Sulfation of alpha-hydroxytamoxifen catalyzed by human hydroxysteroid sulfotransferase results in tamoxifen-DNA adducts.
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.
Shibutani
S
S
Department of Pharmacological Sciences, State University of New York at Stony Brook 11794-8651, USA. shinya@pharm.som.sunysb.edu
Shaw
P M
PM
Suzuki
N
N
Dasaradhi
L
L
Duffel
M W
MW
Terashima
I
I
D000818:Animals; D018736:DNA Adducts / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000378:metabolism*; D006801:Humans; D018411:Spodoptera; D013431:Sulfates / Q000378:metabolism; D015238:Sulfotransferases / Q000502:physiology*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism*
D018736:DNA Adducts; D004965:Estrogen Antagonists; D013431:Sulfates; C110902:alpha-hydroxytamoxifen; D013629:Tamoxifen; D015238:Sulfotransferases; C028152:alcohol sulfotransferase