Carcinogenesis, Vol. 20, No. 10, 2011-2016,
October 1999
© 1999 Oxford University Press
Carcinogenesis |
Further characterization of the DNA adducts formed in rat liver after the administration of tamoxifen, N-desmethyltamoxifen or N,N-didesmethyltamoxifen
MRC Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK
The present study compares the formation of DNA adducts, determined by 32P-postlabelling, in the livers of rats given tamoxifen and the N-demethylated metabolites N-desmethyltamoxifen and N,N-didesmethyltamoxifen. Results show that after 4 days treatment (0.11 mmol/kg i.p.), similar levels of DNA damage were seen after treatment with either tamoxifen or N-desmethyltamoxifen [109 ± 40 (n = 3) and 100 ± 33 (n = 4) adducts/108 nucleotides, respectively], even though the concentration of tamoxifen in the livers of tamoxifen-treated rats was about half that of N-desmethyltamoxifen in the N-desmethyltamoxifen-treated animals (51 ± 16 and 100 ± 8 nmol/g, respectively). Administration of N,N-didesmethyltamoxifen to rats resulted in a 5-fold lower level of damage (19 adducts/108 nucleotides, n = 2). Following 32P-postlabelling and HPLC, hepatic DNA from rats treated with tamoxifen and its metabolites showed distinctive patterns of adducts. Treatment of rats with N,N-didesmethyltamoxifen gave a major product that co-eluted with one of the minor adduct peaks seen in the livers of rats given tamoxifen. Following dosing with N-desmethyltamoxifen, the major product co-eluted with one of the main peaks seen following treatment of rats with tamoxifen. This suggests that tamoxifen can be metabolically converted to N-desmethyltamoxifen prior to activation. However, analysis of the 32P-postlabelled products from the reaction between 
-acetoxytamoxifen and calf thymus DNA showed two main peaks, the smaller one of which (~15% of the total) also co-eluted with that attributed to N-desmethyltamoxifen. This indicates that N-desmethyltamoxifen and N,N-didesmethyltamoxifen are activated in a similar manner to tamoxifen leading to a complex mixture of adducts. Since an HPLC system does not exist that can fully separate all these 32P-postlabelled adducts, care has to be taken when interpreting results and determining the relative importance of individual adducts and the metabolites they are derived from in the carcinogenic process.
1 Present address: Lawrence Livermore National Laboratory,7000 East Avenue L452, CA 94551-9900, USA
2 To whom correspondence should be addressedEmail: eam6{at}le.ac.uk
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