Haber-Weiss and Fenton reaction

Unlike marasmic or well-nourished children, those with kwashiorkor have low transferrin levels and detectable free iron in the plasma (Sive et al., 1996). Uncomplexed iron is extremely toxic due to its ability to generate free radicals by the Haber-Weiss and Fenton reactions.The onslaught of opportunistic infections in the malnourished also elicits production of free radicals and accentuates the oxidative stress. 

Generation of the hydroxyl radical by the nonenzymatic Haber-Weiss and Fenton reactions. In the simplified versions of these reactions shown here, the hansfer of single elechons generates the hydroxyl radical. ROS are shown in blue. In addition to Fe, Cu and many other metals can also serve as single-elechon donors in the Fenton reaction. 

A potentially harmful chemical property of iron and its compounds is the ability to catalytically generate potent hydroxyl radicals that are oxidatively toxic to cells [3,4]. This catalysis (Haber-Weiss and Fenton reactions) occurs with activated oxygen species (superoxide and hydrogen peroxide, O3 and H2O2) as shown below. Superoxide is formed by the univalent reduction of oxygen (xanthine plus xanthine oxidase). 

Klug D, Rabani J, Fridovich I (1972) A direct demonstration of the catalytic action of superoxide dismutase through the use of pulse radiolysis. J Biol Chem 247 4839-4842 Koppenol WH (1983) Thermodynamic of the Fenton-driven Haber-Weiss and related reactions. In Cohen G, Greenwald RA (eds) Oxy radicals and their scavenger systems. Vol I Molecular aspects. Elsevier Biomedical, New York, pp 84-88... 

The superoxide anion radical (O2) dismutates to H2O2, and via a transition metal-catalyzed Haber-Weiss and/or Fenton reactions can give rise to the hydroxyl radical (-OH) (see references). 

Indeed, when present in concentrations sufficient to overwhelm normal antioxidant defences, ROS may be the principal mediators of lung injury (Said and Foda, 1989). These species, arising from the sequential one-electron reductions of oxygen, include the superoxide anion radical, hydrogen peroxide, hypochlorous ions and the hydroxyl radical. The latter species is thought to be formed either from superoxide in the ptesence of iron ions (Haber-Weiss reaction Junod, 1986) or from hydrogen peroxide, also catalysed by ferric ions (Fenton catalysis Kennedy et al., 1989). 

In the presence of trace amounts of iron, superoxide can then reduce Fe3+ to molecular oxygen and Fe2+. The sum of this reaction (equation 2) plus the Fenton reaction (equation 1) produces molecular oxygen plus hydroxyl radical, plus hydroxyl anion from superoxide and hydrogen peroxide, in the presence of catalytic amounts of iron - the so-called Haber-Weiss reaction (equation 3) (Haber and Weiss, 1934). 

In this classical Haber-Weiss cycle iron is being reduced by superoxide anion radical (02T), ascorbic acid or glutathione and subsequently decomposes hydrogen peroxide - formed by spontaneous dismutation of 02T - in the Fenton reaction to produce 0H. This iron-driven 0H formation has a stringent requirement for an available iron coordination site, a sine qua non met not only by hexaaquoiron(III) but by most iron chelates (28). Thus, Fe-EDTA, -EGTA, and -ATP retain a reactive coordination site and catalyze the Haber-Weiss cycle. Phytic acid, however, occupies all available iron coordination sites and consequently fails to support 0H generation (Figure 6). 

Another function of ascorbic add is to generate Fe(II) from Fe (III), which is part of the Haber-Weiss-Fenton Reaction (77). In that reaction, peroxide is reduced to the hydroxyl radical, HO, an extremely powerful oxidizing agent. It should also be noted that ascorbic acid can chelate metals 18 and will promote the carbohydrate-amine browning reaction (79-20). 

Phenolic acids and flavonoids can also act as chelating agents, complexing transition metals that are responsible of the initiation of peroxidative processes (Fenton and Haber-Weiss reactions). This property is much stronger in phenolics having a catechol, pyrogallol, or 3-hydroxy-4-carbonyl group [130]. 

However, under certain circumstances, such as in the presence of transition metal ions, hydroxyl radicals may result from either the Haber-Weiss reaction or the Fenton reaction, which cause lipid peroxidation and cell injury (Fig. 6.10). 

Besides the above hypothesis, there are only a few documented cases where superoxide toxicity does not involve H2O2 and/or metal ions. Accordingly, for the last decade, it was repeatedly stated that 02" served as a precursor of a much more reactive and oxidizing species such as OH. Because the Haber-Weiss reaction was extremely slow, it was suggested that 02 triggered OH production by recycling the reduced form of transition metal ions involved in Fenton reactions [42] ... 

Superoxide is also a product of various enzyme reactions catalyzed by the flavin oxidases (e.g., xanthine oxidase and monoamine oxidase). In addition, 07 is a product of the noncatalytic oxidation of oxyhemoglobin, of which about 3% is converted each day to methemoglobin. Moreover, 02 is readily formed in phagocytic cells (i.e., neutrophils and monocytes) during the respiratory burst. Furthermore, in addition to the Fenton reaction, the Haber-Weiss reaction results in the conversion of 02 to the potent HO via the following reactions (H3) ... 

Although both GPx and Cat are very efficient in removing H202, HO can still be formed in abundance (Fenton and Haber-Weiss chemistry). To partially offset the influence of transition metal ions on free radical production, there are numerous metal-binding proteins which prevent these reactions from taking place these include, among others, ferritin, transferrin, ceruloplasmin, and metallotheinein (Table 2). 

In terms of potential chemical interactions, the effects of NO on ROS-induced injury are multiple, and some effects can be classified as prooxidant and others may be classified as antioxidant still others can be classified as both. In terms of the metal-catalyzed Haber-Weiss reaction, there are two primary effects of -NO. The binding of NO to metal ions will prevent the Fenton reaction and thus results in an antioxidant action. Another important antioxidant action of NO (and its oxidized product N02) is its reaction with hpid radicals, thus resulting in radical chain termination. ... 

The overall reaction is initiated by an electron transfer from ascorbate to 4-NQO with the production of A and 4-NQO" (Reaction 46, l). The 4-NQO" radical reacts rapidly [reported values for similar compounds range from 10 to 10 M V (62,63)] with molecular oxygen to yield superoxide radical (Reaction 46, 2), which dismutates to peroxide and oxygen (Reaction 46, 3) or reacts with ascorbate (Reaction 46, 4). Specific tests with superoxide dismutase and catalase suggest that OH radicals are formed in this system by a Haber-Weiss (64) and/or Fenton (65) type reaction ... 

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