Carcinogenesis, Vol 18, 1949-1954, Copyright © 1997 by Oxford University Press
MM Marques and FA Beland
Tamoxifen is a liver carcinogen in rats and has been shown to increase the
risk of endometrial cancer in women. Recent reports of DNA adducts in
leucocyte and endometrial samples from women treated with tamoxifen
indicate that it may be genotoxic to humans. One of the proposed pathways
for the metabolic activation of tamoxifen involves oxidation to
4-hydroxytamoxifen, which may be further oxidized to an electrophilic
quinone methide. In the present study we show that 4- hydroxytamoxifen
quinone methide reacts with DNA to form covalent adducts. The major
products, which result from 1,8-addition of the exocyclic nitrogen of
deoxyguanosine to the conjugated system of 4- hydroxytamoxifen quinone
methide, are characterized as (E)- and (Z)-
alpha-(deoxyguanosin-N2-yl)-4-hydroxytamoxifen.
ARTICLES
Identification of tamoxifen-DNA adducts formed by 4-hydroxytamoxifen quinone methide
Centro de Quimica Estrutural, Instituto Superior Tecnico, Lisboa, Portugal.
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