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 adduct s in leucocyte and endometrial samples from women treated with tamoxif en indicate that it may be genotoxic to humans. One of the proposed pa thways 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 p roducts, which result from 1,8-addition of the exocyclic nitrogen of d eoxyguanosine to the conjugated system of 4-hydroxytamoxifen quinone m ethide, are characterized as (E)- and )-alpha-(deoxyguanosin-N-2-yl)-4 -hydroxytamoxifen.