Fatty acids free radical damage

Body cells become damaged over time by attacks from molecules known as free peroxide radicals, i.e. unstable, oxygen-containing compounds which are released during metabolism of pol5mnsaturated fatty acids. Free radicals can play a role in a number of diseases by allowing harmful compounds to enter the cell through ieaky cell membranes injured by peroxidation of the membrane s polyunsaturated fatty acids. Vitamin E and other anti-oxidants trap free radicals and interrupt this chain reaction oxidative destruction. 

The brain has a number of characteristics that make it especially susceptible to free- radical-mediated injury. Brain lipids are highly enriched in polyunsaturated fatty acids and many regions of the brain, for example, the substantia nigra and the striatum, have high concentrations of iron. Both these factors increase the susceptibility of brain cell membranes to lipid peroxidation. Because the brain is critically dependent on aerobic metabolism, mitochondrial respiratory activity is higher than in many other tissues, increasing the risk of free radical Teak from mitochondria conversely, free radical damage to mitochondria in brain may be tolerated relatively poorly because of this dependence on aerobic metabolism. 

The high concentration of polyunsaturated fatty acids in cellular and subcellular membranes makes them particularly susceptible to free radical damage. In addition, mitochondrial membranes contain flavins as a part of their basic structure, potentially contributing C>2 resulting in free radical damage. The process of uncontrolled lipid peroxidation can result in the loss of essential polyunsaturated fatty acids, and the formation of toxic hydroperoxides and other secondary products. The loss of essential fatty acids may then result in loss of membrane integrity and loss of function. Extensive oxidation can also lead to rupture of... 

Oxygen radicals and their derivatives can be deadly to cells. The hydroxyl radical causes oxidative damage to proteins and DNA. It also forms lipid peroxides and malondialdehyde from membrane lipids containing polyunsaturated fatty acids. In some cases, free radical damage is the direct cause of a disease state (e.g., tissue damage initiated by exposure to ionizing radiation). In neurodegener-ative diseases, such as Parkinson s disease, or in ischemia-reperfusion injury,... 

Chain reactions that form lipid free radicals and lipid peroxides in membranes make a major contribution to ROS-induced injury (Fig. 24.8). An initiator (such as a hydroxyl radical produced locally in the Fenton reaction) begins the chain reaction. It extracts a hydrogen atom, preferably from the double bond of a polyunsaturated fatty acid in a membrane lipid. The chain reaction is propagated when O2 adds to form lipid peroxyl radicals and lipid peroxides. Eventually lipid degradation occurs, forming such products as malondialdehyde (from fatty acids with three or more double bonds), and ethane and pentane (from the w-terminal carbons of 3 and 6 fatty acids, respectively). Malondialdehyde appears in the blood and urine and is used as an indicator of free radical damage. 

Peroxidation of lipids containing polyunsaturated fatty acids leads to generation of free radicals that may damage tissues and cause disease. 

UV-induced ROS are extremely toxic to cells by causing oxidative damage to all biomolecules (Sies 1991). For instance, lipids, which are major compounds of all biological membranes, may be destroyed by ROS. After a first initiation reaction an unsaturated fatty acid is converted to a peroxyl radical, which in turn attacks another unsaturated fatty acid finally leading to free radical cascades. This photochemical peroxidation of unsaturated fatty acids may be particularly damaging for membrane structure and function (Bischof et al 2006a). 

It is the damage to DNA in the epithelial cells of the skin that is usually considered to be the cause of the development of melanoma due to excessive exposure to sunlight (Chapter 21). However, an alternative or additional mechanism could be the damage to polyunsaturated fatty acids in membrane phospholipid in the epithelial cells. This could be due, as in the case of DNA damage, to the local production of free radicals (Appendix 9.6). The damaged polyunsaturated fatty acids (e.g. peroxidised or hydroperoxide fatty acids) will disrupt the membrane which might facilitate the binding of key proteins of proliferation to these membranes or result in the production of abnormal eicosanoids either of which could facilitate inappropriate proliferation. 

---