Membrane lipid peroxidation free radical formation

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. 

Membrane Lipid Peroxidation and Free Radical Formation... 

De Vos et al. (1989) suggest that the copper-induced damage to the permeability barrier in roots of Silene cucubalus is caused by a direct metal action on both membrane lipids and thiols. They propose that the first damaging effects of copper ions is the oxidation and cross-linking of membrane protein sulphydryls. However, they also adjudge an important role to the copper induced membrane lipid peroxidation, possibly due to direct free radical formation in the membrane this effect could be enhanced by a depletion of thiols such as glutathione which results in a concomitant decrease of the cellular defence system against free radicals. 

Vitamin E (a-tocopherol), a potent antioxidant, appears to offer protection against injuries caused by 02, 03, and N02, and nitrosamine formation. Male rats supplemented with daily doses of 100 mg tocopheryl acetate and exposed to 1.0 ppm 03 have been shown to survive longer than vitamin E-deficient rats. The action of 03 is attributed in part at least to free radical formation. In addition, there is sufficient evidence that vitamin E protects phospholipids of microsomal and mitochondrial membranes from perox-idative damage by reacting with free radicals. Because lipid peroxidation is associated with decrease in oxidase activities, it is expected that the enzyme activity is affected by dietary vitamin E. Maximum activity has been observed when diets included both polyunsaturated fatty acids and vitamin E. 

These fatty acids play an important role also in the amelioration of autoimmune diseases, such as arthritis, and in the inhibition of the rapid proliferation of cancer cells. However, PUFA in membrane lipids are vulnerable to free radical-initiated oxidation, generated by xenobiotics or normal aerobic cellular metabolism that results in the formation of lipid peroxides [84]. 

The lipids that constitute the cell membrane, especially those lipids containing unsaturated double bonds, are susceptible to free radical attack, leading to the formation of lipid peroxides and aldehydes (Kako 1985). A number of short chain fragments produced from peroxidation of polyunsaturated fatty acids as 4-hydroxyperoxy nonenal and 4-hydroxy 2-alkenals react with sulphydryl groups of various enzymes modifying their activities. 

The proximal mechanism for induction of stress protein synthesis leading to the activation of HSF and gene activation is not completely understood, but evidence for several possibilities exists. Activation of HSF by prooxidants does not result in the accumulation of specific stress proteins (Bruce et al. 1993). These results suggest that induction of stress proteins by specific metals, whose toxicity is mediated via oxidative damage to membranes or DNA, may be fundamentally different from that of the heat-induced activation of the stress response (Keyse and Tyrrell 1987 Bruce et al. 1993). Thus, metals such as cadmium, mercury, nickel, arsenite, copper, lead, and iron, which induce oxygen free radicals or promote formation of lipid peroxides (Stacey and Klaassen 1981 Halliwell and Gutteridge 1984 Christie and Costa 1984 Kasprzak 1991 Donati et al. 1991), may... 

Xerxibiotic metabolism, cell swelling, lipid peroxidation, free radical formation, phospholipase activation, caldun sequestration, loss of membrane function, necrosis... 

Halomethyl compounds are subdivided into monohalomethyls, which are alkylating agents, and polyhalomethyls, which must be metabolized to an ultimate species. Reductive dechlorination of carbon tetrachloride 353) to chloroform by rabbit liver microsomes parallels the concentration of cytochrome P-450 in the microsomes but requires anaerobic conditions and NADPH. The identification of hexachloroethane after incubation of NADPH-reduced microsomes with carbon tetrachloride is indicative of homolytic formation of the free radicals of chlorine and trichloromethyl and supports the hypothesis that such species initiate an autocatalytic peroxidation of lipid membranes that results in the observed hepatotoxicity. A similar scheme for radical formation and lipid destruction has been described by Reynolds and Moslen for halothane. In contrast to the reductive dechlorination of carbon tetrachloride, the metabolism of chloroform to carbon dioxide in vitro requires oxygen and produces carbonyl chloride (phosgene) as an intermediate. That this also... 

Hepatotoxicity for most chemical toxins mechanistically proceeds via free radical formation which causes OS that induces lipid peroxidation, membrane damage, and altered enzyme activities, the generation of ROS and hydrophilic toxins. Ethanol,... 

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