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1 Cancer Biomarkers and Prevention Group, University of Leicester, Leicester, United Kingdom;
2 Department of Obstetrics and Gynaecology and
3 MRC Molecular Endocrinology Group, University of Leicester, Leicester, United Kingdom;
4 Jack Birch Unit for Environmental Carcinogenesis, Department of Biology, University of York, York, United Kingdom;
5 York District Hospital, York, United Kingdom;
6 Lawrence Livermore National Laboratory, University of California, Livermore, California; and
7 Syngenta Ltd., Cheshire, United Kingdom
This study was aimed to establish whether tamoxifen binds irreversibly to uterine DNA when given to women. Patients were given a single therapeutic dose of [14C]tamoxifen citrate orally (20 mg, 0.37 or 1.85 MBq) 
18 h prior to hysterectomy or breast surgery. Nonmalignant uterine tissue was separated into myometrium and endometrium. DNA and protein were isolated and bound radiolabel determined by the sensitive technique of accelerator mass spectrometry. Levels of irreversible DNA binding of tamoxifen in the endometrium of treated patients were 237 ± 77 adducts/1012 nucleotides (mean ± SE, n = 10). In myometrial tissues, a similar extent of DNA binding was detected (492 ± 112 adducts/1012 nucleotides). Binding of tamoxifen to endometrial and myometrial proteins was 10 ± 3 and 20 ± 4 fmol/mg, respectively. In breast tissue, sufficient DNA could not be extracted but protein binding was an order of magnitude higher than that seen with endometrial proteins (358 ± 81 fmol/mg). These results demonstrate that after oral administration, tamoxifen forms adducts in human uterine DNA but at low numbers relative to those previously reported in women after long-term tamoxifen treatment where levels, when detected, ranged from 15,000 to 130,000 adducts/1012 nucleotides. Our findings support the hypothesis that the low level of DNA adducts in human uterus is unlikely to be involved with endometrial cancer development.
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D. H. Phillips, A. Hewer, M. R. Osborne, K. J. Cole, C. Churchill, and V. M. Arlt Organ specificity of DNA adduct formation by tamoxifen and {alpha}-hydroxytamoxifen in the rat: implications for understanding the mechanism(s) of tamoxifen carcinogenicity and for human risk assessment Mutagenesis, July 1, 2005; 20(4): 297 - 303. [Abstract] [Full Text] [PDF]
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