Journal Article

Sulfation of alpha-hydroxytamoxifen catalyzed by human hydroxysteroid sulfotransferase results in tamoxifen-DNA adducts.

S Shibutani, P M Shaw, N Suzuki, L Dasaradhi, M W Duffel and I Terashima

in Carcinogenesis

Volume 19, issue 11, pages 2007-2011
Published in print November 1998 | ISSN: 0143-3334
Published online November 1998 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/19.11.2007
Sulfation of alpha-hydroxytamoxifen catalyzed by human hydroxysteroid sulfotransferase results in tamoxifen-DNA adducts.

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The formation of tamoxifen (TAM)-derived DNA adducts was investigated by incubation of DNA with (E)-alpha-hydroxytamoxifen [(E)-alpha-OHTAM], 3'-phosphoadenosine 5'-phosphosulfate (PAPS), and human recombinant sulfotransferase. Using 32P-post-labeling and HPLC analysis, two TAM-DNA adducts were detected in incubations that included the human hydroxysteroid sulfotransferase SULT2A1 (hHST). When compared with standards of stereoisomers of alpha-(N2-deoxyguanosinyl)tamoxifen 3'-monophosphate (dG3'P-N2-TAM), the major adduct was identified chromatographically as an epimer of the transform of dG-N2-TAM, and the minor adduct was identified as an epimer of the cis-form. The amount of TAM adducts formed by hHST was approximately three times less than that formed by an equivalent amount of rat hydroxysteroid (alcohol) sulfotransferase a. These results indicate that sulfation of alpha-OHTAM catalyzed by hHST results in the formation of dG-N2-TAMs, highly miscoding lesions, in human tissues.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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