Antioxidant inhibits tamoxifen–DNA adducts in endometrial explant culture

Abstract

Fresh human endometrial explants were incubated for 24 h at 37 °C with either tamoxifen (10–100 μM) or the vehicle (0.1% ethanol). Three metabolites namely, α-hydroxytamoxifen, 4-hydroxytamoxifen, and N-desmethyltamoxifen were identified in the culture media. Tissue size was limited but DNA adducts formed by the α-hydroxytamoxifen pathway were detected using authentic α-(deoxyguanosyl- N 2) tamoxifen standards. Relative DNA-adduct levels of 2.45, 1.12, and 0.44 per 10 6 nucleotides were detected following incubations with 100, 25, and 10 μM tamoxifen, respectively. The concurrent exposure of the explants to 100 μM tamoxifen with 1 mM ascorbic acid reduced the level of α-hydroxytamoxifen substantially (68.9%). The formation of tamoxifen–DNA adducts detectable in the explants from the same specimens exposed to 100 μM tamoxifen with 1 mM ascorbic acid were also inhibited. These results support the role of oxidative biotransformation of tamoxifen in the subsequent formation of DNA adducts in this tissue.