S. Shibutani et al., ALPHA-HYDROXYTAMOXIFEN IS A SUBSTRATE OF HYDROXYSTEROID (ALCOHOL) SULFOTRANSFERASE, RESULTING IN TAMOXIFEN DNA-ADDUCTS, Cancer research, 58(4), 1998, pp. 647-653
When alpha-hydroxytamoxifen (alpha-OHTAM) was incubated with rat liver
hydroxysteroid (alcohol) sulfotransferase a (STa) and 3'-phosphoadeno
sine 5'-phosphosulfate, (E)-alpha-OHTAM was found to be a better subst
rate for STa than (Z)-alpha-OHTAM. To explore the formation of tamoxif
en (TAM)-derived DNA adducts, DNA was incubated with STa and either (E
)-alpha-OHTAM or (Z)-alpha-OHTAM in the presence of 3'-phosphoadenosin
e 5'-phosphosulfate, Using P-32-postlabeling analysis, the amount of T
AM-DNA adducts resulting from (E)-alpha-OHTAM was 29 times higher than
that observed with (E)-alpha-OHTAM alone. Using (Z)-alpha-OHTAM and S
Ta, some TAM-DNA adducts were also detected but at levels 6.5 times lo
wer than that observed with (E)-alpha-OHTAM and STa. When compared wit
h standards of stereoisomers of 2'-deoxyguanosine 3'-monophosphate-N-2
-tamoxifen, the major tamoxifen adduct was identified chromatographica
lly as an epimer of the trans form of alpha-(N-2-deoxyguanosinyl)tamox
ifen, and the minor adduct was identified as an epimer of the cis form
, In the reaction mixture, a conversion from (E)-alpha-OHTAM to (Z)-al
pha-OHTAM through the carbocation intermediate was also detected, Thes
e results show that sulfation of alpha-OHTAM catalyzed by STa results
in the formation of TAM-DNA adducts.