DNA binding of tamoxifen and its analogues: identification of the tamoxifen-DNA adducts in rat liver

DNA binding of tamoxifen and some structurally-related drugs (toremifene, clomiphene, triparanol and raloxifene) in rat liver was studied using the 32 P-postlabelling method. As only tamoxifen was shown to form high levels of DNA adducts, the identity of these adducts was studied. Recently, we have identified by mass spectroscopy the two main tamoxifen adducts in rat liver DNA as the N -desmethyltamoxifen and tamoxifen adducts of N 2 -deoxyguanosine in which the linkage is through α-carbon in the tamoxifen structure. Minor adducts were identical to different diastereomers of α-( N 2 -deoxyguanosinyl)tamoxifen and of α-( N 6 -deoxyadenosinyl)tamoxifen. Altogether these adducts accounted for at least 95% of adducts formed in vivo, implicating that the α-hydroxylation of the ethyl group is the major activation pathway for DNA adducts.