Identification of tamoxifen-DNA adducts formed by 4-hydroxytamoxifen quinone methide.

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.