Peroxidase Activation of 4-Hydroxytamoxifen to Free Radicals Detected by EPR Spectroscopy
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/H 2O 2 system very much more rapidly than tamoxifen and causes much greater DNA damage determined by 32P-post...
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Published in | Free radical biology & medicine Vol. 22; no. 3; pp. 423 - 431 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
1997
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Subjects | |
Online Access | Get full text |
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Summary: | 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/H
2O
2 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 (a
N ∼ 15.3 G, a
H ∼ 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.
Copyright © 1996 Elsevier Science Inc. |
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ISSN: | 0891-5849 1873-4596 |
DOI: | 10.1016/S0891-5849(96)00345-0 |