Superoxide from iron oxidation

To study the effects of iron overloading on inflammatory cells, Muntane et al. [186] investigated the effect of iron dcxtran administration on the acute and chronic phases of carrageenan-induced glanuloma. It was found that iron dcxtran increased the iron content in plasma and stores, and enhanced lipid peroxidation and superoxide production by inflammatory cells. At the same time, iron dcxtran had a beneficial effect on recovery from the anemia of inflammation. It has been suggested that iron overload may affect nitric oxide production in animals. For example, alveolar macrophages from iron-overloaded rats stimulated with LPS or interferon-7 diminished NO release compared to normal rats [187]. 

Simultaneous generation of nitric oxide and superoxide by NO synthases results in the formation of peroxynitrite. As the reaction between these free radicals proceeds with a diffusion-controlled rate (Chapter 21), it is surprising that it is possible to detect experimentally both superoxide and NO during NO synthase catalysis. However, Pou et al. [147] pointed out that the reason is the fact that superoxide and nitric oxide are generated consecutively at the same heme iron site. Therefore, after superoxide production NO synthase must cycle twice before NO production. Correspondingly, there is enough time for superoxide to diffuse from the enzyme and react with other biomolecules. 

In 1977, Kellogg and Fridovich [28] showed that superoxide produced by the XO-acetaldehyde system initiated the oxidation of liposomes and hemolysis of erythrocytes. Lipid peroxidation was inhibited by SOD and catalase but not the hydroxyl radical scavenger mannitol. Gutteridge et al. [29] showed that the superoxide-generating system (aldehyde-XO) oxidized lipid micelles and decomposed deoxyribose. Superoxide and iron ions are apparently involved in the NADPH-dependent lipid peroxidation in human placental mitochondria [30], Ohyashiki and Nunomura [31] have found that the ferric ion-dependent lipid peroxidation of phospholipid liposomes was enhanced under acidic conditions (from pH 7.4 to 5.5). This reaction was inhibited by SOD, catalase, and hydroxyl radical scavengers. Ohyashiki and Nunomura suggested that superoxide, hydrogen peroxide, and hydroxyl radicals participate in the initiation of liposome oxidation. It has also been shown [32] that SOD inhibited the chain oxidation of methyl linoleate (but not methyl oleate) in phosphate buffer. 

Some other examples of free radical formation in various pathologies are discussed below. (Of course, they are only few examples among many others, which can be found in literature.) Mitochondrial diseases are associated with superoxide overproduction [428] and cytochrome c release [429], For example, mitochondrial superoxide production apparently contributes to hippocampal pathology produced by kainate [430]. It has been found that erythrocytes from iron deficiency anemia are more susceptible to oxidative stress than normal cells but have a good capacity for recovery [431]. The beneficial effects of treatment of iron deficiency anemia with iron dextran and iron polymaltose complexes have been shown [432,433]. 

In the process, the iron is reduced to the ferrous form. Ferric cytochrome c is reduced by nitric oxide through a nitrosyl intermediate to produce ferrous cytochrome c and nitrite (Orii and Shimada, 1978). The nitrosyl cytochrome c absorbs at 560 nm, which is slightly higher than the 550-nm peak observed for reduced cytochrome c. Nitric oxide may be an interference in the assay of superoxide from cultured cells by the cytochrome c method. When nitric oxide reacts with cytochrome c, there is an initial decrease in absorbance at 550 nm as the nitrosyl complex is formed followed by a rise in absorbance as the complex decomposes to nitrite and reduced cytochrome c. This is a potential artifact in studies measuring the release of superoxide from cultured endothelial cells or other cells that make nitric oxide. 

The destructive effect of dioxygen on the iron and molybdenum-iron proteins is thought to result from the oxidation of the clusters, and the formation of superoxide and peroxide which oxidize the proteins irreversibly. In view of this, it is remarkable that aerobic and facultative organisms can fix dinitrogen. The cyanobacteria evolve dioxygen photosynthetically and simultaneously fix dinitrogen 1447... 

