ACTIVATION OF THE TAMOXIFEN DERIVATIVE METABOLITE-E TO FORM DNA-ADDUCTS - COMPARISON WITH THE ADDUCTS FORMED BY MICROSOMAL ACTIVATION OF TAMOXIFEN

(Z)-1,2-Diphenyl-1-(4-hydroxyphenyl)but-1-ene (metabolite E) has been detected in the plasma of patients treated with tamoxifen. We therefor e investigated whether the cis/trans isomers of metabolite E can be ac tivated to form DNA adducts detected by P-32 postlabeling. Microsomal activation of metabolite E produced two major (a and b) and up to six minor DNA adducts. Activation with horseradish peroxidase or silver(I) oxide produced the same adducts (a and b). Microsomal activation of ta moxifen produced one major (no. 6) and several minor DNA adducts. Rech romatography showed that adducts a and b formed by enzymatic and chemi cal activation of metabolite E were the same as adducts 9 and 4 produc ed by microsomal activation of tamoxifen. These results demonstrate th at activation of metabolite E can lead to DNA adduct formation.