title: Tamoxifen-DNA adducts formed by alpha-acetoxytamoxifen N-oxide.
abstract: DNA adduct formation is assumed to be a major carcinogenic event, leading to the development of endometrial cancer in breast cancer patients taking tamoxifen and healthy women enrolled in a tamoxifen chemopreventive trial. To determine whether DNA adducts were formed by tamoxifen, trans- and cis-alpha-acetoxytamoxifen N-oxides were synthesized as model-activated forms via major tamoxifen metabolites, tamoxifen N-oxide and alpha-hydroxytamoxifen N-oxide. When alpha-acetoxytamoxifen N-oxide was reacted with human DNA, at least three DNA adducts were detected by (32)P-postlabeling coupled with HPLC. The total amount of DNA adducts formed by trans-alpha-hydroxytamoxifen N-oxide was 1.5-fold higher than that formed by the cis form. Both trans- and cis-alpha-acetoxytamoxifen N-oxide reacted with 2'-deoxyguanosine, resulting in the formation of three adducts (fr-1, fr-2-1, and fr-2-2). These products were studied using mass spectroscopy and proton magnetic resonance spectroscopy. fr-1 was identified as a mixture of the epimers of trans-alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide. fr-2-1 and fr-2-2 were determined to be epimers of cis-alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide.
authors.affiliation: Second Department of Surgery, School of Medicine, University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan. umemoto@clin.med.tokushima-u.ac.jp
authors.forename: A
authors.initials: A
authors.lastname: Umemoto
authors.forename: Y
authors.initials: Y
authors.lastname: Monden
authors.forename: K
authors.initials: K
authors.lastname: Komaki
authors.forename: M
authors.initials: M
authors.lastname: Suwa
authors.forename: Y
authors.initials: Y
authors.lastname: Kanno
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: C X
authors.initials: CX
authors.lastname: Lin
authors.forename: Y
authors.initials: Y
authors.lastname: Ueyama
authors.forename: M A
authors.initials: MA
authors.lastname: Momen
authors.forename: A
authors.initials: A
authors.lastname: Ravindernath
authors.forename: S
authors.initials: S
authors.lastname: Shibutani
mesh_terms: D000107:Acetylation; D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000737:chemistry*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013431:Sulfates / Q000737:chemistry; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018736:DNA Adducts; D013431:Sulfates; C105080:alpha-acetoxytamoxifen; D013629:Tamoxifen