TY - JOUR
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, David J.
AU - Barnes, Stephen
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 1μM FdUrd but were 9-fold higher with 25 μm FUra. Analysis by high performance liquid chromatography demonstrated that unmetabolized fhioropyrimidines 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 elnted 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 hydrohtse to FBAL and =conjugated bile acids that were identified by gas chromatography-mass spectrometry to be a-muricholic acid (peak 1), cholic acid (peak 2) and chenodeoxycholic acid (peak 3). Thus, the major binary metabolites of FUra and FdUrd were identified as N-(bile acid)-FBAL conjugates. While the N-(bOe 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 1μM FdUrd but were 9-fold higher with 25 μm FUra. Analysis by high performance liquid chromatography demonstrated that unmetabolized fhioropyrimidines 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 elnted 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 hydrohtse to FBAL and =conjugated bile acids that were identified by gas chromatography-mass spectrometry to be a-muricholic acid (peak 1), cholic acid (peak 2) and chenodeoxycholic acid (peak 3). Thus, the major binary metabolites of FUra and FdUrd were identified as N-(bile acid)-FBAL conjugates. While the N-(bOe 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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M3 - Article
C2 - 2964897
AN - SCOPUS:0023934756
SN - 0008-5472
VL - 48
SP - 2010
EP - 2014
JO - Cancer research
JF - Cancer research
IS - 8
ER -