Peroxidase-mediated dealkylation of tamoxifen, detected by electrospray ionization–mass spectrometry, and activation to form DNA adducts

摘要: Abstract Tamoxifen (TAM) is extensively used for the treatment and prevention of breast cancer. Associated with TAM a two- to eightfold increase in risk endometrial To understand mechanisms associated this increased several pathways metabolism DNA adduct formation have been studied. The purpose study was investigate role peroxidase enzymes its activation form adducts. Using advanced tandem mass spectrometry we investigated peroxidase-mediated TAM. Incubation horseradish (HRP) H2O2 produced multiple metabolites. Electrospray ionization–MS/MS analysis metabolites demonstrated peak at 301.3 m/z daughter ions 183.0, 166.9, 128.9, 120.9 m/z, which identified metabolite as E (ME). levels ME were significantly inhibited by addition ascorbic acid incubation mixture. Co-incubation either or HRP three adducts RAL 1.97 ± 0.01 × 10− 7 8.45 ± 2.7 × 10− 7. Oxidation MnO2 quinone methide (MEQM). Furthermore, resulted MEQM. Reaction calf thymus MEQM 9.8 ± 1.0 × 10− 7. Rechromatography analyses indicated that 1, 2, 3 formed same those chemical reaction results these studies demonstrate can both metabolize primary activate intermediate, reacts It possible peroxidase-like activity endometrium could contribute damage genotoxic effects after administration.