Comparison of the DNA adducts formed by tamoxifen and 4-hydroxytamoxifen in vivo

Tamoxifen is a liver carcinogen in rats and has been associated with an inc reased risk of endometrial cancer in women, Recent reports of DNA adducts i n leukocyte and endometrial samples from women treated with tamoxifen sugge st that it may be genotoxic to humans. One of the proposed pathways for the metabolic activation of tamoxifen involves oxidation to 4-hydroxytamoxifen , which may be further oxidized to an electrophilic quinone methide, In the present study, we compared the extent of DNA adduct formation in female Sp rague-Dawley rats treated by gavage with seven daily doses of 54 mu mol/kg tamoxifen or 4-hydroxytamoxifen and killed 24 h after the last dose. Liver weights and microsomal rates of ethoxyresorufin O-deethylation, 4-dimethyla minopyrine N-demethylation and p-nitrophenol oxidation were not altered by tamoxifen or 4-hydroxytamoxifen treatment. Uterine weights were decreased s ignificantly and uterine peroxidase activity was decreased marginally in tr eated as compared with control rats. DNA adducts were assayed by P-32-post- labeling in combination with HPLC. Two major DNA adducts were detected in l iver DNA from rats administered tamoxifen, These adducts had retention time s comparable with those obtained from in vitro reactions of alpha-acetoxyta moxifen and 4-hydroxytamoxifen quinone methide with DNA, Hepatic DNA adduct levels in rats administered 4-hydroxytamoxifen did not differ from those o bserved in control rats. Likewise, adduct levels in uterus DNA from rats tr eated with tamoxifen or 4-hydroxytamoxifen were not different from those de tected in control rats. These data suggest that a metabolic pathway involvi ng 4-hydroxytamoxifen is not a major pathway in the activation of tamoxifen to a DNA-binding derivative in Sprague-Dawley rats.