4-hydroxytamoxifen gives DNA adducts by chemical activation, but not in rat liver cells

The drug tamoxifen shows evidence of genotoxicity, and induces liver tumors in rats. Covalent DNA adducts have been detected in the liver of rats trea ted with tamoxifen, and in rat hepatocytes in culture. These arise primaril y from its metabolite alpha-hydroxytamoxifen, and may also arise, in part, from another metabolite, 4-hydroxytamoxifen. We have prepared two model com pounds for the potential reactive metabolite formed from 4-hydroxytamoxifen in rat liver. One of these was its alpha-acetoxy ester. This was much more reactive than that from tamoxifen, and could not be isolated in pure form. It reacted with DNA in the same way that alpha-acetoxytamoxifen did, to gi ve adducts which were isolated by hydrolysis and chromatography, and identi fied as alkyldeoxyguanosines. The second derivative was alpha,beta-dehydro- 4-hydroxytamoxifen. This also reacts with DNA in vitro, to give the same pr oducts as those from alpha-acetoxy-4-hydroxytamoxifen. Reaction probably pr oceeds through the same resonance-stabilized carbocation in either case. Ho wever, when primary cultures of rat hepatocytes were treated with either 4- hydroxytamoxifen, 4,alpha-dihydroxytamoxifen, or alpha,beta-dehydro-4-hydro xytamoxifen at a concentration of 10 mu M, no adducts could be detected in their DNA by the P-32- postlabeling technique. Similarly, no adducts could be found in the liver DNA of female Fischer F344 rats treated orally (at 0. 12 mmol kg(-1)) with the same substances. If 4-hydroxytamoxifen is metaboli zed to 4,alpha-dihydroxytamoxifen in rat liver, then either this substance is not converted to reactive esters or they are rapidly detoxified.