Oxidations of vincristine catalyzed by peroxidase and ceruloplasmin.
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.
Ahn
S H
SH
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, Univeristy of Iowa, Iowa City 82242, USA.
Duffel
M W
MW
Rosazza
J P
JP
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*
D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine; D014747:Vinblastine; D010544:Peroxidases; D002570:Ceruloplasmin