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. 1998;77(1):79–86. doi: 10.1038/bjc.1998.12

The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate.

M Arellano 1, M Malet-Martino 1, R Martino 1, P Gires 1
PMCID: PMC2151255  PMID: 9459149

Abstract

We report the first demonstration of the biotransformation of the anti-cancer drug 5-fluorouracil (FU) into two new metabolites, alpha-fluoro-beta-hydroxypropionic acid (FHPA) and fluoroacetate (FAC), in the isolated perfused rat liver (IPRL) and in the rat in vivo. IPRL was perfused with solutions of pure FU at two doses, 15 or 45 mg kg(-1) body weight, and rats were injected i.p. with 180 mg of FU kg(-1) body weight. Fluorine-19 NMR analysis of perfusates from IPRL and rat urine showed the presence of the normal metabolites of FU and low amounts of FHPA (0.4% or 0.1% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg(-1) body weight, respectively; 0.08% of the injected FU in rat urine) and FAC (0.1% or 0.03% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg(-1) body weight, respectively; 0.003% of the injected FU in rat urine). IPRL was also perfused with a solution of alpha-fluoro-beta-alanine (FBAL) hydrochloride at 16.6 mg kg(-1) body weight dose equivalent to 15 mg of FU kg(-1) body weight. Low amounts of FHPA (0.2% of injected FBAL) and FAC (0.07%) were detected in perfusates, thus demonstrating that FHPA and FAC arise from FBAL catabolism. As FAC is a well-known cardiotoxic poison, and FHPA is also cardiotoxic at high doses, the cardiotoxicity of FU might stem from at least two sources. The first one, established in previous papers (Lemaire et al, 1992, 1994), is the presence in commercial solutions of FU of degradation products of FU that are metabolized into FHPA and FAC; these are formed over time in the basic medium necessary to dissolve the drug. The second, demonstrated in the present study, is the metabolism of FU itself into the same compounds.

