title: Characterization of the major DNA adduct formed by alpha-hydroxy-N-desmethyltamoxifen in vitro and in vivo.
abstract: Tamoxifen is hepatocarcinogenic in rats and has been associated with an increased risk of endometrial cancer in women. Recent reports suggest that it may be genotoxic in humans. N-Desmethyltamoxifen is a major tamoxifen metabolite that has been proposed to be responsible for one of the major adducts detected in liver DNA of rats treated with tamoxifen. The metabolic activation of N-desmethyltamoxifen to DNA binding products may involve oxidation to alpha-hydroxy-N-desmethyltamoxifen followed by esterification. In the study presented here, we report the synthesis of alpha-hydroxy-N-desmethyltamoxifen and the characterization of the major adduct obtained from alpha-sulfoxy-N-desmethyltamoxifen in vitro as (E)-alpha-(deoxyguanosin-N(2)-yl)-N-desmethyltamoxifen. In addition, we use (32)P-postlabeling in combination with HPLC to compare the adducts formed in the livers of female Sprague-Dawley rats treated by gavage with tamoxifen or equimolar doses of alpha-hydroxy-N-desmethyltamoxifen. We conclude that one of the major adducts formed in vivo and previously suggested to derive from N-desmethyltamoxifen is chromatographically identical to alpha-(deoxyguanosin-N(2)-yl)-N-desmethyltamoxifen.
authors.affiliation: Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Avenida Rovisco Pais, 1049-001 Lisboa, Portugal.
authors.forename: G
authors.initials: G
authors.lastname: Gamboa da Costa
authors.forename: L P
authors.initials: LP
authors.lastname: Hamilton
authors.forename: F A
authors.initials: FA
authors.lastname: Beland
authors.forename: M M
authors.initials: MM
authors.lastname: Marques
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D002458:Cell Fractionation; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018736:DNA Adducts; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D004247:DNA