Peroxidation and Oxidative Stress

Although both metals and glucocorticoids can directly induce MT synthesis, divalent metals like cadmium and zinc are the best-known inducers of MT synthesis. Metal-responsive elements (MREs) and glucocorticoid-responsive elements (GREs) have been identified in MT genes (Palmiter 1987). In addition to these inducers, several other compounds (which do not even bind with MT), oxidative stress, and inflammatory conditions have been shown to induce MT synthesis in various systems. Several mechanisms are proposed for such induction of MT synthesis and they may involve lipid peroxidation with free radical formation, release of cytokines during inflammation, and changes in tissue distribution of zinc. 

The elevated cellular content of MT in the cytoplasm and/or nucleus can alter the intracellular distribution and binding patterns of several metals which can avidly bind with MT. Since the intracellular content of MT is much higher than its extracellular levels under physiological conditions. 

Andrews GK, Gallant KR, Cherian MG (1987) Regulation of the ontogeny of rat liver metallothionein mRNA by zinc. Eur J Biochem 166 527-531 Andrews GK, McMaster MT, De SK, Paria BC, Dey SK (1993) In Suzuki KT, Imura N, Kimura M (eds) Cell-specific expression and regulation of the mouse metallothionein I and II genes in the reproductive tract and preimplantation embryo. Metallothionein III. Birkhauser, Basel, pp 363-380 Bakka A, Webb M (1981) Metabolism of zinc and copper in the neonate changes in the concentration and contents of the thionein bound Zn and Cu with age in the livers of the newborn of various species. Biochem Pharmacol 30 721-725 Bremner I (1993) Involvement of metallothionein in the regulation of mineral metabolism. In Suzuki KT, Imura N, Kimura M (eds) Metallothionein III. Birkhauser, Basel, pp 111-124 

Bremner I, Williams RB, Young BW (1977) Distribution of copper and zinc in the liver of the developing fetus. Br J Nutr 38 87-92 Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V (1991) Treatment of Wilson s disease with zinc IX response of serum lipids. J Lab Clin Med 118 446-470 Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW (1993) The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nature Genet 5 327-337 

Carri MT, Galiazzo F, Ciriolo MR, Rotilio G (1991) Evidence for co-regulation of Cu, Zn superoxide dismutase and metallothionein gene expression in yeast through transcriptional control by copper via the ACE 1 factor. FEBS Lett 278 263-266 

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Therefore, the metabolite interferes with mitochondrial function and decreases the production of ATP and other important cofactors such as NADH and FADH. Therefore, after repeated use of the drug, mitochondrial integrity is reduced and cellular and overall liver fat oxidation is inhibited. Consequently, fat accumulates, seen as microvesicular steatosis. Electron microscopy shows swollen mitochondria and damaged mitochondrial structures. The accumulated lipid may encourage lipid peroxidation and oxidative stress to occur, causing further damage. 

Fig. 7.3 Reactions showing the generation of ROS during lipid peroxidation and oxidative stress. Hydroxyl radical ( OH) lipid radical ( lipid), peroxyl radical (lipid-OO ) lipid peroxide (lipid-OOH) nitric oxide ( NO) nitrogen dioxide (N02) peroxynitrite anion (ONOO-) hypochlorous acid (HOC1), and hydrogen peroxide (H202)...

It is well known that lipid peroxidation, DNA singlestrand breaks, and other forms of DNA damage occur in response to oxidative stress (Ames et al, 1982). Depletion of reduced glutathione also commonly precedes or accompanies lipid peroxidation and oxidative stress (Muldoon and Stohs, 1991 Omar et al, 1990). In an in vivo study, the effects of ricin administered orally on hepatic lipid peroxidation, nonprotein sulfhydryl content, and DNA singlestrand breaks were assessed in mice (Muldoon et al, 1992). The incidence of hepatic DNA damage increased 2.9-, 2.8-, and 2.4-fold relative to control values at 24, 36, and 48 h post-treatment with ricin, respectively. Hepatic nonprotein sulfhydryl concentration decreased significantly from 51 to 65% to control values at 24, 36, and 48 h post-treatment (Figures 25.2 and 25.3). 

Tau binds Cu [176], which is enriched in NETs [16,79]. Recent data indicates that oxidative stress both in cell culture and in SOD2 knockout mice induces tau hyperphosphorylation (Eig. 2). A model emerges where corruption and accumulation of Ab decorated with Cu " " generates hydrogen peroxide and oxidative stress leading to the hyperphosphorylation of tau, and subsequent NET formation. Recent reports have indicated that both Zn and Fe(III) induce aggregation of hyperphosphorylated tau [177] while reduction of Fe (III) to Fe (II) reverses tau aggregation [178]. 

