INTRINSIC REACTIVITY OF TAMOXIFEN AND TOREMIFENE METABOLITES WITH DNA

The antiestrogen tamoxifen is known to cause liver cancer in rats. Thi s may be due to the formation of abundant DNA adducts in rat liver. A likely precursor to some of the tamoxifen adducts in rats is alpha-hyd roxytamoxifen. It is not clear whether the rat data are relevant to hu man exposure. In the present study, we show that one of the major meta bolites in humans reacts with double-stranded DNA in vitro in the abse nce of any metabolizing enzymes or activating chemicals. At least two distinct adduct spots resulting from 4-hydroxy-N-desmethyltamoxifen (m etabolite Ex) were detected by P-32 postlabeling and thin layer chroma tography. The adduct level increases dramatically when metabolite Ex i s irradiated with UV light to fuse into a phenanthrene ring system. 4- hydroxy-N-desmethyltoremifene, which differs from Ex by a single chlor ine atom,forms fewer DNA adducts without irradiation but similar amoun ts after irradiation. These results suggest that the chlorine atom may interfere with drug-DNA interactions which facilitate adduct formatio n.