Qp. Ye et Wj. Bodell, PRODUCTION OF 8-HYDROXY-2'-DEOXYGUANOSINE IN DNA BY MICROSOMAL ACTIVATION OF TAMOXIFEN AND 4-HYDROXYTAMOXIFEN, Carcinogenesis, 17(8), 1996, pp. 1747-1750
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