DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity

Synthesis and Characterization of Polycyclic Aromatic Hydrocarbon <i>o</i>-Quinone Depurinating N7-Guanine Adducts^†

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants which may cause cancer and require metabolic activation to exert their carcinogenic effects. One pathway of activation involves the dihydrodiol dehydrogenase-catalyzed oxidation of non-K region trans-dihydrodiols to yield catechols, which autoxidize to form reactive o-quinones. As a step toward identifying the spectrum of PAH o-quinone−DNA adducts that may form in biological systems, depurinating PAH o-quinone−guanine adducts were synthesized. Naphthalene-1,2-dione, phenanthrene-1,2-dione, and benzo[a]pyrene-7,8-dione were reacted with 5 equiv of 2‘-deoxyguanosine (dGuo) under acidic conditions (1:1 acetic acid/water). The products were purified by reversed-phase HPLC, characterized by a combination of UV spectroscopy, electrospray ionization/tandem mass spectrometry, and high-field proton nuclear magnetic resonance spectroscopy, and identified as 7-(naphthalene-1,2-dion-4-yl)guanine (MH+, m/z 308), 7-(phenanthrene-1,2-dion-4-yl)guanine (MH+, m/z 358), and 7-(benzo[a]pyrene-7,8-dion-10-yl)guanine (MH+, m/z 432), respectively. Reaction at N7 of dGuo leads to cleavage of the glycosidic bond, producing depurinating adducts. Reaction of phenanthrene-1,2-dione with calf thymus DNA led to the formation of the corresponding depurinating adduct. The loss of modified bases in DNA generates apurinic sites which, if unrepaired, can lead to mutations and thus cellular transformation. These synthesized PAH o-quinone−N7-guanine adducts can be used as standards to identify such adducts in vitro and in vivo