Journal Article

<i>N</i>-Demethylation accompanies α-hydroxylation in the metabolic activation of tamoxifen in rat liver cells

David H. Phillips, Alan Hewer, Martin N. Horton, Kathleen J. Cole, Paul L. Carmichael, Warren Davis and Martin R. Osborne

in Carcinogenesis

Volume 20, issue 10, pages 2003-2009
Published in print October 1999 | ISSN: 0143-3334
Published online October 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.10.2003
N-Demethylation accompanies α-hydroxylation in the metabolic activation of tamoxifen in rat liver cells

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Previous work has shown that a major route of activation of tamoxifen to DNA-binding products in rat liver cells is via α-hydroxylation leading to modification of the N2-position of guanine in DNA and to a lesser extent the N6-position of adenine. Improved resolution by HPLC has now identified two major adducts in rat liver DNA, one of them the aforementioned tamoxifen–N2-guanine adduct and the other the equivalent adduct in which the tamoxifen moiety has lost a methyl group. Treatment of rats or rat hepatocytes with N-desmethyltamoxifen gave rise to the second adduct, whereas treatment with tamoxifen or α-hydroxytamoxifen gave rise to both. Furthermore, N,N-didesmethyltamoxifen was found to be responsible for an additional minor DNA adduct formed by tamoxifen, α-hydroxytamoxifen and N-desmethyltamoxifen. The involvement of metabolism at the α position was confirmed in experiments in which [α-D2-ethyl]tamoxifen, but not [β-D3-ethyl]tamoxifen, produced reduced levels of DNA adducts. Tamoxifen N-oxide and α-hydroxytamoxifen N-oxide also gave rise to DNA adducts in rat liver cells, but the adduct patterns were very similar to those formed by tamoxifen and α-hydroxytamoxifen, indicating that the N-oxygen is lost prior to DNA binding. These and earlier results demonstrate that in rat liver cells in vivo and in vitro, Phase I metabolic activation of tamoxifen involves both α-hydroxylation and N-demethylation, which is followed by Phase II activation at the α-position to form a highly reactive sulphate. Detection of tamoxifen-related DNA adducts by 32P-postlabelling is achieved with >90% labelling efficiency.

Keywords: [α-D2-ethyl]tamoxifen, [3,3-2H2]-(Z)-1-[4-[2-(dimethylamino)-ethoxy]phenyl]-1,2-diphenyl-1-butene; [β-D3-ethyl]tamoxifen, [4,4,4-2H3]-(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1,2-diphenyl-1-butene; [D5-ethyl]tamoxifen, [3,3,4,4,4-2H5]-(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1,2-diphenyl-1-butene; PEI, polyethyleneimine; tamoxifen, (Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1,2-diphenyl-1-butene.

Journal Article.  4715 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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