Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4
| Autor: | John R. Soglia, Sabrina X. Zhao, Amit S. Kalgutkar, Cornelis E.C.A. Hop, Kirk R. Henne, Alfin D. N. Vaz, Mary E. Lame, Claire Collin |
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| Rok vydání: | 2005 |
| Předmět: |
Spectrometry
Mass Electrospray Ionization Stereochemistry Metabolite Epoxide Toxicology chemistry.chemical_compound Cytochrome P-450 Enzyme System Cytochrome P-450 CYP3A Benzoquinones medicine Humans Biotransformation Chromatography High Pressure Liquid Chemistry Trazodone General Medicine Glutathione Recombinant Proteins Quinone Liver Electrophile Microsomes Liver Microsome Antidepressive Agents Second-Generation Epoxy Compounds Imines medicine.drug |
| Zdroj: | Chemico-Biological Interactions. 155:10-20 |
| ISSN: | 0009-2797 |
| DOI: | 10.1016/j.cbi.2005.03.036 |
| Popis: | Therapy with the antidepressant trazodone has been associated with several cases of idiosyncratic hepatotoxicity. While the mechanism of hepatotoxicity remains unknown, it is possible that reactive metabolites of trazodone play a causative role. Studies were initiated to determine whether trazodone undergoes bioactivation in human liver microsomes to electrophilic intermediates. LC/MS/MS analysis of incubations containing trazodone and NADPH-supplemented microsomes or recombinant P4503A4 in the presence of glutathione revealed the formation of conjugates derived from the addition of the sulfydryl nucleophile to mono-hydroxylated- and hydrated-trazodone metabolites. Product ion spectra suggested that mono-hydroxylation and sulfydryl conjugation occurred on the 3-chlorophenyl-ring, whereas hydration and subsequent sulfydryl conjugation had occurred on the triazolopyridinone ring system. These findings are consistent with bioactivation sequences involving: (1) aromatic hydroxylation of the 3-chlorophenyl-ring in trazodone followed by the two-electron oxidation of this metabolite to a reactive quinone-imine intermediate, which reacts with glutathione in a 1,4-Michael fashion and (2) oxidation of the pyridinone ring to an electrophilic epoxide, ring opening of which, by glutathione or water generates the corresponding hydrated-trazodone-thiol conjugate or the stable diol metabolite, respectively. The pathway involving trazodone bioactivation to the quinone-imine has also been observed with many para-hydroxyanilines including the structurally related antidepressant nefazodone. It is proposed that the quinone-imine and/or the epoxide intermediate(s) may represent a rate-limiting step in the initiation of trazodone-mediated hepatotoxicity. |
| Databáze: | OpenAIRE |
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