IDENTIFICATION OF THE MAJOR TAMOXIFEN-DEOXYGUANOSINE ADDUCT FORMED INTHE LIVER DNA OF RATS TREATED WITH TAMOXIFEN

The antiestrogenic drug tamoxifen induces liver tumors in rats by a ge notoxic mechanism. The key step has been proposed to be the formation of a reactive carbocation from the metabolite alpha-hydroxytamoxifen. This compound reacts with DNA in vitro to a small extent (1 in 10(5) D NA bases), giving products identical to those found in rat liver cells treated with tamoxifen. Now we have prepared the more reactive alpha- acetoxytamoxifen, which reacts with DNA in vitro to a much greater ext ent (1 in 50 bases). The products of this reaction were subjected to P -32 postlabeling and shown by both TLC and reverse-phase liquid chroma tography to be identical to those isolated from DNA treated with alpha -hydroxytamoxifen and to those found in the liver DNA of rat hepatocyt es treated with tamoxifen or of the livers of rats treated with tamoxi fen. The major product was also isolated as the nucleoside and charact erized by UV, mass, and proton magnetic resonance spectroscopy. It is an adduct of tamoxifen and deoxyguanosine in which the alpha position of tamoxifen is linked covalently to the exocyclic amino group of deox yguanosine.