Journal Article

SHORT COMMUNICATION: Production of 8-hydroxy-2'-deoxguanosine in DNA by microsomal activation of tamoxifen and 4-hydroxytamoxifen

Qiuping Ye and WilliamJ. Bodell

in Carcinogenesis

Volume 17, issue 8, pages 1747-1750
Published in print August 1996 | ISSN: 0143-3334
e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.8.1747
SHORT COMMUNICATION: Production of 8-hydroxy-2'-deoxguanosine in DNA by microsomal activation of tamoxifen and 4-hydroxytamoxifen

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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 dinucle-otide 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 ffects of TAM

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Subjects: Clinical Cytogenetics and Molecular Genetics

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