Peroxidation damage, lipids

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

Chow. C. K., and A. L. Tappel. An enzymatic protective mechanism against lipid peroxidation damage to lungs of ozone-exposed rats. Lipids 7 518-524, 1972. 

Increase of free cytosolic calcium is toxic for various reasons. Among them are the diminution of ATP levels (Tsuji et al. 1994), the protease and lipase activation, and the FR production that causes a peroxidation of lipids. The inflow of calcium in the terminals could also increase the release of endogenous excitatory amino acids and propagate neuronal damage through positive feedback (Choi and Hartley 1993). Glutamic neurotoxicity mediated by calcium follows three stages ... 

Figure 6.20 The role of a-tocopherol (vitamin E) in removing damaging lipid peroxides from membranes. The a-tocopherol is regenerated by ascorbate (vitamin C).

Thus, the susceptibility is the result of accumulation of the drug in the target organ to reach concentrations not achieved in other tissues. This is then followed by what is probably a combination of events such as formation of a reactive intermediate, possibly a free radical, stimulation of lipid peroxidation and depletion of GSH, and then peroxidative damage to cell membranes and mitochondria. Whether metabolic activation by cytochromes P-450, or chemical rearrangement, or reductive activation, or all the three are involved is not currently clear. 

A neuropathy caused by clioquinol (iodochlorohydroxyquin, chinoform) and enhanced by the formation of a clioquinol ferric chelate which initiates lipid peroxidation, leads to complete degeneration of retinal neuroblasts within a day. Vitamin E has a potent protective action against the effects of the chelate [75]. Peroxidative damage to DNA in rat brain, induced by methyl ethyl ketone peroxide, a potent initiator of lipid peroxidation, was inhibited by addition of vitamin E to the diet of rats [76]. 

Peroxynitrite is a nonspecific oxidant that reacts with all classes of biomolecules depleting low-molecular-weight antioxidants, initiating lipid peroxidation, damaging nucleic acids and proteins. Its reactions are much slower than those of the hydroxyl radical but are faster than those of hydrogen peroxide. Comparison of peroxynitrite reactivity with various amino acid residues of human serum albumin have shown that cysteine, methionine, and tryptophan are the most reactive... 

Thus, in vitamin E deficiency, selenium has a beneficial effect in lowering the concentrations of alkylperoxyl radicals, and conversely, in selenium deficiency, vitamin E has a protective effect in reducing the radicals. When selenium is adequate, but vitamin E is deficient, tissues with low activity of glutathione peroxidase [e.g., the central nervous system and (rat) placenta] are especially susceptible to lipid peroxidation, whereas tissues with high activity of glutathione peroxidase are not. Conversely, with adequate vitamin E and inadequate selenium, membrane lipid peroxidation will be inhibited, but tissues with high peroxide production and low catalase activity will still be at risk from peroxidative damage, especially to sulfhydryl proteins. 

In lipid peroxidation, unsaturated fatty acids are peroxidized in the biological membranes of cells and their organelles. This leads to chain breaks in fatty acids with insertion of hydrophilic groups and cis-trans-iso-merization. Membrane-bound proteins are damaged. Lipid radicals (L ) are transformed into unstable lipid-peroxy radicals (LOO ). Lipid peroxidation markers include malondialdehyde and 4-hydroxynonenal. (18, 38, 79, 97) (s. figs. 2.19 21.12)... 

Wolf, G. (1997) gamma-Tocopherol an efficient protector of lipids against nitric oxide- initiated peroxidative damage. NutrRev 55, 376-8. 

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