Formation, prevention, and repair of DNA damage by iron/hydrogen peroxide.

Although oxygen is a powerful oxidant, the triplet ground state of dioxygen constitutes a kinetic barrier for oxidation of biological molecules, which are mostly singlet state (1). However, the unpaired orbitals of dioxygen can sequentially accommodate single electrons to yield O2 ., H2O2, the very reactive zOH, and water (Fig. 1, Reaction 1). The oxidative potential of atmospheric oxygen is maintained by the non-alignment of electron spins, and aerobic life is based upon harnessing energy via the catalytic spin pairing of triplet oxygen by the electron transport chain (2). The latter process occasionally errs, however, giving rise to O2 . and other reactive oxygen species (3) that cause cellular and genetic damage (4–7). Moreover, catabolic oxidases such as xanthine oxidase, anabolic processes such as nucleoside reduction, and defense processes such as phagocytosis also produce oxygen radicals. Although DNA is a biologically important target for reactive oxygen species, free O2 . is relatively unreactive with DNA (8). However, O2 . dismutates (via spontaneous or enzyme-catalyzed reactions) to produce H2O2 (Fig. 1, Reaction 2). O2 . can also reduce and liberate Fe from ferritin (9) (Fig. 1, Reaction 3) or liberate Fe from iron-sulfur clusters (10) (Fig. 1, Reaction 4); subsequently very reactive oxygen species can form via the Fenton reaction (Fig. 1, Reaction 5). Thus, the cytotoxic effects of O2 . (as well as of iron and H2O2) have been linked to DNA damage by way of the Fenton reaction (4, 11, 12) (Fig. 2).