EFFECTS OF CHRONIC ADMINISTRATION OF TAMOXIFEN AND TOREMIFENE ON DNA-ADDUCTS IN RAT-LIVER, KIDNEY, AND UTERUS

To assess the effects of chronic administration of tamoxifen (TAM) and toremifene (TOR) on genetic damage related to carcinogenesis, we meas ured DNA adduct formation by P-32-postlabeling in liver, kidney, and u terus of Fischer rats gi,en TAM or TOR in the diet for 18 months, TAM induced high levels of DNA adducts in the liver in a dose-dependent ma nlier, The total adduct levels were 3000 +/- 870 and 6100 +/- 1500 add ucts per 10(9) nucleotides for the 250- and 500-ppm groups, respective ly, TOR induced a dose-dependent level of adducts that was lower than that observed for TAM. The total hepatic adduct level was 70 +/- 5, 13 0 +/- 20, and 70 +/- 20 for 250, 500, and 750 ppm TOR, respectively, B oth TAM and TOR induced a low level of adducts in the kidney, and TOR significantly enhanced endogenous DIVA adduct formation, The total add uct level was 480 +/- 140, 420 +/- 210, and 680 +/- 80 adducts per 10( 9) nucleotides for control, 500 ppm TAM, and 500 ppm TOR, respectively . Although neither TAR;I nor TOR induced adducts in the uterus, TAM si gnificantly enhanced endogenous DNA modifications in this tissue, The total uterine adduct level was 70 +/- 30, 130 +/- 50, and 70 +/- 20 fo r control, 500 ppm T-IRI, and 500 ppm TOR. respectively, These observa tions demonstrate a correlation between DNA adduct formation and carci nogenicity fur these compounds, The effectiveness of TOR and TAM in in creasing endogenous DNA adducts indicates that a mechanism other than direct DNA damage may also he involved in their carcinogenicity.