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Selected References

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  1. Anand A. J. Fluorouracil cardiotoxicity. Ann Pharmacother. 1994 Mar;28(3):374–378. doi: 10.1177/106002809402800314. [DOI] [PubMed] [Google Scholar]
  2. Arellano M., Malet-Martino M., Martino R., Spector T. 5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model. Br J Cancer. 1997;76(9):1170–1180. doi: 10.1038/bjc.1997.529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baccanari D. P., Davis S. T., Knick V. C., Spector T. 5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11064–11068. doi: 10.1073/pnas.90.23.11064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bosakowski T., Levin A. A. Serum citrate as a peripheral indicator of fluoroacetate and fluorocitrate toxicity in rats and dogs. Toxicol Appl Pharmacol. 1986 Sep 30;85(3):428–436. doi: 10.1016/0041-008x(86)90350-9. [DOI] [PubMed] [Google Scholar]
  5. Burke D. G., Lew D. K., Cominos X. Determination of fluoroacetate in biological matrixes as the dodecyl ester. J Assoc Off Anal Chem. 1989 May-Jun;72(3):503–507. [PubMed] [Google Scholar]
  6. Gamelin E., Gamelin L., Larra F., Turcant A., Alain P., Maillart P., Allain Y. M., Minier J. F., Dubin J. Toxicité cardiaque aiguë du 5-fluorouracile: corrélation pharmacocinétique. Bull Cancer. 1991;78(12):1147–1153. [PubMed] [Google Scholar]
  7. Griffith O. W. Beta-amino acids: mammalian metabolism and utility as alpha-amino acid analogues. Annu Rev Biochem. 1986;55:855–878. doi: 10.1146/annurev.bi.55.070186.004231. [DOI] [PubMed] [Google Scholar]
  8. Hull W. E., Port R. E., Herrmann R., Britsch B., Kunz W. Metabolites of 5-fluorouracil in plasma and urine, as monitored by 19F nuclear magnetic resonance spectroscopy, for patients receiving chemotherapy with or without methotrexate pretreatment. Cancer Res. 1988 Mar 15;48(6):1680–1688. [PubMed] [Google Scholar]
  9. Kamm Y. J., Heerschap A., Rosenbusch G., Rietjens I. M., Vervoort J., Wagener D. J. 5-Fluorouracil metabolite patterns in viable and necrotic tumor areas of murine colon carcinoma determined by 19F NMR spectroscopy. Magn Reson Med. 1996 Sep;36(3):445–450. doi: 10.1002/mrm.1910360317. [DOI] [PubMed] [Google Scholar]
  10. Kaneko M., Kontani Y., Kikugawa M., Tamaki N. Inhibition of D-3-aminoisobutyrate-pyruvate aminotransferase by 5-fluorouracil and alpha-fluoro-beta-alanine. Biochim Biophys Acta. 1992 Jul 13;1122(1):45–49. doi: 10.1016/0167-4838(92)90125-w. [DOI] [PubMed] [Google Scholar]
  11. Keller D. A., Roe D. C., Lieder P. H. Fluoroacetate-mediated toxicity of fluorinated ethanes. Fundam Appl Toxicol. 1996 Apr;30(2):213–219. doi: 10.1006/faat.1996.0058. [DOI] [PubMed] [Google Scholar]
  12. Koenig H., Patel A. Biochemical basis for fluorouracil neurotoxicity. The role of Krebs cycle inhibition by fluoroacetate. Arch Neurol. 1970 Aug;23(2):155–160. doi: 10.1001/archneur.1970.00480260061008. [DOI] [PubMed] [Google Scholar]
  13. Kramer H. L. Liquid chromatographic determination of sodium fluoroacetate (Compound 1080) in meat baits and formulations. J Assoc Off Anal Chem. 1984 Nov-Dec;67(6):1058–1061. [PubMed] [Google Scholar]
  14. LOZERON H. A., GORDON M. P., GABRIEL T., TAUTZ W., DUSCHINSKY R. THE PHOTOCHEMISTRY OF 5-FLUOROURACIL. Biochemistry. 1964 Dec;3:1844–1850. doi: 10.1021/bi00900a009. [DOI] [PubMed] [Google Scholar]
  15. Lemaire L., Malet-Martino M. C., de Forni M., Martino R., Lasserre B. Cardiotoxicity of commercial 5-fluorouracil vials stems from the alkaline hydrolysis of this drug. Br J Cancer. 1992 Jul;66(1):119–127. doi: 10.1038/bjc.1992.227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. MOERTEL C. G., REITEMEIER R. J., BOLTON C. F., SHORTER R. G. CEREBELLAR ATAXIA ASSOCIATED WITH FLUORINATED PYRIMIDINE THERAPY. Cancer Chemother Rep. 1964 Sep;41:15–18. [PubMed] [Google Scholar]
  17. MUKHERJEE K. L., HEIDELBERGER C. Studies on fluorinated pyrimidines. IX. The degradation of 5-fluorouracil-6-C14. J Biol Chem. 1960 Feb;235:433–437. [PubMed] [Google Scholar]
  18. Malet-Martino M. C., Martino R. Magnetic resonance spectroscopy: a powerful tool for drug metabolism studies. Biochimie. 1992 Sep-Oct;74(9-10):785–800. doi: 10.1016/0300-9084(92)90061-i. [DOI] [PubMed] [Google Scholar]
