Formation of tamoxifen-DNA adducts in human endometrial explants exposed to alpha-hydroxytamoxifen.
An increased risk of developing endometrial cancer has been observed in women receiving tamoxifen (TAM) endocrine therapy and chemoprevention. The genotoxic damage induced by TAM metabolites may be involved in the development of endometrial cancer. To investigate the capability of endometrial tissues to form TAM-DNA adducts, primary cultured human endometrial explants were exposed to alpha-hydroxytamoxifen (alpha-OHTAM) and used for quantitative analysis of TAM-DNA adducts, using (32)P-postlabeling/HPLC analysis. A trans isoform of alpha-(N(2)-deoxyguanosinyl)tamoxifen (dG-N(2)-TAM) was detected as the major adduct in eight of nine endometrial explants exposed to 100 microM alpha-OHTAM at levels of 7.7 +/- 5.3 (mean +/- SD) adducts/10(7) nucleotides. Approximately 25- and 37-fold lower amounts of the cis form of dG-N(2)-TAM and another trans isoform were also detected. The dG-N(2)-TAM adduct (3.3 adducts/10(7) nucleotides) was detected in one of three endometrial explants exposed to 25 microM alpha-OHTAM. No TAM-DNA adducts were detected in any unexposed tissues. These results indicate that TAM-DNA adducts are capable of forming through O-sulfonation and/or O-acetylation of alpha-OHTAM in the endometrium. The endometrial explant culture can be used as a model system to explore the genotoxic mechanism of antiestrogens for humans.
Kim
Sung Yeon
SY
Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, USA.
Suzuki
Naomi
N
Laxmi
Y R Santosh
YR
McGarrigle
Barbara P
BP
Olson
James R
JR
Sharma
Moheswar
M
Sharma
Minoti
M
Shibutani
Shinya
S
D000107:Acetylation; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000032:analysis* / Q000378:metabolism; D004717:Endometrium / Q000378:metabolism*; D005260:Female; D006801:Humans; D008954:Models, Biological; D010761:Phosphorus Radioisotopes; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D013450:Sulfones / Q000737:chemistry / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism*
D018931:Antineoplastic Agents, Hormonal; D018736:DNA Adducts; D010761:Phosphorus Radioisotopes; D020033:Protein Isoforms; D013450:Sulfones; C110902:alpha-hydroxytamoxifen; D013629:Tamoxifen