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Tamoxifen Metabolic Activation: Comparison of DNA Adducts Formed by Microsomal and Chemical Activation of Tamoxifen and 4-Hydroxytamoxifen with DNA Adducts Formed in Vivo¹

Division of Toxicology, Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030 [B. M., P. S., K. R.], and Brain Tumor Research Center, Department of Neurological Surgery, School of Medicine, University of California, San Francisco, California 94143-0806 [D. N. P., W. J. B.]

One of our laboratories recently showed by ³²P-postlabeling that administration of tamoxifen to mice induces two groups of hepatic DNA adducts comprising two major spots, nos. 3 and 5, respectively. 4-Hydroxytamoxifen and -hydroxytamoxifen appear to be the proximate metabolites of groups I and II adducts, respectively. The relative significance of these two adduct groups for tamoxifen carcinogenicity remains to be established. To determine the activation mechanism(s) of tamoxifen and 4-hydroxytamoxifen, in vivo adducts were compared by ³²P-postlabeling with adducts generated by microsomal or chemical activation in vitro. Microsomal activation of 4-hydroxytamoxifen and tamoxifen, respectively, in the presence of DNA and cumene hydroperoxide, induced two adducts, which mapped similarly to the corresponding in vivo adduct spots 3 and 5. Chemical oxidation of 4-hydroxytamoxifen with silver(II) oxide, followed by incubation of the product(s) with DNA, elicited the formation of a major spot (Q1), while tamoxifen itself did not react. Rechromatographic analyses revealed that in vitro fractions 3 and Q1 (from 4-hydroxytamoxifen) matched the major in vivo group I adduct fraction 3, consistent with the hypothesis that 4-hydroxytamoxifen is a precursor for adduct fraction 3 in vivo. The in vitro adduct fraction 5 (from tamoxifen) was identical to that formed in vivo, indicating that the metabolic pathway for the formation of group II adducts did not involve 4-hydroxytamoxifen. In conclusion, the results support a model where primary metabolites of tamoxifen undergo secondary metabolism to form DNA adducts, which are detected in vivo after treatment with tamoxifen or 4-hydroxytamoxifen.

¹ This work was supported by NIH Grants CA 32157 and CA 13525.

² To whom requests for reprints should be addressed, at Division of Toxicology, Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-4465; Fax: (713) 798-3145.

Received 10/ 5/95. Accepted 11/14/95.

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