New Biological Reactive Intermediates
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).
KeywordsHuman Liver Microsome Reactive Metabolite Thiophene Ring Mercapturic Acid Thiophene Derivative
Unable to display preview. Download preview PDF.
- 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
- 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
- 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
- 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
- Raasch, M.S., 1985, Chemistry of heterocyclic compounds, thiophene and its derivatives, (Gronowitz S., edit.) Wiley, New-York, 44: 871.Google Scholar
- 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