K. Pongracz et al., ACTIVATION OF THE TAMOXIFEN DERIVATIVE METABOLITE-E TO FORM DNA-ADDUCTS - COMPARISON WITH THE ADDUCTS FORMED BY MICROSOMAL ACTIVATION OF TAMOXIFEN, Cancer research, 55(14), 1995, pp. 3012-3015
(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.