Journal Article

Further characterization of the DNA adducts formed in rat liver after the administration of tamoxifen, <i>N</i>-desmethyltamoxifen or <i>N</i>,<i>N</i>-didesmethyltamoxifen

Karen Brown, Robert T. Heydon, Rebekah Jukes, Ian N.H. White and Elizabeth A. Martin

in Carcinogenesis

Volume 20, issue 10, pages 2011-2016
Published in print October 1999 | ISSN: 0143-3334
Published online October 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.10.2011
Further characterization of the DNA adducts formed in rat liver after the administration of tamoxifen, N-desmethyltamoxifen or N,N-didesmethyltamoxifen

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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 α-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.

Journal Article.  3566 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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