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Metabolic activation of the phenothiazine antipsychotics chlorpromazine and thioridazine to electrophilic iminoquinone species in human liver microsomes and recombinant P450s.
Chem Biol Interact. 2009 Oct 07; 181(2):220-6.CB

Abstract

The phenothiazine-derived antipsychotics, namely chlorpromazine and thioridazine, have been associated with very rare but severe incidences of hepatotoxicity in patients. While the mechanism of idiosyncratic hepatotoxicity remains unknown, it is possible that metabolic activation and subsequent covalently binding of reactive metabolites to cellular proteins play a causative role. Studies were initiated to determine whether chlorpromazine and thioridazine undergo cytochrome P450 (P450)-mediated bioactivation in human liver microsomes to electrophilic intermediates. LC/MS/MS analysis of incubations containing chlorpromazine or thioridazine in the presence of NADPH and glutathione (GSH) revealed the formation of GSH conjugates derived from the addition of the sulfydryl nucleophile to monohydroxy metabolites of chlorpromazine and thioridazine, respectively. Formation of reactive intermediates of chlorpromazine and thioridazine was primarily mediated by heterologously expressed recombinant CYP2D6, and to a less extent, CYP1A2. The 7-hydroxyl metabolites of chlorpromazine and thioridazine were also detected by tandem mass spectrometry. A tentative pathway states that after initial 7-hydroxylation, a bioactivation sequence involves P450-catalyzed oxidation of the phenothiazine core to an electrophilic quinone imine intermediate, which is subsequently attacked by glutathione yielding the sulfydryl conjugates. The results from the current investigation constitute the first report on the cytochrome P450-catalyzed bioactivation of the phenothiazine antipsychotics chlorpromazine and thioridazine.

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Publisher Full Text

Authors+Show Affiliations

Wen B
Department of Drug Metabolism and Pharmacokinetics, Roche Palo Alto, CA 94304, USA. bo.wen@roche.com
Zhou M
No affiliation info available

MeSH

Antipsychotic AgentsBiotransformationChlorpromazineChromatography, High Pressure LiquidCytochrome P-450 CYP2D6Cytochrome P-450 CYP2D6 InhibitorsDose-Response Relationship, DrugEnzyme InhibitorsGlutathioneHumansIn Vitro TechniquesMicrosomes, LiverQuinidineQuinonesTandem Mass SpectrometryThioridazine

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19482014

Citation

Wen, Bo, and Mingyan Zhou. "Metabolic Activation of the Phenothiazine Antipsychotics Chlorpromazine and Thioridazine to Electrophilic Iminoquinone Species in Human Liver Microsomes and Recombinant P450s." Chemico-biological Interactions, vol. 181, no. 2, 2009, pp. 220-6.
Wen B, Zhou M. Metabolic activation of the phenothiazine antipsychotics chlorpromazine and thioridazine to electrophilic iminoquinone species in human liver microsomes and recombinant P450s. Chem Biol Interact. 2009;181(2):220-6.
Wen, B., & Zhou, M. (2009). Metabolic activation of the phenothiazine antipsychotics chlorpromazine and thioridazine to electrophilic iminoquinone species in human liver microsomes and recombinant P450s. Chemico-biological Interactions, 181(2), 220-6. https://doi.org/10.1016/j.cbi.2009.05.014
Wen B, Zhou M. Metabolic Activation of the Phenothiazine Antipsychotics Chlorpromazine and Thioridazine to Electrophilic Iminoquinone Species in Human Liver Microsomes and Recombinant P450s. Chem Biol Interact. 2009 Oct 7;181(2):220-6. PubMed PMID: 19482014.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metabolic activation of the phenothiazine antipsychotics chlorpromazine and thioridazine to electrophilic iminoquinone species in human liver microsomes and recombinant P450s. AU - Wen,Bo, AU - Zhou,Mingyan, Y1 - 2009/05/29/ PY - 2009/04/02/received PY - 2009/05/20/revised PY - 2009/05/22/accepted PY - 2009/6/2/entrez PY - 2009/6/2/pubmed PY - 2009/9/4/medline SP - 220 EP - 6 JF - Chemico-biological interactions JO - Chem Biol Interact VL - 181 IS - 2 N2 - The phenothiazine-derived antipsychotics, namely chlorpromazine and thioridazine, have been associated with very rare but severe incidences of hepatotoxicity in patients. While the mechanism of idiosyncratic hepatotoxicity remains unknown, it is possible that metabolic activation and subsequent covalently binding of reactive metabolites to cellular proteins play a causative role. Studies were initiated to determine whether chlorpromazine and thioridazine undergo cytochrome P450 (P450)-mediated bioactivation in human liver microsomes to electrophilic intermediates. LC/MS/MS analysis of incubations containing chlorpromazine or thioridazine in the presence of NADPH and glutathione (GSH) revealed the formation of GSH conjugates derived from the addition of the sulfydryl nucleophile to monohydroxy metabolites of chlorpromazine and thioridazine, respectively. Formation of reactive intermediates of chlorpromazine and thioridazine was primarily mediated by heterologously expressed recombinant CYP2D6, and to a less extent, CYP1A2. The 7-hydroxyl metabolites of chlorpromazine and thioridazine were also detected by tandem mass spectrometry. A tentative pathway states that after initial 7-hydroxylation, a bioactivation sequence involves P450-catalyzed oxidation of the phenothiazine core to an electrophilic quinone imine intermediate, which is subsequently attacked by glutathione yielding the sulfydryl conjugates. The results from the current investigation constitute the first report on the cytochrome P450-catalyzed bioactivation of the phenothiazine antipsychotics chlorpromazine and thioridazine. SN - 1872-7786 UR - https://www.unboundmedicine.com/medline/citation/19482014/Metabolic_activation_of_the_phenothiazine_antipsychotics_chlorpromazine_and_thioridazine_to_electrophilic_iminoquinone_species_in_human_liver_microsomes_and_recombinant_P450s_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0009-2797(09)00215-4 DB - PRIME DP - Unbound Medicine ER -