ALPHA-TOCOPHEROL INDUCES OXIDATIVE DAMAGE TO DNA IN THE PRESENCE OF COPPER(II) IONS

There is currently much interest in the possibility that dietary antio xidants may confer protection from certain diseases, such as atheroscl erosis and cancer. The importance of alpha-tocopherol (vitamin E) as a biological antioxidant is widely recognized. However, pro-oxidant pro perties of alpha-tocopherol have been observed in chemical systems, an d it has been reported that the vitamin can induce tumor formation and act as a complete tumor promotor in laboratory animals. In the presen t communication, we find that alpha-tocopherol can act as a potent DNA -damaging agent in the presence of copper(II) ions, using a simplified , in vitro model, alpha-Tocopherol was found to promote copper-depende nt reactive oxygen species formation from molecular oxygen, resulting in DNA base oxidation and backbone cleavage. Neither alpha-tocopherol nor Cu(II) alone induced DNA damage. Bathocuproine, a Cu(I)-specific c helator, and catalase inhibited the DNA damage, whereas free hydroxyl radical scavengers did not. The order of DNA cleavage sites was thymin e, cytosine > guanine residues. Examinations using an oxygen electrode and cytochrome c indicate that molecular oxygen was consumed in the r eaction of alpha-tocopherol and Cu(II) and that superoxide was formed. Stoichiometry studies showed that two Cu(II) ions could be reduced by each alpha-tocopherol molecule. Electron spin resonance spin-trapping investigations were then used to demonstrate that hydrogen peroxide i nteracts with Cu(I) to generate the reactive species responsible for D NA damage, which is either the hydroxyl radical or a species of simila r reactivity. These findings may be of relevance to the tumorigenic pr operties of the vitamin reported in the literature. However, further s tudies are required to establish the significance of these reactions u nder in vivo conditions.