| Autor: |
Costa, G. Gamboa da, Hamilton, L. P., Beland, F. A., Marques, M. M. |
| Zdroj: |
Chemical Research in Toxicology; March 2000, Vol. 13 Issue: 3 p200-207, 8p |
| Abstrakt: |
Tamoxifen is hepatocarcinogenic in rats and has been associated with an increased risk of endometrial cancer in women. Recent reports suggest that it may be genotoxic in humans. N-Desmethyltamoxifen is a major tamoxifen metabolite that has been proposed to be responsible for one of the major adducts detected in liver DNA of rats treated with tamoxifen. The metabolic activation of N-desmethyltamoxifen to DNA binding products may involve oxidation to α-hydroxy-N-desmethyltamoxifen followed by esterification. In the study presented here, we report the synthesis of α-hydroxy-N-desmethyltamoxifen and the characterization of the major adduct obtained from α-sulfoxy-N-desmethyltamoxifen in vitro as (E)-α-(deoxyguanosin-N2-yl)-N-desmethyltamoxifen. In addition, we use 32P-postlabeling in combination with HPLC to compare the adducts formed in the livers of female Sprague-Dawley rats treated by gavage with tamoxifen or equimolar doses of α-hydroxy-N-desmethyltamoxifen. We conclude that one of the major adducts formed in vivo and previously suggested to derive from N-desmethyltamoxifen is chromatographically identical to α-(deoxyguanosin-N2-yl)-N-desmethyltamoxifen. |
| Databáze: |
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