title: Characterization of human cytochrome P450 enzymes involved in the metabolism of cyamemazine.
abstract: Recombinant human liver microsomal enzymes of the cytochrome P450 family (CYP1A2, CYP2A6, CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1) were used to determine the metabolic fate of the antipsychotic anxiolytic agent cyamemazine. An LC/MS-MS tandem methodology was developed specifically for identifying the presence of cyamemazine and its metabolites in reaction media. All P450 enzymes investigated, with the exception of CYP2A6 and CYP2E1, degraded cyamemazine, albeit to a different extent, with CYP1A2, CYP2C8 and CYP2C19 being the most efficient (>80%). However, in microsomes prepared from native human hepatocytes, only relatively specific competitors (inhibitors and/or substrates) of CYP1A2, CYP2C8, CYP2C9 and CYP3A4 reduced notably the degradation cyamemazine. The main routes of cyamemazine biotransformation are N-mono-demethylation (CYP1A2, CYP3A4 and CYP2C8) and mono-oxidation (either S-oxidized or hydroxylated derivatives which could not be discriminated because characterized by the same mass value) by CYP1A2 and CYP2C9. Secondary metabolic routes yields N,N-di-demethylated and N-demethylated mono-oxidized products. Thus, under in vitro conditions, cyamemazine is extensively degraded by at least four distinct P450 enzymes, into two primary hydrophilic metabolites. These results suggest that cyamemazine detoxification process is unlikely to be significantly impaired by co-administration of therapeutic agents that are substrates of the CYP metabolic system.
authors.affiliation: CHU Toulouse, Toulouse, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Arbus
authors.forename: Amine
authors.initials: A
authors.lastname: Benyamina
authors.forename: Pierre-Michel
authors.initials: PM
authors.lastname: Llorca
authors.forename: Franck
authors.initials: F
authors.lastname: Baylé
authors.forename: Norbert
authors.initials: N
authors.lastname: Bromet
authors.forename: Frédéric
authors.initials: F
authors.lastname: Massiere
authors.forename: Ricardo P
authors.initials: RP
authors.lastname: Garay
authors.forename: Ahcène
authors.initials: A
authors.lastname: Hameg
mesh_terms: D002853:Chromatography, Liquid / Q000379:methods; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D004347:Drug Interactions; D004789:Enzyme Activation; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D010640:Phenothiazines / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism*; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D010640:Phenothiazines; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; C028457:cyamemazine