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-Hydroxytamoxifen, a Metabolite of Tamoxifen with Exceptionally High DNA-binding Activity in Rat Hepatocytes¹

Section of Molecular Carcinogenesis Haddon Laboratories [D. H. P., P. L. C., A. H., K. J. C.] and CRC Centre for Cancer Therapeutics [G. K. P.], Institute of Cancer Research, Cotswold Rood, Sutton, Surrey SM2 5NG, England

It has been proposed that the antiestrogen tamoxifen induces liver tumors in rats and genotoxic effects in vitro through metabolic activation involving, initially, -hydroxylation of the ethyl group. To test this hypothesis, the extent of DNA adduct formation in primary rat hepatocytes treated with tamoxifen and -hydroxytamoxifen was investigated. Hepatocytes from female Fischer F-344 rats were treated with 1 or 10 µM concentrations of either -hydroxytamoxifen or tamoxifen. DNA was isolated and analyzed for the presence of DNA adducts by ³²P postlabeling. Chromatography on polyethyleneimine cellulose thin layer chromatography and reverse-phase high performance liquid chromatography revealed that the same pattern of adducts was formed by both compounds. However, the level of adduct formation was 25 and 49 times greater with -hydroxytamoxifen than with tamoxifen at 1 and 10 µM, respectively. The formation of -hydroxytamoxifen as a metabolite of tamoxifen was demonstrated by mass spectrometric analysis of the extracted culture medium. -Hydroxytamoxifen was found to react with DNA in the absence of metabolizing enzymes. These results demonstrate the involvement of -hydroxylation in the metabolic activation of tamoxifen.

¹ Supported by the Cancer Research Campaign.

² To whom requests for reprints should be addressed.

Received 8/ 5/94. Accepted 9/19/94.

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