Carcinogenesis, Vol. 21, No. 9, 1737-1744,
September 2000
© 2000 Oxford University Press
Carcinogenesis |
Identification of hepatic tamoxifen–DNA adducts in mice: 
-(N2-deoxyguanosinyl)tamoxifen and -(N2-deoxyguanosinyl)tamoxifen N-oxide
Second Department of Surgery, School of Medicine, University of Tokushima, Kuramoto-cho 3-18-15, Tokushima 770-8503,
1 Pharmaceuticals Group, Nippon Kayaku Co. Ltd, Shimo 3-31-12, Kita-ku, Tokyo 115-8588, Japan and
2 Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA
Tamoxifen–DNA adducts detected in the liver of mice treated with tamoxifen have not yet been identified. In the present study a new type of tamoxifen–DNA adduct, four stereoisomers of 
-(N2-deoxyguanosinyl)tamoxifen N-oxide 3'-monophosphate (dG3'P-N2-TAM N-oxide) were prepared as standard DNA adducts by reacting 2'-deoxyguanosine 3'-monophosphate with trans--acetoxytamoxifen N-oxide in addition to four stereoisomers of -(N2-deoxyguano- sinyl)tamoxifen 3'-monophosphate (dG3'P-N2-TAM) that was reported previously. Liquid chromatography-electrospray ionization–mass spectrometry of the reaction products gave the most abundant ion at m/z 731 ([M – H]–), which corresponded to dG3'P-N2-TAM N-oxide. The modified products digested by alkaline phosphatase corresponded to the isomers of dG-N2-TAM N-oxide whose structures were identified previously by mass spectrometry and nuclear magnetic resonance. Using these standard markers, we analyzed the hepatic DNA adducts of female DBA/2 mice treated with tamoxifen at a dosage of 120 mg/kg/day for 7 days by 32P-post-labeling coupled with an HPLC/radioactive detector. Mixtures of eight isomers of dG3'P-N2-TAM and dG3'P-N2-TAM N-oxide were separated into six peaks, since each of the cis epimers were not separated under the present HPLC conditions. Nine adducts were detected in all liver samples of mice. An epimer of trans-dG3'P-N2-TAM was detected as the principal DNA adduct at a level of 29.0 adducts/108 nucleotides, which accounted for 53.3% of the total tamoxifen–DNA adducts. Lesser amounts of cis-dG3'P-N2-TAM (2.8%) were also observed. An epimer of the trans-dG3'P-N2-TAM N-oxide (3.9 adducts/108 nucleotides) was detected as the third biggest adduct (7.2% of the total). The cis-dG3'P-N2-TAM N-oxide (0.4 adducts/108 nucleotides) accounted for 0.7% of the total. Thus, dG3'P-N2-TAM and dG3'P-N2-TAM N-oxide were identified in tamoxifen-treated mouse liver.
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