Paraquat redox cycling

Elevated O2 concentrations Exposure to activated phagocytic cells Exposure to redox cycling drugs (e.g. alloxan, paraquat, menadione)... 

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

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)... 

Scheme 3.9 Redox cycling of paraquat. Modified from [49].

With paraquat, doxorubicin, and nitrofurantoin, once the electron is donated to oxygen, another can be acquired, and so the process can continue as long as there is a source of electrons and the chemicals are present. This is called "redox cycling" (see chap. 6). 

The production of active oxygen species may lead to a cycle of oxidation and reduction (redox cycle) with electrons being donated to oxygen to yield superoxide. This is the case with paraquat and also a number of cytotoxic quinones. Thus, there is a cyclic process, which produces superoxide by adding electrons from paraquat (see chap. 7) or a semiquinone, for example, to oxygen (Fig. 6.10). The superoxide produced may then be metabolized to hydrogen peroxide by superoxide dismutase, which is further metabolized to water by catalase (Fig. 6.10). 

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

Superoxide generated by xanthine oxidase or in the redox cycling of paraquat can cause the reductive release of F3 from ferritin, a process that is dependent on the activity of microsomal NADPH-cytochrome P-450 reductase [119]. Iron appears to be an essential component in the formation of reactive species such as superoxide and hydroxyl radical via redox cycling of cephaloridine. Addition of EDTA or of the specific iron chelator desferrioxamine to an incubation system containing renal cortex microsomes and cephaloridine depressed cephaloridine-induced peroxidation of microsomal lipids significantly EDTA showed a weaker effect than desferrioxamine at equimolar concentrations. By chelating F3 preferentially [120], desferrioxamine reduced the availability of F2 produced by the iron redox cycle and decreased cephaloridine-stimu-lated peroxidation of membrane lipids [36, 37]. 

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). 

The mechanism of toxicity involves an initial reaction between paraquat and an electron donor such as NADPH ("figure 121). Paraquat readily accepts an electron and forms a stable radical cation. However, under aerobic conditions this electron is transferred to oxygen giving rise to superoxide. As there is a ready supply of oxygen in the lung tissue, this process can then be repeated and a redox cycle is set up. This cycle causes two effects, both of which may be responsible for the toxicity ... 

Superoxide generated by xanthine oxidase or in the redox cycling of paraquat can cause the reductive re-... 

FIGURE 2.9 Abortive redox cycling, oxidation of NADPH, and superoxide production with paraquat. 

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