Prevention of quinone-mediated DNA arylation by antioxidants.
High performance liquid chromatographic (HPLC) analysis showed that the prototype antioxidant ascorbate (vitamin C) inhibits the DNA adducts induced by synthetic estrogen diethylstilbestrol (DES) and the antiestrogen metabolite 4-hydroxytamoxifen (4-OHTam). Treatment of salmon testes DNA with 4-OHTam quinone or 4-OHTam in the presence of horseradish peroxidase and hydrogen peroxide (H(2)O(2)) generated the same DNA adduct profile. Vitamin C and N-acetylcysteine (NAC) inhibited the formation of 4-OHTam-dG adducts in a dose-dependent manner. To determine whether the same antioxidants also protect cellular DNA, HL-60 cells were used as cell culture model. Cells treated with 10 microM 4-OHTam in the presence of 1 microM H(2)O(2 )for 24 h gave 4-OHTam-dG adducts approximately 4 x 10(-7), n = 3. Treatment of the cells with 100 microM 4-OHTam, without H(2)O(2), produced the same level of adducts. Supplementation of the incubation media with vitamin C (2.5 mM) or NAC (5 mM) inhibited the formation of DNA adducts. Thus, antioxidants may protect susceptible cells from genotoxicity associated with 4-OHTam activation.
Sharma
M
M
Department of Molecular and Cellular Biophysics, Roswell Park Cancer Institute, Buffalo, New York, 14263, USA.
Slocum
H K
HK
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D018736:DNA Adducts / Q000187:drug effects* / Q000378:metabolism*; D004054:Diethylstilbestrol / Q000378:metabolism* / Q000494:pharmacology*; D006735:Horseradish Peroxidase; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D012474:Salmon; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D013737:Testis
D000975:Antioxidants; D018736:DNA Adducts; C068149:diethylstilbesterol-DNA adduct; D013629:Tamoxifen; C016601:afimoxifene; D004054:Diethylstilbestrol; D006861:Hydrogen Peroxide; D006735:Horseradish Peroxidase; D001205:Ascorbic Acid; D000111:Acetylcysteine