Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4

被引：43

作者：

Kalgutkar, AS ^{[1
]}

Henne, KR ^{[1
]}

Lame, ME ^{[1
]}

Vaz, ADN ^{[1
]}

Collin, C ^{[1
]}

Soglia, JR ^{[1
]}

Zhao, SX ^{[1
]}

Hop, CECA ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Pharmacokinet Dynam & Metab Dept, Groton, CT 06340 USA

来源：

CHEMICO-BIOLOGICAL INTERACTIONS | 2005年 / 155卷 / 1-2期

关键词：

trazodone; metabolite; bioactivation; p450; hepatotoxicity; oxidation;

D O I：

10.1016/j.cbi.2005.03.036

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 suifydryl nucleophile to mono-hydroxylated- and hydrated-trazodone metabolites. Product ion spectra suggested that mono-hydroxylation and suifydryl 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. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

引用

页码：10 / 20

页数：11

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