Tamoxifen reduces endogenous and UV light-induced oxidative damage to DNA, lipid and protein in vitro and in vivo.
We have investigated the effect of tamoxifen (TAM) on endogenous or ultraviolet radiation (UVR)-induced oxidative damage to macromolecules in vitro and in vivo. In a system containing calf thymus DNA exposed to a germicidal UV lamp, both TAM and 4-hydroxytamoxifen (4-OH-TAM) inhibited UVR-induced the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in DNA in a dose-dependent manner. At low concentrations, 4-OH-TAM quenched 8-OHdG more potently than TAM. However, the reduction of 8-OHdG by TAM and 4-OH-TAM became similar at a concentration of 10 microM. In contrast, ascorbic acid had the similar effect to TAM, whereas glutathione exhibited little effect on UVR-induced 8-OHdG. The order of quenching efficacy was: 4-OH-TAM > TAM approximately = ascorbic acid > glutathione. We have further determined the effect of TAM on endogenous 8-OHdG formation, lipid peroxidation, and protein oxidation in the skin of SENCAR mice. Topical application of 5 micromol TAM significantly reduced the level of 8-OHdG in mouse epidermis by approximately 27% (P < 0.05). Endogenous lipid peroxidation and protein oxidation, measured as malondialdehyde (MDA) and carbonyl groups, were also substantially reduced by topical TAM. Further study was conducted to evaluate the effect of TAM on UVR-induced 8-OHdG and MDA in skin of hairless mice. In mice subacutely exposed to low dose (3.4 kJ/m2 x six doses) and high dose (16.8 kJ/m2 x three doses) of UVB irradiation, TAM significantly blocked the formation of 8-OHdG in mouse epidermis by 57-81% and MDA by 37-65%, respectively. Our studies suggest that reduction of oxidative damages to biological macromolecules in vitro and in vivo may at least in part explain the anti-carcinogenic and chemopreventive actions of tamoxifen.
Department of Dermatology, The Mount Sinai Medical Center, New York, NY 10029, USA. hw@doc.mssm.edu
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D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002417:Cattle; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D005260:Female; D051379:Mice; D008812:Mice, Hairless; D018384:Oxidative Stress / Q000187:drug effects*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology*; D014466:Ultraviolet Rays
D013629:Tamoxifen; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D003849:Deoxyguanosine