Superoxide may leach iron from iron-sulfur clusters. It has recently been proposed that this may be functional in DNA oxidation, namely, to increase hydroxy radical production [19], Again, the cluster is destroyed in the act. 

Sulfur cycling is affected in a variety of ways, including UV photoinhibition of organisms such as bacterioplankton and zooplankton that affect sources and sinks of DMS and UV-initiated CDOM-sensitized photoreactions that oxidize DMS and produce carbonyl sulfide. Metal cycling also interacts in many ways with UVR via direct photoreactions of dissolved complexes and of metal oxides and indirect reactions that are mediated by photochemically-produced ROS. Photoreactions can affect the biological availability of essential trace nutrients such as iron and manganese, transforming the metals from complexes that are not readily assimilated into free metal ions or metal hydroxides that are available. Such photoreactions can enhance the toxicity of metals such as copper and can initiate metal redox reactions that transform non-reactive ROS such as superoxide into potent oxidants such as hydroxyl radicals. 

A few of the electrons going through complexes 1 and 111 react with oxygen to form the superoxide anion radical (02 ) (Fig. 2) (Shigenaga et al. 1999). This radical has little reactivity alone, except that it can dislodge iron from iron-sulfur complexes. However, 02 reacts with nitric oxide (NO ) to form the highly reactive. 

In contrast to bovine Cu2Zn2- and iron superoxide dismutase from P. leiognathi, the iron enzyme from E. coli exhibits saturation kinetics during catalytic action A group which ionizes with a pK, = 8.8 was found to be responsible for this phenomenon. For the dismutation of superoxide by iron SOD s a ruction scheme is proposed which includes alternate r uction-oxidation of the metal ... 

Human oxyhaemoglobin (Hb02) in the presence of excess nucleophile ie.g. N, SCN , F", Cl ) has been shown to form cleanly the oxidized methaemoglobin (metHb) with the nucleophile as the ligand. The rates, which are sensitive to pH and the nucleophilicity of the anionic nucleophile (N"), obey the law Rate = [HbOJ-[N ][H+]. This autoxidation process therefore appears to involve the nucleophilic displacement of superoxide from a protonated intermediate and can reasonably account for normal metHb formation in the erythrocyte where Cl can serve as the nucleophile. [MetHb formation by electron-transfer agents such as NOg", which are not normally present, can follow a different course, e.g. direct electron transfer to bound Og to form iron(m) peroxide.]... 

Uptake ean similarly be increased by exogenous sources of AOS. Brief exposure to whole cigarette smoke, which is a highly concentrated source of AOS and other radicals, and then to a mineral dust suspension produces considerably greater uptake of asbestos, titanium dioxide, fibrous silicon carbide, and talc (51 -53 Fig. 2). The increase in uptake is proportional to the dose of cigarette smoke, and the smoke effect can be inhibited by catalase, superoxide dismutase (which destroys superoxide anion), or deferoxamine (see Fig. 2). The effects of low levels of ozone are similar (Fig. 3), but differ from cigarette smoke in that superoxide dismutase is not protective (126). Smoke also fails to enhance the uptake of nonfibrous silicon carbide or iron oxide (hematite 53) the latter observation is particnlarly interesting because it was recently shown (127) that hematite does not catalyze the formation of AOS. This observation emphasizes the idea that redox-active surface iron, as opposed to compositional iron, is cracial to AOS formation and particle nptake. 

Nitric oxide has also been implicated in PD. Thus animals with MPTP-induced Parkinsonism not only show extensive gliosis in the substantia nigra (like humans) in which the glial cells produce NO, but Liberatore and colleagues have found that in iNOS (inducible nitric oxide synthase) knock-out mice the toxicity of MPTP is halved. Since NO releases iron from ferritin and produces toxic peroxinitrate in the presence of superoxide radicals it could accelerate, even if it does not initiate, dopaminergic cell death (see Hirsch and Hunot 2000 for further details). 

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