Characterization of the major DNA adduct formed by alpha-hydroxy-N-desmethyltamoxifen in vitro and in vivo.
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.
Gamboa da Costa
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Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Avenida Rovisco Pais, 1049-001 Lisboa, Portugal.
Hamilton
L P
LP
Beland
F A
FA
Marques
M M
MM
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
D018931:Antineoplastic Agents, Hormonal; D018736:DNA Adducts; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D004247:DNA