Idoxifene derivatives are less reactive to DNA than tamoxifen derivatives,both chemically and in human and rat liver cells

The drug tamoxifen shows evidence of genotoxicity, and induces liver tumour s in rats. Covalent DNA adducts have been detected in the liver of rats tre ated with tamoxifen, and these arise through metabolism at the a-position t o give an ester which reacts with DNA, (E)-1-(4-iodophenyl)-2-phenyl-1-[4-( 2-pyrrolidinoethoxy)phenyl]-but-1-ene (idoxifene) is an analogue of tamoxif en in which formation of DNA adducts is greatly reduced; we could not detec t any adducts in the DNA of cultured rat hepatocytes treated with 10 mu M i doxifene, after analysis by the P-32-post-labelling method. The metabolite (Z)-4-(4-iodophenyl) -4-[4- (2-pyrrolidinoethoxy)phenyl]-3-phenyl-3-buten-2 -ol (alpha-hydroxyidoxifene) gave adducts in rat hepatocytes, but far fewer than the corresponding tamoxifen metabolite. In human hepatocytes, neither idoxifene nor tamoxifen induced detectable levels of DNA adducts, We prepa red the alpha-acetoxy ester of idoxifene as a model for the ultimate reacti ve metabolite formed in rat liver. It was less reactive than alpha-acetoxyt amoxifen, as might be expected on mechanistic grounds. It reacted with DNA in the same way, to give adducts which were probably N-2-alkyldeoxyguanosin es, but to a lower extent. All these results indicate that idoxifene is muc h less genotoxic than tamoxifen, and should therefore be a safer drug.