DETERMINATION OF DNA-DAMAGE IN F344 RATS INDUCED BY GEOMETRIC ISOMERSOF TAMOXIFEN AND ANALOGS

To investigate the activation mechanisms involved in tamoxifen carcino genicity, analogues of tamoxifen isomers modified at the ethyl group w ere synthesized and assessed for their ability to induce hepatic DNA d amage following their administration to female F344 rats. The cis isom er was prepared by acid-catalyzed isomerization of tamoxifen and isola ted by preparative HPLC. The active metabolite alpha-hydroxytamoxifen and geometric isomers of bromotamoxifen and C-desmethylenetamoxifen, a nalogues in which the ethyl group has been replaced by a bromine atom and methyl group, respectively, were synthesized according to publishe d procedures. The levels of hepatic DNA adducts induced were determine d by P-32-postlabeling. Bromotamoxifen and tamoxifen 1,2-epoxide cause d no detectable DNA damage relative to controls. Trans isomers of tamo xifen, C-desmethylenetamoxifen, and alpha-hydroxytamoxifen all produce d DNA adducts at a 5-90-fold higher level than the corresponding cis i somers. In contrast, both the cis and trans isomers of alpha-hydroxyta moxifen showed similar reactivity toward calf thymus DNA in vitro. Mol ecular models of alpha-hydroxytamoxifen isomers suggest this differenc e in DNA adduct-forming ability is due to steric hindrance of the enzy mes involved in the activation of this metabolite. There were high add uct levels in the liver, but no uterine DNA adducts were detected in r ats treated with alpha-hydroxytamoxifen, This suggests that in contras t to the liver, alpha-hydroxytamoxifen is not further activated in rat uterus. This may help to explain the absence of uterine tumors in rat s following long-term tamoxifen treatment.