholic acid (peak 3). Thus, the major biliary metabolites of FUra and FdUrd were identified as N-(bile acid)-FBAL conjugates. While the N-(bile acid)-FBAL conjugates were the major metabolites in bile, dihydroFUra was the major (>70%) metabolite eliminated into perfusate. In summary, these results demonstrate that FUra and FdUrd undergo similar metabolism in the isolated perfused rat liver and, as was observed in humans, the major biliary fluoropyrimidine metabolites are conjugates of FBAL and bile acids.

AB - We have recently demonstrated that the major biliary metabolite of 5-fluorouracil (FUra) in cancer patients is a conjugate of the FUra catabolite 2-fluoro-β-alanine (FBAL) and cholic acid (D.J. Sweeny, S. Barnes, G. Heggie, and R.B. Diasio. Proc. Natl. Acad. Sci. USA, 84: 5439-5443, 1987). This finding prompted us to further examine the metabolism and biliary excretion of clinically relevant concentrations of the fluoropyrimidines FUra and 5-fluoro-2'-deoxyuridine (FdUrd) using the isolated perfused rat liver. During infusion of fluoropyrimidines, rates of appearance of metabolites in bile were similar with both 1 μM FUra and 1 μM FdUrd but were 9-fold higher with 25 μM FUra. Analysis by high performance liquid chromatography demonstrated that unmetabolized fluoropyrimidines and known catabolites (i.e., FBAL) accounted for less than 15% of the total metabolites in bile and that the majority of the biliary metabolites were eluted as three distinct nonpolar compounds. Fast atom bombardment-mass spectrometry demonstrated that these unique metabolites had molecular weights of 497 (peak 1), 497 (peak 2), and 481 (peak 3). These metabolites were hydrolyzed by cholylglycine hydrolase to FBAL and unconjugated bile acids that were identified by gas chromatography-mass spectrometry to be α-muricholic acid (peak 1), cholic acid (peak 2), and chenodeoxycholic acid (peak 3). Thus, the major biliary metabolites of FUra and FdUrd were identified as N-(bile acid)-FBAL conjugates. While the N-(bile acid)-FBAL conjugates were the major metabolites in bile, dihydroFUra was the major (>70%) metabolite eliminated into perfusate. In summary, these results demonstrate that FUra and FdUrd undergo similar metabolism in the isolated perfused rat liver and, as was observed in humans, the major biliary fluoropyrimidine metabolites are conjugates of FBAL and bile acids.

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