Copper lipid peroxidation

Copper reduces glutathione, which is necessary for normal cell viability. The amino acid transferases are inhibited in the presence of excess copper lipid peroxidation also occurs. Copper combines with thiol groups, which reduces the oxidation state II to I in copper and oxidizes the thiol groups to disulfides, especially in the cell membrane. 

Sandman, G. Boger, P. (1980). Copper mediated lipid peroxidation processes in photosynthetic membranes. Plant Physiology, 66, 797-800. 

Sato, M. et al.. Effect of sodium copper chlorophyUin on lipid peroxidation. IX. On the antioxidative components in commercial preparations of sodium copper chlorophyUin, Chem. Pharm. Bull, 34, 2428, 1986. 

In this reaction scheme, the steady-state concentration of peroxyl radicals will be a direa function of the concentration of the transition metal and lipid peroxide content of the LDL particle, and will increase as the reaction proceeds. Scheme 2.2 is a diagrammatic representation of the redox interactions between copper, lipid hydroperoxides and lipid in the presence of a chain-breaking antioxidant. For the sake of clarity, the reaction involving the regeneration of the oxidized form of copper (Reaction 2.9) has been omitted. The first step is the independent decomposition of the Upid hydroperoxide to form the peroxyl radical. This may be terminated by reaction with an antioxidant, AH, but the lipid peroxide formed will contribute to the peroxide pool. It is evident from this scheme that the efficacy of a chain-breaking antioxidant in this scheme will be highly dependent on the initial size of the peroxide pool. In the section describing the copper-dependent oxidation of LDL (Section 2.6.1), the implications of this idea will be pursued further. 

An example of an experiment in which LDL has been treated with 15-lipoxygenase and the oxidation monitored by the formation of conjugated diene is shown in Fig. 2.2. In the absence of transition metal, a rapid increase in absorbance occurs, with no lag phase, which ceases after a period of about 90 min under these conditions. If copper is added to promote LDL oxidation at this point, LDL treated with lipoxygenase oxidizes at a faster rate with a short lag phase when compared to the control. During this procedure there is only a minimal loss of a-tocopherol and so we may ascribe the shortened lag phase to the increase in lipid peroxides brought about by lipoxygenase treatment. A similar result was found when LDL was supplemented with preformed fatty acid hydroperoxides (O Leary eta/., 1992). 

The potency of a chain-breaking antioxidant, which scavenges peroxyl radicals, will decrease as the concentration of lipid peroxides in the LDL particle increases (Scheme 2.2). This is illustrated in the experiment shown in Fig. 2.3 in which the antioxidant potency of a peroxyl radical scavenger (BHT) decreases as a function of added exogenous hpid hydroperoxide. If the endogenous lipid peroxide content of LDL were to vary between individuals, this could explain the observed diferences in the effectiveness of a-tocopherol in suppressing lipid peroxidation promoted by copper. 

It has to be acknowle(%fd that the artefactual insertion of lipid peroxides during the preparation of LDL could also contribute to an apparent increased oxidizability of an individual s LDL. Flowever, this does appear to depend on the donor, since LDL prepared under apparendy identical conditions shows a transition metal-dependent variation in oxidizability (Dieber-Rotheneder et td., 1991 Smith etal., 1993). Clearly, an assessment of the oxidizability of LDL after addition of copper as a risk feaor for coronary heart disease is needed to answer this question. 

Stocker, R and Ames, B. (1987). Potential role of conjugated bilirubin and copper in the metabolism of lipid peroxides in bile. Proc. Natl Acad. Sci. USA 84, 8130-8134. 

Caeruloplasmin (Cp) is an acute phase glycoprotein with a copper transport function. At least 90% of total plasma copper is bound to Cp with the remaining 10% associated with albumin, histidine and small peptides. Lipid peroxidation requires the presence of trace amounts of transition metals and the copper-containing active site of Cp endows it with antioxidant capacity... 

Copper salts such as CuS04 are potent catalysts of the oxidative modification of LDL in vitro (Esterbauer et al., 1990), although more than 95% of the copper in human serum is bound to caeruloplasmin. Cp is an acute-phase protein and a potent inhibitor of lipid peroxidation, but is susceptible to both proteolytic and oxidative attack with the consequent release of catalytic copper ions capable of inducing lipid peroxidation (Winyard and... 

Lavelli V, Peri C and Rizzolo A. 2000. Antioxidant activity of tomato products as studied by model reactions using xanthine oxidase, myeloperoxidase, and copper-induced lipid peroxidation. J Agric Food Chem 48(5) 1442—1448. 

The regulation of superoxide formation by SOD can affect both in vivo and ex vivo lipid peroxidation. Thus, SOD inhibited lipid peroxidation in cats following regional intestinal ischemia and reperfusion [33], Similarly, the treatment of rats with polyethylene glycol superoxide dismutase (PEG-SOD) prevented the development of lipid peroxidation in hepatic ischemia-reperfusion injury [34], Interesting data have been reported by Bartoli et al. [35]. They showed that SOD depletion in the liver of rats feeding with a copper-deficient diet... 

