Peroxidation, lipid, free radicals produced

Lipid peroxidation is probably the most studied oxidative process in biological systems. At present, Medline cites about 30,000 publications on lipid peroxidation, but the total number of studies must be much more because Medline does not include publications before 1970. Most of the earlier studies are in vitro studies, in which lipid peroxidation is carried out in lipid suspensions, cellular organelles (mitochondria and microsomes), or cells and initiated by simple chemical free radical-produced systems (the Fenton reaction, ferrous ions + ascorbate, carbon tetrachloride, etc). In these in vitro experiments reaction products (mainly, malon-dialdehyde (MDA), lipid hydroperoxides, and diene conjugates) were analyzed by physicochemical methods (optical spectroscopy and later on, HPLC and EPR spectroscopies). These studies gave the important information concerning the mechanism of lipid peroxidation, the structures of reaction products, etc. 

Fig. 3. Autoxidation of polyunsaturated fatty acids in phospholipid membranes. Addition of oxygen to lipid free radicals is extremely fast. It yields peroxyl radicals ROO which will tend to capture labile hydrogen atoms of neighbouring polyunsaturated lipids. Accidentally produced free radicals will therefore initiate a chain reaction of lipid peroxidation which will propagate along membranes. This process can result in several dozen propagation steps before it is stopped by a termination reaction. Examples of such termination reactions are the recombination of peroxyl radicals and the formation of a stable free radical from a free radical scavenger (scavH). Termination through recombination of low steady-state concentration of alkyl radicals is unlikely in aerobic medium.

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. 

Free radicals are known to cause damage to myelin, the lipid cell membrane, and DNA of cells. A likely candidate for a mechanism of neural tissue damage due to electrochemical products is peroxidation of the myelin by free radicals produced on the electrode surface. Several researchers [130, 131, 132, 133, 134, 135] have demonstrated the great susceptibility of myelin to free radical damage. Damage... 

One of the important consequences of neuronal stimulation is increased neuronal aerobic metabolism which produces reactive oxygen species (ROS). ROS can oxidize several biomoiecules (carbohydrates, DNA, lipids, and proteins). Thus, even oxygen, which is essential for aerobic life, may be potentially toxic to cells. Addition of one electron to molecular oxygen (O,) generates a free radical [O2)) the superoxide anion. This is converted through activation of an enzyme, superoxide dismurase, to hydrogen peroxide (H-iO,), which is, in turn, the source of the hydroxyl radical (OH). Usually catalase... 

Patients in which oxidative damage may be an important aetiological factor cataract formation include those with Down s syndrome, since there is now evidence that they have increased indices of free-radical activity and lipid peroxidation. It has been su ested that this is due to the increased levels of Cu/Zn-SOD (carried on chromosome 21) generating increased concentrations of hydrogen peroxide (Bras etal., 1989). In the presence of superoxide radicals these produce highly reactive hydroxyl radicals. 

In this chapter the generation of free radicals, mainly superoxide and nitric oxide, catalyzed by prooxidant enzymes will be considered. Enzymes are apparently able to produce some other free radicals (for example, HO and N02), although their formation is not always rigorously proved or verified. The reactions of such enzymes as lipoxygenase and cyclooxygenase also proceed by free radical mechanism, but the free radicals formed are consumed in their catalytic cycles and probably not to be released outside. Therefore, these enzymes are considered separately in Chapter 26 dedicated to enzymatic lipid peroxidation. 

LOX-catalyzed oxidation of LDL has been studied in subsequent studies [26,27]. Belkner et al. [27] showed that LOX-catalyzed LDL oxidation was not restricted to the oxidation of lipids but also resulted in the cooxidative modification of apoproteins. It is known that LOX-catalyzed LDL oxidation is regio- and enantio-specific as opposed to free radical-mediated lipid peroxidation. In accord with this proposal Yamashita et al. [28] showed that LDL oxidation by 15-LOX from rabbit reticulocytes formed hydroperoxides of phosphatidylcholine and cholesteryl esters regio-, stereo-, and enantio-specifically. Sigari et al. [29] demonstrated that fibroblasts with overexpressed 15-LOX produced bioactive minimally modified LDL, which is probably responsible for LDL atherogenic effect in vivo. Ezaki et al. [30] found that the incubation of LDL with 15-LOX-overexpressed fibroblasts resulted in a sharp increase in the cholesteryl ester hydroperoxide level and a lesser increase in free fatty acid hydroperoxides. 

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