PT - JOURNAL ARTICLE AU - Sung Yeon Kim AU - Y. R. Santosh Laxmi AU - Naomi Suzuki AU - Kenichiro Ogura AU - Tadashi Watabe AU - Michael W. Duffel AU - Shinya Shibutani TI - FORMATION OF TAMOXIFEN-DNA ADDUCTS VIA <em>O</em>-SULFONATION, NOT <em>O</em>-ACETYLATION, OF α-HYDROXYTAMOXIFEN IN RAT AND HUMAN LIVERS AID - 10.1124/dmd.105.005330 DP - 2005 Nov 01 TA - Drug Metabolism and Disposition PG - 1673--1678 VI - 33 IP - 11 4099 - http://dmd.aspetjournals.org/content/33/11/1673.short 4100 - http://dmd.aspetjournals.org/content/33/11/1673.full SO - Drug Metab Dispos2005 Nov 01; 33 AB - 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 α-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, α-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 α-hydroxylated TAM and its metabolites. The American Society for Pharmacology and Experimental Therapeutics