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Effects of Chronic Administration of Tamoxifen and Toremifene on DNA Adducts in Rat Liver, Kidney, and Uterus¹

Department of Clinical Investigation, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030 [D. L., M. W.]; Department of Oncology, University of Wisconsin, McArdle Laboratory for Cancer Research, Madison, Wisconsin 53706 [Y. D., H. C. P.]; and Robert H. Lurie Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611 [V. C. J.]

To assess the effects of chronic administration of tamoxifen (TAM) and toremifene (TOR) on genetic damage related to carcinogenesis, we measured DNA adduct formation by ³²P-postlabeling in liver, kidney, and uterus of Fischer rats given TAM or TOR in the diet for 18 months. TAM induced high levels of DNA adducts in the liver in a dose-dependent manner. The total adduct levels were 3000 ± 870 and 6100 ± 1500 adducts per 10⁹ nucleotides for the 250- and 500-ppm groups, respectively. TOR induced a dose-dependent level of adducts that was lower than that observed for TAM. The total hepatic adduct level was 70 ± 5, 130 ± 20, and 70 ± 20 for 250, 500, and 750 ppm TOR, respectively. Both TAM and TOR induced a low level of adducts in the kidney, and TOR significantly enhanced endogenous DNA adduct formation. The total adduct level was 480 ± 140, 420 ± 210, and 680 ± 80 adducts per 10⁹ nucleotides for control, 500 ppm TAM, and 500 ppm TOR, respectively. Although neither TAM nor TOR induced adducts in the uterus, TAM significantly enhanced endogenous DNA modifications in this tissue. The total uterine adduct level was 70 ± 30, 130 ± 50, and 70 ± 20 for control, 500 ppm TAM, and 500 ppm TOR, respectively. These observations demonstrate a correlation between DNA adduct formation and carcinogenicity for these compounds. The effectiveness of TOR and TAM in increasing endogenous DNA adducts indicates that a mechanism other than direct DNA damage may also be involved in their carcinogenicity.

¹ This work was supported by NIH Grants CA-07175, CA22484, CA45700, and CA57245.

² To whom requests for reprints should be addressed, at University of Wisconsin, McArdle Laboratory for Cancer Research, 1400 University Avenue, Madison, WI 53706.

Received 1/30/97. Accepted 2/28/97.

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