Fresh human endometrial explants were incubated for 24h at 37degreesC with either tamoxifen (10-100 muM) or the vehicle (0.1% ethanol). Three metabolites namely, alpha-hydroxytamoxifen, 4-hydroxytamoxifen, and N-desmethyttamoxifen were identified in the culture media. Tissue size was limited but DNA adducts formed by the alpha-hydroxytamoxifen pathway were detected using authentic alpha-(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 muM tamoxifen, respectively. The concurrent exposure of the explants to 100 muM tamoxifen with 1 mM ascorbic acid reduced the level of alpha-hydroxytamoxifen substantially (68.9%). The formation of tamoxifen-DNA adducts detectable in the explants from the same specimens exposed to 100 muM 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. (C) 2003 Elsevier Science (USA). All rights reserved.