Lipid peroxidation is promoted by many drugs and chemicals and perhaps by elevated concentrations of oxygen. Some chemicals, such as CC14, initiate lipid peroxidation as the direct result of radical formation. Other substances may cause lipid peroxidation by affecting oxygen activation or the redox state of the cell. This type of lipid peroxidation appears to involve iron, although oher transition metals may also be involved. Two initiators (the hydroxyl radical or a ferrous-O2-ferric complex) could be formed by the following mechanisms depending on the nature of the chelator, the oxidation state of the iron, and its reactivity. A. For ferrous chelates: 1. Reaction with H2O2 to produce the hydroxyl radical: Fe++ + H2O2 greater than .OH + OH-+ Fe+++ 2. Oxidation of ferrous to ferric for formation of the Fe++-O2-Fe+++ complex. Oxidation may be by O2 or H2O2 although the latter could form the hydroxyl radical by reaction with ferrous. B. For ferric chelates: 1. Partial reduction to form the Fe++-O2-Fe+++ complex. Reduction may be by superoxide anion or other cellular reductants. 2. Reduction followed by autoxidation to produce H2O2 and subsequent reaction with Fe++ to form the hydroxyl radical (Fe+++ + e- greater than Fe++, 2Fe++ + O2 greater than H2O2 + 2Fe+++, H2O2 + Fe++ greater than .OH + OH-+ Fe+++) C. Direct interaction of a ferrous chelate with a ferric chelate and O2 (Fe++-O2-Fe+++). We propose to study cellular forms of iron from livers of normal animals and iron-loaded animals to determine the oxidation state of the iron, and the ability of the iron to undergo oxidation by H2O2 (for the ferrous chelates), or reduction by superoxide anion, GSH and NADPH-cytochrome P450 (for the ferric chelates). The chelates will then be tested for their ability to initiate lipid peroxidation; alone, when combined with other chelates, during oxidation by H2O2, and during reduction by superoxide anion, GSH or NADPH-cytochrome P450 reductase. The mechanism of initiation will be investigated by determining the sensitivity of the lipid peroxidation to inhibition by hydroxyl radical traps and catalase, and the importance of the ratio of ferrous to ferric.
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