In contrast to transition metals iron and copper, which are well-known initiators of in vitro and in vivo lipid peroxidation (numerous examples of their prooxidant activities are cited throughout this book), the ability of nontransition metals to catalyze free radical-mediated processes seems to be impossible. Nonetheless, such a possibility is suggested by some authors. For example, it has been suggested that aluminum toxicity in human skin fibroblasts is a consequence of the enhancement of lipid peroxidation [74], In that work MDA formation was inhibited by SOD, catalase, and vitamins E and C. It is possible that in this case aluminum is an indirect prooxidant affecting some stages of free radical formation. 

In 1989, we showed [142] that the Fe2+(rutin)2 complex is a more effective inhibitor than rutin of asbestos-induced erythrocyte hemolysis and asbestos-stimulated oxygen radical production by rat peritoneal macrophages. Later on, to evaluate the mechanisms of antioxidant activities of iron rutin and copper-rutin complexes, we compared the effects of these complexes on iron-dependent liposomal and microsomal lipid peroxidation [165], It was found that the iron rutin complex was by two to three times a more efficient inhibitor of liposomal peroxidation than the copper-rutin complex, while the opposite tendency was observed in NADPH-dependent microsomal peroxidation. On the other hand, the copper rutin complex was much more effective than the iron rutin complex in the suppression of microsomal superoxide production, indicating that the copper rutin complex indeed acquired additional SOD-dismuting activity because superoxide is an initiator of NADPH-dependent... 

Superoxide-dismuting activity of copper rutin complex was confirmed by comparison of the inhibitory effects of this complex and rutin on superoxide production by xanthine oxidase and microsomes (measured via cytochrome c reduction and by lucigenin-amplified CL, respectively) with their effects on microsomal lipid peroxidation [166]. An excellent correlation between the inhibitory effects of both compounds on superoxide production and the formation of TBAR products was found, but at the same time the effect of copper rutin complex was five to nine times higher due to its additional superoxide dismuting capacity. 

Thus, the mechanism of MT antioxidant activity might be connected with the possible antioxidant effect of zinc. Zinc is a nontransition metal and therefore, its participation in redox processes is not really expected. The simplest mechanism of zinc antioxidant activity is the competition with transition metal ions capable of initiating free radical-mediated processes. For example, it has recently been shown [342] that zinc inhibited copper- and iron-initiated liposomal peroxidation but had no effect on peroxidative processes initiated by free radicals and peroxynitrite. These findings contradict the earlier results obtained by Coassin et al. [343] who found no inhibitory effects of zinc on microsomal lipid peroxidation in contrast to the inhibitory effects of manganese and cobalt. Yeomans et al. [344] showed that the zinc-histidine complex is able to inhibit copper-induced LDL oxidation, but the antioxidant effect of this complex obviously depended on histidine and not zinc because zinc sulfate was ineffective. We proposed another mode of possible antioxidant effect of zinc [345], It has been found that Zn and Mg aspartates inhibited oxygen radical production by xanthine oxidase, NADPH oxidase, and human blood leukocytes. The antioxidant effect of these salts supposedly was a consequence of the acceleration of spontaneous superoxide dismutation due to increasing medium acidity. 

The inhibition of lipid peroxidation by metalloporphyrins apparently depends on metal ions because only compounds with transition metals were efficient inhibitors. Therefore, the most probable mechanism of inhibitory effects of metalloporphyrins should be their disuniting activity. Manganese metalloporphyrins seem to be more effective inhibitors than Trolox (/5o = 204 pmol I 1) and rutin (/50 112 pmol I 1), and practically equal to SOD (/50= 15 pmol I 1). The mechanism of inhibitory activity of manganese and zinc metalloporphyrins might be compared with that of copper- and iron-flavonoid complexes [167,168], which exhibited enhanced antiradical properties due to additional superoxide-dismuting activity. 

Adults require 1-2 mg of copper per day, and eliminate excess copper in bile and feces. Most plasma copper is present in ceruloplasmin. In Wilson s disease, the diminished availability of ceruloplasmin interferes with the function of enzymes that rely on ceruloplasmin as a copper donor (e.g. cytochrome oxidase, tyrosinase and superoxide dismutase). In addition, loss of copper-binding capacity in the serum leads to copper deposition in liver, brain and other organs, resulting in tissue damage. The mechanisms of toxicity are not fully understood, but may involve the formation of hydroxyl radicals via the Fenton reaction, which, in turn initiates a cascade of cellular cytotoxic events, including mitochondrial dysfunction, lipid peroxidation, disruption of calcium ion homeostasis, and cell death. 

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