Production of 8-hydroxy-2'-deoxguanosine in DNA by microsomal activation of tamoxifen and 4-hydroxytamoxifen.
Using rat liver microsomal preparations, we have investigated the activation of the anti-estrogen compound tamoxifen (TAM) and its metabolite 4-hydroxytamoxifen (4-OH-TAM) to form 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in DNA. When reduced nicotinamide adenine dinucleotide phosphate (NADPH) was used as a cofactor in microsomal activation of either TAM or 4-OH-TAM, the levels of 8-OH-dG were 3-fold higher than in microsomes plus cofactor only. In contrast, no significant increase in the level of 8-OH-dG was detected in DNA samples from microsomal activation 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 addition 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 presence of either sodium azide, superoxide dismutase or mannitol inhibited 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 formation 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.
Ye
Q
Q
Department of Neurological Surgery, University of California, San Francisco 94143-0806, USA.
Bodell
W J
WJ
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001711:Biotransformation; D002374:Catalase / Q000378:metabolism; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D005260:Female; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
D017382:Reactive Oxygen Species; D013629:Tamoxifen; C016601:afimoxifene; D009249:NADP; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D002374:Catalase; D013482:Superoxide Dismutase; D003849:Deoxyguanosine