Increased risk of developing
endometrial cancers has been observed in women treated with
tamoxifen (TAM), a widely used drug for
breast cancer therapy and
chemoprevention. The carcinogenic effect may be due to genotoxic DNA damage induced by TAM. In fact, TAM-
DNA adducts were detected in the endometrium of women treated with this drug. TAM is alpha-hydroxylated by
cytochrome P450 3A4 followed by O-sulfonation by
hydroxysteroid sulfotransferase, and reacts with
guanine residues in
DNA, resulting in the formation of alpha-(N2-deoxyguanosinyl)tamoxifen adducts. During this metabolic process, short-lived carbocations are produced at the ethyl moiety of TAM as reactive intermediates. TAM-
DNA adducts promote primarily G -->T transversions in mammalian cells. The same mutations have been frequently detected at
codon 12 of the K-ras gene in the endometrial tissue of women treated with this drug. TAM-
DNA adducts, if not readily repaired, may act as initiators, leading to development of
endometrial cancers. The reactivity of TAM metabolites with
DNA is inhibited in
toremifene, where the
hydrogen atom has been replaced by a
chlorine atom at the ethyl moiety. Therefore,
toremifene may be a safer alternative to TAM. This article describes an overview of the mechanism of TAM-
DNA adduct formation, mutagenic events of this adduct, and detection of TAM-
DNA adducts in the endometrium of women treated with TAM.