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

Abstract

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.

Chronic and Acute Toxicities of Aflatoxins: Mechanisms of Action

“…Moreover, the concomitant production of 8-OH-dG by ODD, discussed above, may enhance the epigenetic effect, as this adduct was shown to increase cytosine methylation at the -*CpG-islands [99]. On the other hand, it is well established that reactive LPO-induced aldehydes are more mutagenic than the free radicals and the highly reactive AFBO [83]. Indeed, reactive aldehydes can act remotely from the site of their formation, contrary to the short-lived and highly instable free radicals and epoxides.…”

“…As was mentioned above, AFB1 can also induce DNA damage by OS indirectly via the production of ROS which, in turn, attack oxidatively membrane phospholipids and release different mutagenic aldehydes (Figure 1). Among 33 known LPO-derived aldehydes, malondialdehyde (MDA), acrolein (Acr), 4-hydroxy-2-nonenal (HNE), and 4-oxo-2(E)-nonenal (ONE) are the most predominant and can react with DNA bases to generate pro-mutagenic exocyclic DNA adducts leading to genomic instability and possibly to carcinogenicity [83][84][85][86][87][88][89]. For example, acetaldehyde (Ace), Acr, Cro, and HNE can bind to the DNA guanine residue to from the highly mutagenic 1,N 2 -propano-2 -deoxyguanosine (1,N 2 -propanodGuo, 1,N 2 -PdG) adduct [70,88,[90][91][92].…”

The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress

“…A consensus exists that RAs play a dual role in cellular processes: They are known to modify proteins [49][50][51], DNA [52,53], and lipids [16,54], but are also involved in important signaling pathways [50]. However, the molecular mechanisms of their action are still far from being well understood.…”

Pathological mechanism of hidden blood loss after TKA: oxidative stress induced by free fatty acids

“…In addition, the carbonyl products of lipid peroxidation (such as malondialdehyde) can also attack the amino groups of membrane protein molecules, resulting in intramolecular and intermolecular cross-linking of proteins. On the other hand, free radicals can also covalently bind directly to enzymes or receptors on the membrane [29][30][31][32]. These oxidations damage the spatial con guration of enzymes, receptors and ion channels embedded in the membrane system, destroying the integrity of the membrane and affecting the function of the membrane and antigen speci city, which eventually leads to the cell damage and lesions.…”