Lipid peroxidation is the metabolic process in which reactive oxygen species (ROS) result in the oxidative deterioration of lipids. This may significantly affect cell membrane structure and function.
Lipid peroxidation most often affects polyunsaturated fatty acids, because they contain methylene –CH2– groups which contain hydrogen that is especially reactive with ROS. Increased ROS production occurs in inflammation, during radiation, or during metabolism of hormones, drugs, and environmental toxins. This can overwhelm endogenous protective antioxidant mechanisms and increase ROS-mediated damage to membrane structure and function. Such ROS reactions can also lead to protein damage, including DNA repair enzymes and polymerases, impairment, and production of aldehyde by-products such as malondialdehyde (MDA; β-hydroxy-acrolein) and 4-hydroxy-2-nonenal (HNE). MDA is formed during homolytic decomposition of lipid hydroperoxides that contain more than two double bonds. MDA reacts with DNA to form primarily a propane adduct with 2′-deoxyguanosine (M1G-dR). Although they have important physiological roles in cell proliferation, transformation, differentiation, and apoptosis these aldehydes are also strongly carcinogenic. Mutagenicity of MDA and HNE, the major aldehyde products, has been clearly demonstrated. These can promote the formation of DNA-adducts which are required to be repaired in order to maintain the fidelity of the DNA. If not, DNA mutations can occur. For example, the reaction between the epoxide of HNE with DNA leads to the formation of unsubstituted etheno-dAdo adducts. Etheno adducts are mutagenic and have been detected in human tissue samples providing an important link between lipid peroxidation and in vivo DNA-adduct formation. Alternatively, lipid peroxidation and ROS are triggers and essential mediators of apoptosis, which eliminates precancerous and cancerous, virus-infected and otherwise damaged cells. This suppression of cell cancer growth is enhanced by pro-oxidants and eliminated by antioxidants, and this elimination is proportional to the inhibition of lipid peroxidation products by antioxidants. Lipid peroxidation may also play an important role in the potential anticarcinogenic effects of other dietary factors including soy, marine n-3 fatty acids, isothiocyanates, green tea, and vitamin D and calcium.
As with any radical reaction, the reaction consists of three major steps: initiation, propagation, and termination. Initiation is the step whereby a fatty acid radical is produced. The initiators in living cells are most notably ROS such as hydroxyl radical, which combines with a hydrogen atom to make water and a fatty acid radical. The fatty acid radical is not a stable molecule, so it reacts readily with molecular oxygen, thereby creating a peroxyl-fatty acid radical. This too is an unstable species that reacts with another free fatty acid producing a different fatty acid radical and a hydrogen peroxide molecule or a cyclic peroxide molecule if it had reacted with itself. This cycle propagates itself as the new fatty acid radical reacts in the same way. This results in a chain reaction and the only way to stop a radical reaction is for two radicals to react and produce a non-radical species. This occurs when the concentration of radical species is high enough for there to be a high probability of two radicals actually colliding. However, in organisms there are a number of different molecules which bind and quench free radicals and so protect lipids from oxidation. These are usually lipid-soluble vitamins such as alpha-tocopherol or vitamin E.
ROS-mediated formation of lipid hydroperoxides involves the initial abstraction of a bis-allylic methylene hydrogen atom. Lipid hydroperoxides can also be formed by the action of cyclooxygenases and lipoxygenases on polyunsaturated fatty acids (PUFAs). LOX- and COX-mediated pathways of PUFA metabolism can potentially provide a rich source of lipid hydroperoxides.
Chronic inflammation, part of the host immune response, has long been recognized to be associated with the development and progression of cancer. The combination of excess oxidant production and antioxidant depletion, and therefore, oxidative stress, may play a role in the development and progression of cancers. High ROS generation and persistent oxidative stress have been recognized as characteristic features of carcinoma cells both in vivo and in vitro. Also, it is widely accepted that patients with advanced cancer have reduced circulating antioxidant concentrations. Therefore, in the cancer patient the risk for structural and functional damage of cell membranes is likely to be increased. Higher levels of circulating plasma MDA have been observed in different malignancies, including lung, gastrointestinal, and hormone-dependent cancers. However, whether such increased MDA concentrations are primarily due to the tumor, the inflammatory response or some other factors remain to be determined.