PRODUCTION OF 8-HYDROXY-2'-DEOXYGUANOSINE IN DNA BY MICROSOMAL ACTIVATION OF TAMOXIFEN AND 4-HYDROXYTAMOXIFEN

Using rat liver microsomal preparations, we have investigated the acti vation of the anti-estrogen compound tamoxifen (TAM) and its metabolit e 4-hydroxytamoxifen (4-OH-TAM) to form 8-hydroxy-2'-deoxyguanosine (8 -OH-dG) in DNA, When reduced nicotinamide adenine dinucleotide phospha te (NADPH) was used as a cofactor in microsomal activation of either T AM or 4-OH-TAM, the levels of 8-OH-dG were 3-fold higher than in micro somes plus cofactor only, In contrast, no significant increase in the level of 8-OH-dG was detected in DNA samples from microsomal activatio n of either TAM or 4-OH-TAM with cumene hydroperoxide as the cofactor, These results demonstrate that the microsomal activation of TAM and 4 -OH-TAM to form 8-OH-dG is dependent upon the cofactor used, The addit ion of either EDTA or catalase to the activation system significantly decreased the formation of 8-OH-dG by TAM, but not by 4-OH-TAM, The pr esence of either sodium azide, superoxide dismutase or mannitol inhibi ted the formation of 8-OH-dG by both TAM and 4-OH-TAM, Taken together these findings indicate that microsomal activation of TAM and 4-OH-TAM with NADPH generates reactive oxygen species which result in the form ation of 8-OH-dG. We propose that the formation of 8-OH-dG by TAM and its metabolites may contribute to the observed carcinogenic effects of TAM