Carcinogenesis, Vol. 20, No. 10, 2003-2009,
October 1999
© 1999 Oxford University Press
Carcinogenesis |
N-Demethylation accompanies 
-hydroxylation in the metabolic activation of tamoxifen in rat liver cells
Institute of Cancer Research, Haddow Laboratories, Cotswold Road, Sutton SM2 5NG, UK
Previous work has shown that a major route of activation of tamoxifen to DNA-binding products in rat liver cells is via 
-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 -hydroxytamoxifen gave rise to both. Furthermore, N,N-didesmethyltamoxifen was found to be responsible for an additional minor DNA adduct formed by tamoxifen, -hydroxytamoxifen and N-desmethyltamoxifen. The involvement of metabolism at the position was confirmed in experiments in which [-D2-ethyl]tamoxifen, but not [ß-D3-ethyl]tamoxifen, produced reduced levels of DNA adducts. Tamoxifen N-oxide and -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 -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 -hydroxylation and N-demethylation, which is followed by Phase II activation at the -position to form a highly reactive sulphate. Detection of tamoxifen-related DNA adducts by 32P-postlabelling is achieved with >90% labelling efficiency.
Abbreviations: [-D2-ethyl]tamoxifen, [3,3-2H2]-(Z)-1-[4-[2-(dimethylamino)-ethoxy]phenyl]-1,2-diphenyl-1-butene; [ß-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.
1 Present address: Imperial College School of Medicine, Division of Biomedical Sciences, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, UK
2 To whom correspondence should be addressed Email: davidp{at}icr.ac.uk
Deceased. Formerly of CRC Centre for Cancer Therapeutics, Institute of Cancer Research,Cotswold Road, Sutton SM2 5NG, UK
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