Tamoxifen DNA damage detected in human endometrium using accelerator mass spectrometry.
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 [(14)C]tamoxifen citrate orally (20 mg, 0.37 or 1.85 MBq) approximately 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/10(12) nucleotides (mean +/- SE, n = 10). In myometrial tissues, a similar extent of DNA binding was detected (492 +/- 112 adducts/10(12) 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 15000 to 130000 adducts/10(12) 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.
Martin
Elizabeth A
EA
Cancer Biomarkers and Prevention Group, University of Leicester, Leicester, United Kingdom. elizabeth.martin@astrazeneca.com
Brown
Karen
K
Gaskell
Margaret
M
Al-Azzawi
Farook
F
Garner
R Colin
RC
Boocock
David J
DJ
Mattock
Elizabeth
E
Pring
David W
DW
Dingley
Karen
K
Turteltaub
Kenneth W
KW
Smith
Lewis L
LL
White
Ian N H
IN
D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000601:surgery; D002250:Carbon Radioisotopes; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D013058:Mass Spectrometry; D008875:Middle Aged; D011485:Protein Binding; D013629:Tamoxifen / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000601:surgery
D018931:Antineoplastic Agents, Hormonal; D002250:Carbon Radioisotopes; D013629:Tamoxifen; D004247:DNA