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Activation of the Tamoxifen Derivative Metabolite E to Form DNA Adducts: Comparison with the Adducts Formed by Microsomal Activation of Tamoxifen¹

Brain Tumor Research Center of the Department of Neurological Surgery [K. P., D. N. P., W. J. B.], and Department of Pharmaceutical Chemistry and Mass Spectrometry Facility [T. N., A. L. B.], School of Medicine, University of California, San Francisco, California 94143

(Z)-1,2-Diphenyl-1-(4-hydroxyphenyl)but-1-ene (metabolite E) has been detected in the plasma of patients treated with tamoxifen. We therefore investigated whether the cis/trans isomers of metabolite E can be activated to form DNA adducts detected by ³²P postlabeling. Microsomal activation of metabolite E produced two major (a and b) and up to six minor DNA adducts. Activation with horsearadish peroxidase or silver(I)oxide produced the same adducts (a and b). Microsomal activation of tamoxifen produced one major (no. 6) and several minor DNA adducts. Rechromatography showed that adducts a and b formed by enzymatic and chemical activation of metabolite E were the same as adducts 9 and 4 produced by microsomal activation of tamoxifen. These results demonstrate that activation of metabolite E can lead to DNA adduct formation.

¹ This work was supported by NIH Grant CA 13525 and by Biomedical Research Training Program of the National Center for Research Resources, NIH NCRR BRTP 01614.

² To whom requests for reprints should be addressed, at Department of Neurological Surgery, c/o The Editorial Office, 1360 Ninth Avenue, Suite 210, San Francisco, CA 94122.

Received 4/21/95. Accepted 6/ 2/95.

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