ACTIVATION OF 4-HYDROXYTAMOXIFEN AND THE TAMOXIFEN DERIVATIVE METABOLITE-E BY UTERINE PEROXIDASE TO FORM DNA-ADDUCTS - COMPARISON WITH DNA-ADDUCTS FORMED IN THE UTERUS OF SPRAGUE-DAWLEY RATS TREATED WITH TAMOXIFEN

Daily intraperitoneal treatment of female Sprague-Dawley rats with eit her 5, 10 or 20 mg/kg tamoxifen (TAM) for 1 week increased the level o f peroxidase activity in the uterus 2- to 10-fold compared to the cont rol level. Using uterine extracts prepared from control and TAM treate d animals, we investigated the activation of 4-hydroxytamoxifen (4-HO- TAM) and (E,Z)-1,2-diphenyl-1-(4-hydroxyphenyl)-but-1-ene (cis/trans-m etabolite E) to form DNA adducts, Activation of 4-HO-TAM by uterine ex tracts prepared from either control or TAM-treated rats produced one m ajor (a) and two minor DNA (b and c) adducts. A similar activation of cis/trans-metabolite E produced two adducts (d and e), There was good correlation between levels of uterine peroxidase activity and levels o f DNA adducts formed by 4-HO-TAM and cis/trans-metabolite E. Activatio n of 4-HO-TAM and cis/trans-metabolite E with horseradish peroxidase ( HRP) produced the same adducts as observed by activation with uterine extract, Treatment of Sprague-Dawley rats with 5 and 10 mg/kg for 7 da ys produced eleven DNA adducts in the liver with no adducts detected i n the uterus, However, treatment of rats with 20 mg/kg of TAM for 7 da ys produced the same adduct pattern in the liver and also one major ad duct (1) in the uterus with a relative adduct level of 6.4 +/- 4.1 x 1 0(-9). Tamoxifen-DNA adduct 1 detected both in the liver and in the ut erus of treated rats was similar to adducts produced by activation of 4-HO-TAM with either uterine extract or HRP. The results of these stud ies suggest a general model whereby the tamoxifen metabolite 4-HO-TAM is further activated in the uterus by peroxidase enzymes to form DNA a dducts.