Bioactivation of the tricyclic antidepressant amitriptyline and its metabolite nortriptyline to arene oxide intermediates in human liver microsomes and recombinant P450s.
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Wen B, Ma L, Zhu M
Bioactivation of the tricyclic antidepressant amitriptyline and its metabolite nortriptyline to arene oxide intermediates in human liver microsomes and recombinant P450s.
Chem Biol Interact. 2008 May 9;173(1):59-67. doi: 10.1016/j.cbi.2008.02.001. Epub 2008 Feb 14.
- PubMed ID
- 18359012 [ View in PubMed]
- Abstract
Amitriptyline, the most widely used tricyclic antidepressant, has been associated with very rare but severe incidences of hepatotoxicity in patients. While the mechanism of idiosyncratic hepatotoxicity remains unknown, it is proposed that metabolic activation of amitriptyline and subsequent covalently binding of reactive metabolites to cellular proteins play a causative role. Studies were initiated to determine whether amitriptyline undergoes cytochrome P450 (P450)-mediated bioactivation in human liver microsomes to electrophilic intermediates. LC/MS/MS analysis of incubations containing amitriptyline and NADPH-supplemented microsomes in the presence of glutathione (GSH) revealed the formation of GSH conjugates derived from the addition of the sulfydryl nucleophile to hydrated metabolites of amitriptyline and nortriptyline, the major N-dealkylated metabolite of amitriptyline. Formation of GSH conjugates was primarily catalyzed by heterologously expressed recombinant CYP2D6, CYP3A4, CYP3A5, and to a less extent, CYP1A2. Corresponding dihydrodiol metabolites of amitriptyline and nortriptyline were also detected by tandem mass spectrometry. These findings are consistent with a bioactivation sequence involving initial P450-catalyzed oxidation of the aromatic nucleus in amitriptyline to an electrophilic arene oxide intermediate, which is subsequently attacked by glutathione and water yielding the sulfydryl conjugate and the dihydrodiol metabolite, respectively. The results from the current investigation constitute the first report on the cytochrome P450-catalyzed bioactivation of the antidepressants amitriptyline and nortriptyline. It is proposed that the arene oxide intermediate(s) may represent a rate-limiting step in the initiation of amitriptyline and nortriptyline-mediated hepatotoxicity.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Amitriptyline Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Amitriptyline Cytochrome P450 2D6 Protein Humans UnknownSubstrateDetails Amitriptyline Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Amitriptyline Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails Nortriptyline Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Nortriptyline Cytochrome P450 2D6 Protein Humans UnknownSubstrateInhibitorDetails Nortriptyline Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Nortriptyline Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails