Tamoxifen-DNA adducts formed by alpha-acetoxytamoxifen N-oxide.
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.
Umemoto
A
A
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
Monden
Y
Y
Komaki
K
K
Suwa
M
M
Kanno
Y
Y
Suzuki
M
M
Lin
C X
CX
Ueyama
Y
Y
Momen
M A
MA
Ravindernath
A
A
Shibutani
S
S
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*
D018931:Antineoplastic Agents, Hormonal; D018736:DNA Adducts; D013431:Sulfates; C105080:alpha-acetoxytamoxifen; D013629:Tamoxifen