title: Intrinsic reactivity of tamoxifen and toremifene metabolites with DNA.
abstract: The antiestrogen tamoxifen is known to cause liver cancer in rats. This 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-hydroxytamoxifen. It is not clear whether the rat data are relevant to human exposure. In the present study, we show that one of the major metabolites in humans reacts with double-stranded DNA in vitro in the absence of any metabolizing enzymes or activating chemicals. At least two distinct adduct spots resulting from 4-hydroxy-N-desmethyltamoxifen (metabolite Bx) were detected by 32P postlabeling and thin layer chromatography. The adduct level increases dramatically when metabolite Bx is irradiated with UV light to fuse into a phenanthrene ring system. 4-hydroxy-N-desmethyltoremifene, which differs from Bx by a single chlorine atom, forms fewer DNA adducts without irradiation but similar amounts after irradiation. These results suggest that the chlorine atom may interfere with drug-DNA interactions which facilitate adduct formation.
authors.affiliation: Hematology & Oncology, UC Davis Cancer Center, Sacramento, California 95817, USA.
authors.forename: U
authors.initials: U
authors.lastname: Hellmann-Blumberg
authors.forename: M G
authors.initials: MG
authors.lastname: Cartner
authors.forename: G T
authors.initials: GT
authors.lastname: Wurz
authors.forename: M W
authors.initials: MW
authors.lastname: DeGregorio
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy; D002853:Chromatography, Liquid; D018736:DNA Adducts / Q000187:drug effects*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000139:chemically induced; D013629:Tamoxifen / Q000009:adverse effects / Q000031:analogs & derivatives*; D017312:Toremifene / Q000031:analogs & derivatives*; D014466:Ultraviolet Rays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018736:DNA Adducts; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D017312:Toremifene