title: Reactive intermediates produced from the metabolism of the vanilloid ring of capsaicinoids by p450 enzymes.
abstract: This study characterized electrophilic and radical products derived from the metabolism of capsaicin by cytochrome P450 and peroxidase enzymes. Multiple glutathione and β-mercaptoethanol conjugates (a.k.a., adducts), derived from the trapping of quinone methide and quinone intermediates of capsaicin, its analogue nonivamide, and O-demethylated and aromatic hydroxylated metabolites thereof, were produced by human liver microsomes and individual recombinant human P450 enzymes. Conjugates derived from concomitant dehydrogenation of the alkyl terminus of capsaicin were also characterized. Modifications to the 4-OH substituent of the vanilloid ring of capsaicinoids largely prevented the formation of electrophilic intermediates, consistent with the proposed structures and mechanisms of formation for the various conjugates. 5,5'-Dicapsaicin, presumably arising from the bimolecular coupling of free radical intermediates was also characterized. Finally, the analysis of hepatic glutathione conjugates and urinary N-acetylcysteine conjugates from mice dosed with capsaicin confirmed the formation of glutathione conjugates of O-demethylated quinone methide and 5-OH-capsaicin in vivo. These data demonstrated that capsaicin and structurally similar analogues are converted to reactive intermediates by certain P450 enzymes, which may partially explain conflicting reports related to the cytotoxic, pro-carcinogenic, and chemoprotective effects of capsaicinoids in different cells and/or organ systems.
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah , 30 S. 2000 E., Room 201 Skaggs Hall, Salt Lake City, Utah 84112, United States.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reilly
authors.forename: Fred
authors.initials: F
authors.lastname: Henion
authors.forename: Tim S
authors.initials: TS
authors.lastname: Bugni
authors.forename: Manivannan
authors.initials: M
authors.lastname: Ethirajan
authors.forename: Chris
authors.initials: C
authors.lastname: Stockmann
authors.forename: Kartick C
authors.initials: KC
authors.lastname: Pramanik
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Srivastava
authors.forename: Garold S
authors.initials: GS
authors.lastname: Yost
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D000818:Animals; D002211:Capsaicin / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D045563:Indolequinones / Q000032:analysis / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D010103:Oxygen Isotopes / Q000737:chemistry; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: C483184:5,5'-dicapsaicin; D045563:Indolequinones; D010103:Oxygen Isotopes; D011994:Recombinant Proteins; C068040:quinone methide; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D002211:Capsaicin; D000111:Acetylcysteine