Superoxide, also radical

Although this mechanism could explain the inertness of di-t-butyl sulphide towards oxidation due to the absence of a-hydrogen atoms, it was later ruled out by Tezuka and coworkers They found that diphenyl sulphoxide was also formed when diphenyl sulphide was photolyzed in the presence of oxygen in methylene chloride or in benzene as a solvent. This implies that a-hydrogen is not necessary for the formation of the sulphoxide. It was proposed that a possible reactive intermediate arising from the excited complex 64 would be either a singlet oxygen, a pair of superoxide anion radical and the cation radical of sulphide 68 or zwitterionic and/or biradical species such as 69 or 70 (equation 35). 

NADH, which enters the Krebs cycle. However, during cerebral ischaemia, metabolism becomes anaerobic, which results in a precipitous decrease in tissue pH to below 6.2 (Smith etal., 1986 Vonhanweh etal., 1986). Tissue acidosis can now promote iron-catalysed free-radical reactions via the decompartmentalization of protein-bound iron (Rehncrona etal., 1989). Superoxide anion radical also has the ability to increase the low molecular weight iron pool by releasing iron from ferritin reductively (Thomas etal., 1985). Low molecular weight iron species have been detected in the brain in response to cardiac arrest. The increase in iron coincided with an increase in malondialdehyde (MDA) and conjugated dienes during the recirculation period (Krause et al., 1985 Nayini et al., 1985). 

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). 

Nitrosoarenes are readily formed by the oxidation of primary N-hydroxy arylamines and several mechanisms appear to be involved. These include 1) the metal-catalyzed oxidation/reduction to nitrosoarenes, azoxyarenes and arylamines (144) 2) the 02-dependent, metal-catalyzed oxidation to nitrosoarenes (145) 3) the 02-dependent, hemoglobin-mediated co-oxidation to nitrosoarenes and methe-moglobin (146) and 4) the 0 2-dependent conversion of N-hydroxy arylamines to nitrosoarenes, nitrosophenols and nitroarenes (147,148). Each of these processes can involve intermediate nitroxide radicals, superoxide anion radicals, hydrogen peroxide and hydroxyl radicals, all of which have been observed in model systems (149,151). Although these radicals are electrophilic and have been suggested to result in DNA damage (151,152), a causal relationship has not yet been established. Nitrosoarenes, on the other hand, are readily formed in in vitro metabolic incubations (2,153) and have been shown to react covalently with lipids (154), proteins (28,155) and GSH (17,156-159). Nitrosoarenes are also readily reduced to N-hydroxy arylamines by ascorbic acid (17,160) and by reduced pyridine nucleotides (9,161). 

Figure 5.2. Pathways of oxygen reduction. The sequential reduction of molecular oxygen, ultimately to water, is shown. Abbreviations 02 % superoxide free radical H202, hydrogen peroxide OH, hydroxide ion -OH, hydroxyl free radical e, electron H+, hydrogen ion. Singlet states of oxygen are also shown as i +02and Ag02.

The superoxide anion radical and hydrogen peroxide are not particularly harmful to cells. It is the product of hydrogen peroxide decomposition, the hydroxyl radical (HO ), that is responsible for most of the cytotoxicity of oxygen radicals. The reaction can he catalyzed hy several transition metals, including copper, manganese, cohalt, and iron, of which iron is the most ahimdant in the human body (Reaction 2 also called the Fenton reaction). To avoid iron-catalyzed reactions, iron is transported and stored chiefly as Fe(III), although redox active iron can be formed in oxidative reactions, and Fe(III) can be reduced by semiquinone radicals (Reaction 3). 

It is important to note that the oxidation produces the superoxide free radical. Since it is toxic, the radical produced in reaction (a) must be removed. This is done in a reaction catalysed by superoxide dismutase, which produces hydrogen peroxide. However, this also must be removed (see Appendix 9.6 for discussion of free radicals). Removal of hydrogen peroxide is achieved in a reaction with reduced glutathione, catalysed by glutathionine peroxidase. 

Our radiolysis studies also indicate that phosphonates react quite slowly with the superoxide anion radical. Although our studies do not support the formation of radical cations as an initial oxidation step, we cannot rule out the possibility that radical cations are not involved in the oxidation of the C—P bond, as previously proposed [44], It is also possible that more electron-rich organphosphorus compounds or organophosphorus compounds in the adsorbed state may exhibit different redox and hydroxyl radical chemistries than what is observed under pulse radiolysis employing homogeneous conditions. 

Tertiary amine oxides and hydroxy la mines are also reduced by cytochromes P-450. Hydroxylamines, as well as being reduced by cytochromes P-450, are also reduced by a flavoprotein, which is part of a system, which requires NADH and includes NADH cytochrome b5 reductase and cytochrome b5. Quinones, such as the anticancer drug adriamycin (doxorubicin) and menadione, can undergo one-electron reduction catalyzed by NADPH cytochrome P-450 reductase. The semiquinone product may be oxidized back to the quinone with the concomitant production of superoxide anion radical, giving rise to redox cycling and potential cytotoxicity. This underlies the cardiac toxicity of adriamycin (see chap. 6). 

Molecular oxygen usually reacts rapidly with only those organic substrates, such as dihydroflavins, that are able to form stable free radicals. However, the endiolate anion of Eq. 13-50 may be able to donate a single electron to 02 to form a superoxide-organic radical pair prior to formation of the peroxide (see also Eq. 15-30). Similar oxygenase side reactions have been observed for a variety of other enzymes that utilize carbanion mechanisms.283 The reaction of rubisco with 02 is of both theoretical and practical interest, the latter because of its significance in lowering the yield in photosynthesis (Chapter 23). 

It also combines very rapidly with superoxide anion radical to form peroxynitrite (Eq. 18-62).513 This is another reactive oxidant which, because of its relatively high pfCa of 6.8, is partially protonated and able to diffuse through phospholipids within cells.514 515... 

The major in situ process that results in the formation of H202 is undoubtedly photochemical (e.g., 12, 15, 49, 50). Photochemical formation of H202 in fresh and salt waters probably results from the disproportionation of the superoxide ion radical, 02 (8, 9, 15, 51, 52). The kinetics of superoxide disproportionation are well established (53), and its steady-state concentration can be calculated. Because of the known effects of superoxide ion in cells (47), its presence in surface waters may be important in biologically mediated processes. However, other sources, such as biological formation (e.g., 45, 54), redox chemistry (21, 24, 29, 31, 32), wet (e.g., 55) and dry (50, 56, 57) deposition, and surfaces (e.g., 58) may also be important. 

---