title: Oxidations of vincristine catalyzed by peroxidase and ceruloplasmin.
abstract: The dimeric Catharanthus alkaloid vincristine (1) is oxidized to the same ring fission product in incubations with either horseradish peroxidase or the human serum copper oxidase ceruloplasmin. Horseradish peroxidase-catalyzed oxidation of vincristine requires hydrogen peroxide, whereas ceruloplasmin-catalyzed oxidation of vincristine requires chlorpromazine as a "shuttle oxidant". Preparative-scale incubations allowed for the production, isolation, structural characterization, and biological evaluation of the metabolite. The metabolite was identified as the heterocyclic ring cleavage product N-formylcatharinine (5). N-Formylcatharinine was 118 times less active than vincristine in an in vitro test against a human T-cell leukemic cell line. Therefore, these enzyme-catalyzed reactions lead to bioinactivation of vincristine.
authors.affiliation: Division of Medicinal and Natural Products Chemistry, College of Pharmacy, Univeristy of Iowa, Iowa City 82242, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Ahn
authors.forename: M W
authors.initials: MW
authors.lastname: Duffel
authors.forename: J P
authors.initials: JP
authors.lastname: Rosazza
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D001711:Biotransformation; D002570:Ceruloplasmin / Q000378:metabolism*; D002855:Chromatography, Thin Layer; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015458:Leukemia, T-Cell / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D010544:Peroxidases / Q000378:metabolism*; D013055:Spectrophotometry, Infrared; D014747:Vinblastine / Q000378:metabolism; D014750:Vincristine / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine; D014747:Vinblastine; D010544:Peroxidases; D002570:Ceruloplasmin