Superoxide anion redox cycling

Nitrobenzyl chlorides are also reduced by microsomes through one-electron reduction mechanism. Moreno et al. [47] suggested that p- and o-nitrobenzyl chlorides are reduced by rat hepatic microsomes to unstable radical anions, which are decomposed to form benzyl radicals under anaerobic conditions. However, in the presence of dioxygen the radical anions of these compounds participate in futile redox cycling yielding superoxide (Figure 24.2). In contrast to p- and o-nitrobenzyl chlorides, m-nitrobenzyl chloride was reduced by microsomes to a relatively stable m-nitrobenzyl radical anion. 

FIGURE 8.25 Redox cycle of paraquat leading to the production of superoxide anion and a similar structure formed by oxidation of MPTR... 

A semiquinone can be readily oxidized to the parent compormd by molecular oxygen and can then re-enter the reductase-catalyzed reaction. The enzymatic reduction and autoxidation of quinones rmder aerobic conditions generates superoxide anion radicals, and this process is known as redox cycling (Figure 2). Flydroquinones are less prone to transfer electrons to oxygen, because the second-electron potential is often too high. 

In addition, several redox-cycling quinones, including paraquat, diaquat, doxombicin, and daunomycin, have been found to mediate the release of iron from iron stores (e.g., ferritin) that is induced by organic radicals or the superoxide anion radical (Aust et al, 1985)... 

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). 

An example of free radical formation is molecular oxygen, which can accept electrons from a variety of sources to produce reactive oxygen species (ROS) such as the superoxide radical, the hydroxyl radical, and the nitric oxide radical. The superoxide anion radical is formed when one electron is taken up by one of the 2p orbitals of molecular oxygen. Certain drugs and other xenobiotics have the capacity to undergo so-called redox cycles, whereby they provide electrons to molecular oxygen and form super oxide. 

Figure 27.11. Formation of superoxide anion (02 ) by the herbicide paraquat (PQ2+) via redox cycling.

Superoxide anions can also be formed as a result of redox cycling induced inter alia by the herbicide paraquat (Sandy et al., 1986 Smith, 1986). The cycling process consumes intracellular reducing agents and results in eventual exhaustion of NADPH. The action of paraquat is particularly insidious because it is selectively accumulated in the airway epithelium by an energy-dependent mechanism and exerts much of its toxic action at this site (Vijeyaratnam and Corrin, 1971 Rose et al., 1976). 

Detection of primary radical anions in microsomal incubations generally is possible only under anaerobic conditions. In the presence of air a redox cycle is set up, as referred to above. Thus, in initially aerobic systems, the primary radical can be detected only after a lag time that corresponds to the time required to deplete oxygen in the medium. During this lag time the superoxide radical is generated, which can be spin trapped using the nitrone 5,5 -dimethylpyrroline-l-oxide (DMPO) [187]. 

TNT enhances the NAD(P)H-dependent formation of superoxide (02 ) and hydrogen peroxide (H2O2) in rat microsomes and mitochondria due to the single-electron enzymatic reduction of TNT and its subsequent redox cycling [25], The single-electron enzymatic reduction of nitroaromatics (ArNO to their anion-radicals (ArN02 )... 

---