  19. Martino R., Lopez A., Malet-Martino M. C., Bernadou J., Armand J. P. Release of fluoride ion from 5'-deoxy-5-fluorouridine, an antineoplastic fluoropyrimidine, in humans. Drug Metab Dispos. 1985 Jan-Feb;13(1):116–118. [PubMed] [Google Scholar]
  20. Martino R., Malet-Martino M. C., Vialaneix C., Lopez A., Bon M. 19F nuclear magnetic resonance analysis of the carbamate reaction of alpha-fluoro-beta-alanine (FBAL), the major catabolite of fluoropyrimidines. Application to FBAL carbamate determination in body fluids of patients treated with 5'-deoxy-5-fluorouridine. Drug Metab Dispos. 1987 Nov-Dec;15(6):897–904. [PubMed] [Google Scholar]
  21. Moore D. H., Fowler W. C., Jr, Crumpler L. S. 5-Fluorouracil neurotoxicity. Gynecol Oncol. 1990 Jan;36(1):152–154. doi: 10.1016/0090-8258(90)90127-7. [DOI] [PubMed] [Google Scholar]
  22. Okeda R., Shibutani M., Matsuo T., Kuroiwa T., Shimokawa R., Tajima T. Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and alpha-fluoro-beta-alanine. Acta Neuropathol. 1990;81(1):66–73. doi: 10.1007/BF00662639. [DOI] [PubMed] [Google Scholar]
  23. Okuno I., Meeker D. L., Felton R. R. Modified gas-liquid chromatographic method for determination of compound 1080 (sodium fluoroacetate). J Assoc Off Anal Chem. 1982 Sep;65(5):1102–1105. [PubMed] [Google Scholar]
  24. Ozawa H., Tsukioka T. Gas chromatographic determination of sodium monofluoroacetate in water by derivatization with dicyclohexylcarbodiimide. Anal Chem. 1987 Dec 15;59(24):2914–2917. doi: 10.1021/ac00151a016. [DOI] [PubMed] [Google Scholar]
  25. PIHL A., FRITZSON P. The catabolism of C14-labeled beta-alanine in the intact rat. J Biol Chem. 1955 Jul;215(1):345–351. [PubMed] [Google Scholar]
  26. Porter D. J., Harrington J. A., Almond M. R., Chestnut W. G., Tanoury G., Spector T. Enzymatic elimination of fluoride from alpha-fluoro-beta-alanine. Biochem Pharmacol. 1995 Oct 26;50(9):1475–1484. doi: 10.1016/0006-2952(95)02053-5. [DOI] [PubMed] [Google Scholar]
  27. Ray A. C., Post L. O., Reagor J. C. High pressure liquid chromatographic determination of sodium fluoroacetate (compound 1080) in canine gastric content. J Assoc Off Anal Chem. 1981 Jan;64(1):19–24. [PubMed] [Google Scholar]
  28. Rezkalla S., Kloner R. A., Ensley J., al-Sarraf M., Revels S., Olivenstein A., Bhasin S., Kerpel-Fronious S., Turi Z. G. Continuous ambulatory ECG monitoring during fluorouracil therapy: a prospective study. J Clin Oncol. 1989 Apr;7(4):509–514. doi: 10.1200/JCO.1989.7.4.509. [DOI] [PubMed] [Google Scholar]
  29. Robben N. C., Pippas A. W., Moore J. O. The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy. Cancer. 1993 Jan 15;71(2):493–509. doi: 10.1002/1097-0142(19930115)71:2<493::aid-cncr2820710235>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  30. Tamaki N., Kaneko M., Mizota C., Kikugawa M., Fujimoto S. Purification, characterization and inhibition of D-3-aminoisobutyrate aminotransferase from the rat liver. Eur J Biochem. 1990 Apr 20;189(1):39–45. doi: 10.1111/j.1432-1033.1990.tb15457.x. [DOI] [PubMed] [Google Scholar]
  31. Walsh C. Fluorinated substrate analogs: routes of metabolism and selective toxicity. Adv Enzymol Relat Areas Mol Biol. 1983;55:197–289. doi: 10.1002/9780470123010.ch3. [DOI] [PubMed] [Google Scholar]
  32. Yonaha K., Suzuki K., Toyama S. Streptomyces beta-alanine:alpha-ketoglutarate aminotransferase, a novel omega-amino acid transaminase. Purification, crystallization, and enzymologic properties. J Biol Chem. 1985 Mar 25;260(6):3265–3268. [PubMed] [Google Scholar]
  33. Zhang R. W., Soong S. J., Liu T. P., Barnes S., Diasio S. B. Pharmacokinetics and tissue distribution of 2-fluoro-beta-alanine in rats. Potential relevance to toxicity pattern of 5-fluorouracil. Drug Metab Dispos. 1992 Jan-Feb;20(1):113–119. [PubMed] [Google Scholar]
  34. de Forni M., Malet-Martino M. C., Jaillais P., Shubinski R. E., Bachaud J. M., Lemaire L., Canal P., Chevreau C., Carrié D., Soulié P. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol. 1992 Nov;10(11):1795–1801. doi: 10.1200/JCO.1992.10.11.1795. [DOI] [PubMed] [Google Scholar]

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