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Identification of the Major Tamoxifen-Deoxyguanosine Adduct Formed in the Liver DNA of Rats Treated with Tamoxifen¹

Section of Molecular Carcinogenesis, Haddow Laboratories [M. R. O., A. H., P. L. C., D. H. P.] and CRC Centre for Cancer Therapeutics [I. R. H.], Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, England

The antiestrogenic drug tamoxifen induces liver tumors in rats by a genotoxic mechanism. The key step has been proposed to be the formation of a reactive carbocation from the metabolite -hydroxytamoxifen. This compound reacts with DNA in vitro to a small extent (1 in 10⁵ DNA bases), giving products identical to those found in rat liver cells treated with tamoxifen. Now we have prepared the more reactive -acetoxytamoxifen, which reacts with DNA in vitro to a much greater extent (1 in 50 bases). The products of this reaction were subjected to ³²P postlabeling and shown by both TLC and reverse-phase liquid chromatography to be identical to those isolated from DNA treated with -hydroxytamoxifen and to those found in the liver DNA of rat hepatocytes treated with tamoxifen or of the livers of rats treated with tamoxifen. The major product was also isolated as the nucleoside and characterized by UV, mass, and proton magnetic resonance spectroscopy. It is an adduct of tamoxifen and deoxyguanosine in which the position of tamoxifen is linked covalently to the exocyclic amino group of deoxyguanosine.

¹ This work was supported by grants from the Cancer Research Campaign, United Kingdom.

² To whom requests for reprints should be addressed.

Received 7/27/95. Accepted 10/31/95.

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