Use of Isotopes and LC-MS-ESI-TOF for Mechanistic Studies of Tienilic Acid Metabolic Activation

  • Maya Belghazi
  • Pascale Jean
  • Sonia Poli
  • Jean-Marie Schmitter
  • Daniel Mansuy
  • M. Patrick Dansette
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 500)

Abstract

Tienilic Acid (TA) is a uricosuric drug marketed in 1978 and which caused a number of rare immunoallergic hepatitis. It was withdrawn in US in 1980, in France in 1992. Early batches of tienilic acid also contained 0.1–0.5% tienilic acid isomer. Tienilic acid isomer (TAI), has been shown to be metabolised by Cytochrome P450 into a reactive thiophene 1-oxide which either binds to proteins, or can be trapped by sulfur nucleophiles (Valadon et al. 1996). Tienilic acid is metabolized by human cytochrome P450 2C9 into 5-hydroxytienilic acid (a major metabolite representing 70% of the dose excreted in human urine) but it also forms (a) reactive metabolite(s) which binds covalently to CYP 2C9 and it is a mechanism based inhibitor of CYP 2C9. Adding glutathione to incubations decreases the covalent binding, but only to 1 mol/mol P450. However the reactive metabolite of tienilic acid is still unknown. Recently Koenigs et al. have shown using ESI-LC-MS that CYP 2C9 binds ≈ 2 mol of TA in absence of GSH and only one in presence of 3 mM GSH (Koenigs et al. 1999).

Keywords

Adduct Palladium NADPH Deuterium Epoxide 

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References

  1. Bonierbale E., Valadon P., Pons C., Desfosses B., Dansette P. M. and Mansuy D. (1999), Opposite behaviors of reactive metabolites of tienilic acid and its isomer toward liver proteins: Use of specific antitienilic acidprotein adduct antibodies and the possible relationship with different hepatotoxic effects of the two compounds, Chem Res Toxicol, 12, 286–296. and references therein.PubMedCrossRefGoogle Scholar
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Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Maya Belghazi
    • 1
  • Pascale Jean
    • 2
  • Sonia Poli
    • 1
  • Jean-Marie Schmitter
    • 1
  • Daniel Mansuy
    • 2
  • M. Patrick Dansette
    • 1
  1. 1.CNRS UMR 8601 ParisUniversité René DescartesParisFrance
  2. 2.CNRS UMR 5472Université de Bordeaux ITalenceFrance

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