Rojkind, M., Dominguez-Rosales, J. A., Nieto, N., and Greenwel, P. (2002) Role of hydrogen peroxide and oxidative stress in healing responses. Cell Mol. Life. Sci. 59, 1872-1891. 

There is also intriguing evidence that (co-3) fatty acids induce apo B degradation via mechanisms that do not involve the conventional proteasomal or lysosomal degradation pathways. In the presence of (cu-3) fatty acids, apo B degradation was shown to occur in a post-ER, pre-secretion process (E.A. Fisher, 2004). Lipid peroxidation and oxidative stress mechanisms were implicated in the increased degradation and decreased secretion of apo... 

Mercury induces lipid peroxidation and oxidative stress and involves changes in the glutathione level (Fukino et al., 1984 Rana et al., 1995). 

Ellis et al. [72] recently studied the effects of short- and long-term vitamin C therapy in the patients with chronic heart failure (CHF). It was found that oxygen radical production and TBAR product formation were higher in patients with CHF than in control subjects. Both short-term (intravenous) and long-term (oral) vitamin C therapy exhibited favorable effects on the parameters of oxidative stress in patients the treatments decreased oxygen radical formation and the level of lipid peroxidation and improved flow-mediated dilation in brachial artery. However, there was no correlation between changes in endothelial function and oxidative stress. 

The above findings are supported in the other studies of the inhibitory effects of flavonoids on iron-stimulated lipid peroxidation. Quercetin was found to be an inhibitor of iron-stimulated hepatic microsomal lipid peroxidation (/50 = 200 pmol I ) [134]. Flavonoids eriodictyol, luteolin, quercetin, and taxifolin inhibited ascorbate and ferrous ion-stimulated MDA formation and oxidative stress (measured by fluorescence of 2,7,-dichlorodihydro-fluorescein) in cultured retinal cells [135]. It should be mentioned that in recent work Heijnen et al. [136] revised the structure activity relationship for the protective effects of flavonoids against lipid peroxidation. 

Abuja, P.M. andAlbertini, R. (2001) Methods for monitoring oxidative stress, lipid peroxidation and oxidation resistance of lipoproteinOn. Chim. Acta, 306 1-17. 

Ghyczy M, Boros M (2001) Electrophilic methyl groups present in the diet ameliorate pathological states induced by reductive and oxidative stress a hypothesis. Br J Nutr 85 409-414 Gilbert BC, Silvester S (1997) EPR studies of the role of copper in bio-organic free radical reactions. Copper-catalyzed oxidations of thiols with peroxides, especially those involving glutathione. Nukleonika 42 307-322... 

PCNs, particularly penta- and hexaCNs, induce hepatic ethoxyresorufin O-deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH) activities [45,46] and oxidative stress resulting in increased lipid peroxidation, decreased hepatic vitamins A and E, and decreased catalase and superoxide... 

Blokhina, O. 2000. Anoxia and Oxidative Stress Lipid Peroxidation, Antioxidant Status and Mitochondrial Functions in Plants. Ph.D. Dissertation, Faculty of Sciences, University of Helsinki... 

Such imbalanced antioxidant systems in schizophrenia could lead to oxidative stress- and ROS-mediated injury as supported by increased lipid peroxidation products and reduced membrane polyunsaturated fatty acids (PUFAs). Decrease in membrane phospholipids in blood cells of psychotic patients (Keshavan et al., 1993 Reddy et al., 2004) and fibroblasts from drug-naive patients (Mahadik et al., 1994) as well as in postmortem brains (Horrobin et al., 1991) have indeed been reported. It has also been suggested that peripheral membrane anomalies correlate with abnormal central phospholipid metabolism in first-episode and chronic schizophrenia patients (Pettegrewet al., 1991 Yao et al., 2002). Recently, a microarray and proteomic study on postmortem brain showed anomalies of mitochondrial function and oxidative stress pathways in schizophrenia (Prabakaran et al., 2004). Mitochondrial dysfunction in schizophrenia has also been observed by Ben-Shachar (2002) and Altar et al. (2005). As main ROS producers, mitochondria are particularly susceptible to oxidative damage. Thus, a deficit in glutathione (GSH) or immobilization stress induce greater increase in lipid peroxidation and protein oxidation in mitochondrial rather than in cytosolic fractions of cerebral cortex (Liu et al., 1996). 

Depletion of cellular GSH has been widely studied with hundreds of chemicals including APAP and bromobenzene. These studies demonstrated very clearly that bioactivation followed by GSH adduct formation causes depletion of cytosolic glutathione and oxidative stress as indicated by indicators including enhanced levels of GSSG, lipid peroxidation, and loss of membrane integrity. 

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