| Abstract | Tamoxifen undergoes sequential metabolism to N-desmethyltamoxifen and N,N-didesmethyltamoxifen. Whereas N-desmethyltamoxifen is a major metabolite in humans, nonhuman primates, and rats, appreciable concentrations of N,N-didesmethyltamoxifen are formed in humans and nonhuman primates but not in rats. This difference in the extent of N,N-didesmethyltamoxifen formation may be important because it has been proposed that N,N-didesmethyltamoxifen inhibits the cytochrome P450 (CYP)-catalyzed alpha-hydroxylation of tamoxifen and resultant tamoxifen-DNA adduct formation. To test this hypothesis directly, we compared the extent of tamoxifen-DNA adduct formation in rats co-administered 27micromol N,N-didesmethyltamoxifen per kg body weight and either 27micromol tamoxifen per kg body weight or 27micromol alpha-hydroxytamoxifen per kg body weight daily for 7days. Female Sprague-Dawley rats treated with N,N-didesmethyltamoxifen had a 44% decrease (p >0.05) in CYP 3A2 content (the CYP isoform responsible for tamoxifen alpha-hydroxylation), an 18% decrease (p =0.010) in CYP 3A activity, and higher blood levels of tamoxifen and N-desmethyltamoxifen compared to rats treated with solvent. Total tamoxifen-DNA adduct levels were 4.1-fold higher (p <0.001) in rats given alpha-hydroxytamoxifen as compared to tamoxifen. N,N-Didesmethyltamoxifen treatment caused a 1.2-fold increase in total tamoxifen-DNA adduct levels with both tamoxifen and alpha-hydroxytamoxifen, a difference that was not significant. These results indicate that, with this experimental model, N,N-didesmethyltamoxifen does not impair the metabolism of tamoxifen to a reactive electrophile. |
| Authors | Gonçalo Gamboa da Costa, M Matilde Marques, Xin Fu, Mona I Churchwell, Yu-Ping Wang, Daniel R Doerge, Frederick A Beland
(Affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade Técnica de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.)
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| Journal | Cancer letters
(Cancer Lett)
Vol. 257
Issue 2
Pg. 191-8
(Nov 18 2007)
ISSN: 0304-3835 Ireland |
| PMID | 17765393
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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| Chemical References |
- DNA Adducts
- Membrane Proteins
- N,N-didesmethyltamoxifen
- alpha-hydroxytamoxifen
- Tamoxifen
- Aryl Hydrocarbon Hydroxylases
- Cyp3a2 protein, rat
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| Topics |
- Animals
- Aryl Hydrocarbon Hydroxylases
(antagonists & inhibitors, metabolism)
- Blotting, Western
- Chromatography, High Pressure Liquid
- DNA Adducts
(analysis, chemistry, drug effects)
- Female
- Liver
(chemistry, drug effects, metabolism)
- Membrane Proteins
(antagonists & inhibitors, metabolism)
- Molecular Structure
- Rats
- Rats, Sprague-Dawley
- Spectrometry, Mass, Electrospray Ionization
- Tamoxifen
(analogs & derivatives, blood, chemistry, toxicity)
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