Mechanism of metal-mediated oxidative DNA damage

We investigated mechanisms of oxidative DNA damage caused by carcinogenic metal compounds. Chromate(VI), nickel(II), cobalt(II), iron(III)-nitrilotriacetate and copper(II) induced DNA damage generating active oxygen species in the presence of hydrogen peroxide (H2O2). DNA damage was enhanced by endogenous reductants such as ascorbate, NADH and glutathione. An indirect mechanism of carcinogenesis by lead was studied using delta-aminolevulinic acid, which caused DNA damage in the presence of Cu(II). On the basis of these findings, we reviewed the mechanism of metal carcinogenesis mediated by active oxygen species. We also studied a mechanism of DNA damage induced by the interaction of metal ions and ''non-mutagenic'' carcinogens. Benzoquinone and its derivatives such as metabolites of benzene, o-phenylphenol, pentachlorophenol and p-dichlorobenzene caused Cu (II) -dependent DNA damage via H2O2 generation through a redox cycle of benzoquinone derivatives which required NADH for reduction. Tryptophan metabolites and caffeic acid induced Cu(II) -mediated DNA damage through H2O2 formation, which was enhanced by preincubation with Mn(II). It can be concluded that most of ''non-mutagenic'' carcinogens generate H2O2, which causes metal-dependent DNA damage.