The potential for the anti-
breast cancer drug
tamoxifen [(Z)-1-[4-[2-( dimethylamino)ethoxy]phenyl]-1,2-
diphenyl-1-
butene] to induce genotoxic damage (
DNA adducts) in the human endometrium was investigated in vivo and in vitro. Endometria from
hysterectomy patients who were not on
tamoxifen were sectioned and maintained in short-term organ culture. The cultures were treated with either
solvent vehicle (
DMSO),
tamoxifen,
alpha-hydroxytamoxifen [(E)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1,2-
diphenyl-1-buten-3- ol; the major
DNA-reactive metabolite in the rat], or
benzo(a)pyrene.
DNA was isolated and analyzed by 32P postlabeling. Chromatography on
polyethyleneimine-cellulose TLC plates revealed
DNA adducts in endometria treated with
alpha-hydroxytamoxifen identical to those seen previously in the rat liver. However, no adducts were seen from treatment with
tamoxifen itself. The viability of the
enzyme-metabolizing systems of the endometrial samples was demonstrated by the detection of expected
DNA adducts induced by
benzo(a)pyrene. Examination by liquid chromatography-mass spectrometry of the explant
culture media from endometria treated with
tamoxifen revealed the presence of the alpha-hydroxy metabolite in a dose-dependent manner, although apparently at levels insufficient to produce detectable
DNA adducts. Endometrial
DNA obtained from 18 patients undergoing daily treatment with 10-40 mg
tamoxifen for 3 months-9 years was also analyzed. No evidence for any
DNA adducts induced by
tamoxifen was found in any of the patients examined. These data suggest that the genotoxic events observed with
tamoxifen in the rat may not apply to the human endometrium.