Membrane disruption, free radical

Carbon tetrachloride is metabolized by cytochrome P-450 to the reactive metabolites trichloromethyl free radical and trichloromethylperoxy free radical. The trichloromethyl free radical may bind directly to cellular macromolecules such as lipids and proteins, and also to DNA, disrupting cell processes and breaking down membranes. The free radical can take part in anaerobic reactions, subsequently forming such toxic compounds as chloroform, hexachloroethane, and carbon monoxide. Aerobic biotransformation of the... 

Mitochondrial permeability transition involves the opening of a larger channel in the inner mitochondrial membrane leading to free radical generation, release of calcium into the cytosol and caspase activation. These alterations in mitochondrial permeability lead eventually to disruption of the respiratory chain and dqDletion of ATP. This in turn leads to release of soluble intramito-chondrial membrane proteins such as cytochrome C and apoptosis-inducing factor, which results in apoptosis. 

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. 

The finding that water-soluble flavonoids could exert their beneficial properties at the hydrophobic portion of the membrane was also observed in in vivo studies and in cells in culture. For example, erythrocytes obtained from animals fed a flavanol- and procyanidin-rich meal showed reduced susceptibility to free-radical-mediated hemolysis [Zhu et al., 2002]. Consistently, we demonstrated that procyanidin hexamers, which interact with membranes but would not be internalized, protected Caco-2 cells from AMVN- and bile-induced oxidation [Erlejman et al., 2006]. When liposomes were preincubated with a series of flavonoids with diverse hydrophobicity, not only hydrophobic flavonoids prevented AMVN-mediated lipid oxidation but also the more hydrophilic ones [Erlejman et al., 2004]. Similarly to what was previously found in liposomes, the protective effects of flavonoids against AMVN-supported oxidation was strongly associated with their capacity to prevent membrane disruption by detergents, supporting the hypothesis of a physical protection of membranes by preventing oxidants to reach fatty acids. 

During hemoglobin degradation, free heme, ferriprotoporphyrin-IX or Fe(II) PPIX (Fig. 2) is released in the digestive vacuole. The toxicity of heme to the parasite has been demonstrated [27-30] it is supposed to cause the disruption of metabolic functions by means of peroxidation of membranes and inhibitions of enzymes via the generation of oxidative free radicals [31],... 

Fig. 2.8. Factors controlling the production of free radicals in cells and tissues (Rice-Gvans, 1990a). Free radicals may be generated in cells and tissues through increased radical input mediated by the disruption of internal processes or by external influences, or as a consequence of decreased protective capacity. Increased radical input may arise through excessive leukocyte activation, disrupted mitochondrial electron transport or altered arachidonic acid metabolism. Delocalization or redistribution of transition metal ion complexes may also induce oxidative stress, for example, microbleeding in the brain, in the eye, in the rheumatoid joint. In addition, reduced activities or levels of protectant enzymes, destruction or suppressed production of nucleotide coenzymes, reduced levels of antioxidants, abnormal glutathione metabolism, or leakage of antioxidants through damaged membranes, can all contribute to oxidative stress.

Peroxidation of lipid molecules invariably changes or damages lipid molecular structure. In addition to the self-destructive nature of membrane lipid peroxidation, the aldehydes that are formed can cross-link proteins. When the damaged lipids are the constituents of biologic membranes, the cohesive lipid bilayer arrangement and stable structural organization is disrupted (see Fig. 24.7). Disruption of mitochondrial membrane integrity may result in further free radical production. 

Mechanisms These anthracyclines can intercalate between base pairs, inhibit topoisomerase II, and generate free radicals. They block the synthesis of RNA and DNA and cause DNA strand scission. Membrane disruption also occurs. Anthracyclines are CCNS drugs. 

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