Formation of tamoxifen-DNA adducts via O-sulfonation, not O-acetylation, of alpha-hydroxytamoxifen in rat and human livers.
Tamoxifen (TAM) is used as the standard endocrine therapy for breast cancer patients and as a chemopreventive agent for women at high risk for this disease. Unfortunately, treatment of TAM increases the incidence of endometrial cancer; this may be due to the genotoxic damage induced by TAM metabolites. Formation of TAM-DNA adducts in rat liver correlates with the development of hepatocarcinoma. TAM-DNA adducts are proposed to be formed through O-sulfonation and/or O-acetylation of alpha-hydroxylated TAM and its metabolites. However, the role of O-sulfonation and O-acetylation in the formation of TAM-DNA adducts has not been extensively investigated. Rat or human hydroxysteroid sulfotransferases (HST), acetyltransferases, and liver cytosol were incubated with calf thymus DNA, alpha-OHTAM, and either 3'-phosphoadenosine 5'-phosphosulfate (PAPS) or acetyl coenzyme A (acetyl-CoA) as a cofactor and analyzed for TAM-DNA adduct formation, using 32P postlableling/polyacrylamide gel electrophoresis analysis. TAM-DNA adduct was formed when PAPS, not acetyl-CoA, was used. No TAM-DNA adducts were produced using human N-acetyltransferase I and II. HST antibody inhibited approximately 90% of TAM-DNA adduct formation generated by the cytosol or HST, suggesting that HST is primarily involved in the formation of TAM-DNA adducts. The formation of TAM-DNA adducts with rat liver cytosol and HST was much higher than that of human liver cytosol and HST. Our results indicate that TAM-DNA adducts are formed via O-sulfonation, not O-acetylation, of alpha-hydroxylated TAM and its metabolites.
Kim
Sung Yeon
SY
Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, NY 11794-8651, USA.
Laxmi
Y R Santosh
YR
Suzuki
Naomi
N
Ogura
Kenichiro
K
Watabe
Tadashi
T
Duffel
Michael W
MW
Shibutani
Shinya
S
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013450:Sulfones / Q000378:metabolism; D015238:Sulfotransferases / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
D018736:DNA Adducts; D013450:Sulfones; C110902:alpha-hydroxytamoxifen; D013629:Tamoxifen; D000123:Acetyltransferases; D015238:Sulfotransferases; C028152:alcohol sulfotransferase