Peroxidase activation of 4-hydroxytamoxifen to free radicals detected by EPR spectroscopy.
Free Radic Biol Med
; 22(3): 423-31, 1997.
Article
em En
| MEDLINE
| ID: mdl-8981033
ABSTRACT
4-Hydroxytamoxifen is a major metabolite of the antiestrogenic drug tamoxifen used in the treatment of women with breast cancer. 4-Hydroxytamoxifen is broken down by a horseradish peroxidase/H2O2 system very much more rapidly than tamoxifen and causes much greater DNA damage determined by 32P-postlabelling. EPR spin trapping of 4-hydroxytamoxifen reaction products in the presence of the free radical trap 5,5-dimethyl-1-pyrroline N-oxide, together with glutathione as a hydrogen donor, resulted in the generation of a species with the characteristics of the glutathione thiyl radical (aN approximately 15.3 G, aH approximately 16.2 G). Support for the creation of thiyl radicals comes from the close to stoichiometric time dependent formation of glutathione disulfide concomitant with the loss of glutathione. Similar results were obtained using 4-hydroxytoremifene but no radical formation or glutathione loss could be detected using 3-hydroxytamoxifen (droloxifene). On-line LC-ESI MS analysis of the incubation products from 4-hydroxytamoxifen has identified three products with a protonated molecular mass of 773, consistent with the formation of dimers of 4-hydroxytamoxifen. The role that radical mechanisms have in the carcinogenic effects of tamoxifen in the endometrium or other target organs of women taking this drug remains to be established.
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Base de dados:
MEDLINE
Assunto principal:
Tamoxifeno
/
Espectroscopia de Ressonância de Spin Eletrônica
/
Peroxidase do Rábano Silvestre
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
1997
Tipo de documento:
Article