Antioxidative reaction pathways

Antioxidative reaction pathways. The prevention of damage in cellular systems can be considered a two-level process. First, the cell would minimize the production and availability of prooxidant factors and substances. The compartmentalization of prooxidant enzymes in organelles such as mitochondria, and the sequestering of transition metals by specific proteins are examples of this level of defense. The second level of defense involves the scavenging and neutralization of pro-oxidants. These antioxidant pathways in mitochondria are depicted by darker lines in... 

The antioxidant activity afforded by NO is most important if it translates into a meaningful therapeutic event. To test the importance of this reaction pathway to cell survival, we compared viability of the cells exposed to in the presence or absence of NO, When cells are exposed to 20 pM there was appreciable loss of cell membrane integrity as measured by trypan blue dye exclusion (Kelley et al, 1999) the addition of NO deaeased cell membrane damage (Figure 6). 

If the antioxidant reaction proceeds via electron transfer from antioxidant to radical, then the increased polarity of the solvent (Solv) will help to stabilize the polar transition state. If the solvent basicity increases, then the reaction may proceed first via deprotonation of the antioxidant by the solvent to form an antioxidant anion, which would be much more reactive in terms of electron transfer to the radical than the protonated phenol. The reaction pathway may be shown to be three steps (equations 38-40), especially in strongly basic solvents . ... 

Cl. Carr, A. C., McCall, M. R., and Frei, B., Oxidation of LDL by myeloperoxidase and reactive nitrogen species Reaction pathways and antioxidant protection. Arterioscler. Thromb. Vase. Biol. 20, 1716-1723 (2000). 

Figure 1. A schematic of die potential reaction pathways that intact the oxidative deterioration of foods. Mn and Mn " are transition metals in their reduced and oxidized states RH, ROOH and AOH are an unsaturated fatty acid, lipid hydroperoxide and chain breaking antioxidant and R , RO ROO are alkyl, alkoxyl and peroxyl radicals, and Oj and LOX are singlet oxygen and lipoxygenase, respectively.

The discovery and characterization of the thiyl/thiolate conjugation equilibrium (3) [14] is one of the most significant contributions of the pulse radiolysis technique to the chemistry of cellular oxidative stress. Without such measurements, including the direct observation of the reduction of thiyl radicals by ascorbate [13] and electron transfer from disulphide radical anions to oxygen [ 15], it would be indeed difficult to prepare a reasoned argument for the competing reaction pathways from a quantitative viewpoint. Further work is needed to develop these concepts further. Not least, the dimension of space (as well as an appreciation of interfacial phenomena) needs to be added to the dimension of time if we are to model realistically the cellular environment and assess quantitatively, for example, the importance of the synergy between the lipophilic phenolic antioxidant, vitamin E and the hydrophilic electron-donor, vitamin C (ascorbate) [134]. 

Fig. 22. Remarkable activation-by-ligand-oxidation pathways for the reaction of ruthenium-arenes with thiolates. (a) Reaction of [Ru (r 6-bip)(en)(OH2)]+ with GSH (b) direct synthesis of ruthenium-arene sulfenato complexes (c) the air-stable thiolato complexes are oxidized in the presence of the antioxidant GSH.

Chelators of transition metals, mainly iron and copper, are usually considered as antioxidants because of their ability to inhibit free radical-mediated damaging processes. Actually, the so-called chelating therapy has been in the use probably even earlier than antioxidant therapy because it is an obvious pathway to treat the development of pathologies depending on metal overload (such as calcium overload in atherosclerosis or iron overload in thalassemia) with compounds capable of removing metals from an organism. Understanding of chelators as antioxidants came later when much attention was drawn to the possibility of in vivo hydroxyl radical formation via the Fenton reaction ... 

Vitamin C is essential for the formation of collagen, the principal structural protein in skin, bone, tendons, and ligaments, being a cofactor in the hydroxylation of the amino acids proline to 4-hydroxyproline, and of lysine to 5-hydroxylysine. These hydroxyamino acids account for up to 25% of the collagen structure. Vitamin C is also associated with some other hydroxylation reactions, e.g. the hydroxylation of tyrosine to dopa (dihydroxyphenylalanine) in the pathway to catecholamines (see Box 15.3). Deficiency leads to scurvy, a condition characterized by muscular pain, skin lesions, fragile blood vessels, bleeding gums, and tooth loss. Vitamin C also has valuable antioxidant properties (see Box 9.2), and these are exploited commercially in the food industries. 

Polyphenols can act as antioxidants by a number of potential pathways. The most important is likely to be by free radical scavenging, in which the polyphenol can break the radical chain reaction. Polyphenols are effective antioxidants in a wide range of chemical oxidation systems, being capable of scavenging peroxyl radicals, alkyl peroxyl radicals, superoxide, hydroxyl radicals, nitric oxide and peroxynitrate in aqueous and organic environments [121]. This activity is due to the ability of donating an H atom from an aromatic hydroxyl group to a free radical, and the major ability of an aromatic structure to support an unpaired electron by delocalization around the 7i-electron system. Phenolic acids... 

The lipoxygenase system also competes for released arachidonic acid in a way that seems to be tissue-selective, giving rise to hydroperoxy fatty acids (HPETE) which can be converted into leukotrienes or reduced to hydroxy fatty acid (HETE) products [115]. The basic scheme for these metabolic conversions involving arachidonic acid is presented in Figure 5.2. Both of the main enzymatic pathways of arachidonic acid metabolism are thought to involve free-radical-mediated reactions [108] and the antioxidant capacity of vitamin E could therefore allow the vitamin to modify the products of these pathways. 

It has been proposed that the highly oxidizing species ferrylMb is, at least in part, responsible for the oxidative damage caused by the reperfusion of ischemic tissues. We have determined the rate constants for the reactions of ferrylMb and ferrylHb with NO ((17.1 0.3) x 106 m-1 s-1 and (24 + 1) x 106 m-1 s-1 at pH 7.0 and 20 °C) [23, 24]. The large value of these rate constants implies that these reactions are very likely to occur in vivo and might represent a detoxifying pathway for ferrylMb and ferrylHb and, thus, an additional antioxidant function of NO. ... 

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