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Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4.
Chem Biol Interact. 2005 Jun 30; 155(1-2):10-20.CB

Abstract

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.

Authors+Show Affiliations

Kalgutkar AS
Pharmacokinetics Dynamics and Metabolism Department, Pfizer Global Research and Development, Eastern Point Road, Groton, MA 06340, USA. amit_kalgutkar@groton.pfizer.com
Henne KR
No affiliation info available
Lame ME
No affiliation info available
Vaz AD
No affiliation info available
Collin C
No affiliation info available
Soglia JR
No affiliation info available
Zhao SX
No affiliation info available
Hop CE
No affiliation info available

MeSH

Antidepressive Agents, Second-GenerationBenzoquinonesBiotransformationChromatography, High Pressure LiquidCytochrome P-450 CYP3ACytochrome P-450 Enzyme SystemEpoxy CompoundsHumansIminesLiverMicrosomes, LiverRecombinant ProteinsSpectrometry, Mass, Electrospray IonizationTrazodone

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15978881

Citation

Kalgutkar, Amit S., et al. "Metabolic Activation of the Nontricyclic Antidepressant Trazodone to Electrophilic Quinone-imine and Epoxide Intermediates in Human Liver Microsomes and Recombinant P4503A4." Chemico-biological Interactions, vol. 155, no. 1-2, 2005, pp. 10-20.
Kalgutkar AS, Henne KR, Lame ME, et al. Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4. Chem Biol Interact. 2005;155(1-2):10-20.
Kalgutkar, A. S., Henne, K. R., Lame, M. E., Vaz, A. D., Collin, C., Soglia, J. R., Zhao, S. X., & Hop, C. E. (2005). Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4. Chemico-biological Interactions, 155(1-2), 10-20.
Kalgutkar AS, et al. Metabolic Activation of the Nontricyclic Antidepressant Trazodone to Electrophilic Quinone-imine and Epoxide Intermediates in Human Liver Microsomes and Recombinant P4503A4. Chem Biol Interact. 2005 Jun 30;155(1-2):10-20. PubMed PMID: 15978881.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4. AU - Kalgutkar,Amit S, AU - Henne,Kirk R, AU - Lame,Mary E, AU - Vaz,Alfin D N, AU - Collin,Claire, AU - Soglia,John R, AU - Zhao,Sabrina X, AU - Hop,Cornelis E C A, Y1 - 2005/04/18/ PY - 2005/01/20/received PY - 2005/03/09/revised PY - 2005/03/09/accepted PY - 2005/6/28/pubmed PY - 2005/8/24/medline PY - 2005/6/28/entrez SP - 10 EP - 20 JF - Chemico-biological interactions JO - Chem Biol Interact VL - 155 IS - 1-2 N2 - 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. SN - 0009-2797 UR - https://www.unboundmedicine.com/medline/citation/15978881/Metabolic_activation_of_the_nontricyclic_antidepressant_trazodone_to_electrophilic_quinone_imine_and_epoxide_intermediates_in_human_liver_microsomes_and_recombinant_P4503A4_ DB - PRIME DP - Unbound Medicine ER -
Grapherence [↓4]

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