New Biological Reactive Intermediates

Metabolic Activation of Thiophene Derivatives
  • Daniel Mansuy
  • Patrick M. Dansette
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 387)


Metabolic activation of benzene rings as well as that of many aromatic heterocycles such as furans generally involves the intermediate formation of arene oxides as electrophilic reactive metabolites. Much less was known until very recently about the metabolic oxidative activation of thiophene derivatives (Rance, 1989). A first report on the metabolism of thiophene itself in rats has shown the formation of thiophene-derived mercapturates in urine and proposed the intermediate formation of a thiophene epoxide (Bray et al., 1971). More recently, it has been shown that the major oxidized metabolites of several 2-aroylthiophenes, such as tienilic acid (Mansuy et al., 1984) were derived from 5-hydroxylation of their thiophene ring (Neau et al., 1990).


Human Liver Microsome Reactive Metabolite Thiophene Ring Mercapturic Acid Thiophene Derivative 
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  1. Beaune, P., Pessayre, D., Dansette, P., Mansuy, D. and Manns, M. 1994, Autoantibodies against cytochrome P450: Role in human diseases, Advances in Pharmacology. 30: 199–245.PubMedCrossRefGoogle Scholar
  2. Bray, H.G., Carpanini F.M.B. and Waters, B.D. 1971, The metabolism of thiophene in the rabbit and in the rat, Xenobiotica 1: 157–168.PubMedCrossRefGoogle Scholar
  3. Dansette, P.M., Amar, C, Valadon, P., Pons, C, Beaune, P.H. and Mansuy, D. 1991, Hydroxylation and formation of electropholic metabolites of tienilic acid and its isomer by human liver microsomes: Catalysis by a P450 IIC different from that responsible for mephenytoin hydroxylation, Biochem. Pharmacol 41: 553–560.PubMedCrossRefGoogle Scholar
  4. Dansette, P.M., Thang, D.C., El Amri, H. and Mansuy, D. 1992, Evidence for thiophene-S-oxide as a primary reactive metabolite of thiophene in vivo: Formation of a dihydrothiophene sulfoxide mercapturic acid, Biochem. Biophys. Res. Commun. 186: 1624–1630.PubMedCrossRefGoogle Scholar
  5. Lecoeur, S., Bonierbale, E., Challine, D., Gautier, J.C., Valadon, P., Dansette, P.M., Catinot, R., Ballet, F., Mansuy D. and Beaune, P.H. 1994, Specificity of in vitro covalent binding of tienilic acid metabolites to human liver microsomes in relationship to the type of hepatotoxicity: Comparison with two directly hepatotoxic drugs, Chem. Res. Toxicol. 7: 434–442.PubMedCrossRefGoogle Scholar
  6. Lopez-Garcia, M.P., Dansette, P.M., Valadon, P., Amar, C, Beaune, P.H., Guengerich, F.P. and Mansuy, D. 1993, Human liver P450s expressed in yeast as tools for reactive metabolite formation studies: Oxidative activation of tienilic acid by P450 2C9 and P450 2C10, Eur. J. Biochem. 213: 223–232.PubMedCrossRefGoogle Scholar
  7. Lopez-Garcia, M.R, Dansette, P.M. and Mansuy, D. 1994, Thiophene derivatives as new mechanism-based inhibitors of cytochromes P450: Inactivation of yeast expressed human liver cytochrome P450 2C9 by tienilic acid, Biochemistry 33: 166–175.PubMedCrossRefGoogle Scholar
  8. Mansuy, D., Dansette, P., Foures, C., Jaouen, M., Moinet, G. and Bayer, N. 1984, Metabolic hydroxylation of the thiophene ring: Isolation of 5-hydroxytienilic acid as the major urinary metabolite in rat and man, Biochem. Pharmacol. 33: 1429–1435.PubMedCrossRefGoogle Scholar
  9. Mansuy, D. 1990, Formation of reactive metabolites and appearance of anti-organelle antibodies in man, Advances in Exp. Med. and Biol. 283: 133–137.CrossRefGoogle Scholar
  10. Mansuy, D., Valadon, P., Erdelmeier, I., Lopez-Garcia, M. R, Amar, C, Girault, J.P. and Dansette, P.M. 1991, Thiophene-S-oxides as new reactive metabolites: Formation by cytochrome P450-dependent oxidation and reaction with nucleophiles, J. Am. Chem. Soc. 113: 7825–7826.CrossRefGoogle Scholar
  11. Neau, E., Dansette, P.M., Andronik, V. and Mansuy, D. 1990, Evidence for 5-hydroxylation of 2-aroyl-thiophenes as a general metabolic pathway using a simple UV-visible assay, Biochem. Pharmacol. 39, 1101–1107.PubMedCrossRefGoogle Scholar
  12. Poupon, R., Homberg, J.C., Abuaf, N., Petit, J., Bodin, F. and Darnis, F. 1980, Atteintes hépatiques dues à l’acide ténilique. Six observations avec présence d’anticorps antireticulum endoplasmique, Nouv. Presse Med. 9: 1881–1884.PubMedGoogle Scholar
  13. Pouzet, P., Erdelmeier, I., Ginderow, D., Mornon, J.P., Dansette, P. and Mansuy, D., 1995, Thiophene-S-oxides: Convenient preparation, first complete structural characterization and unexpected dimerization of one of them, 2,5-dipheny1-1-oxide, JCS Chem. Comm. in press.Google Scholar
  14. Raasch, M.S., 1985, Chemistry of heterocyclic compounds, thiophene and its derivatives, (Gronowitz S., edit.) Wiley, New-York, 44: 871.Google Scholar
  15. Rance, D.J., 1989, Sulfur-containing drugs and related organic compounds, chemistry, biochemistry and toxicology: Metabolism of sulfur functional groups (Damani L.A. Edit.) 1 part B, Ellis Horwood Ldt, Chichester, 217–268.Google Scholar
  16. Zimmerman, H.J., Lewis, J.H., Ishak, K.G. and Maddrey, W. 1984, Ticrynafen-associated hepatic injury: Analysis of 340 cases, Hepatology 4: 315–323.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Daniel Mansuy
    • 1
  • Patrick M. Dansette
    • 1
  1. 1.Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (URA 400)Université Paris VParis Cedex 06France

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