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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM033443-03
Application #
3283179
Study Section
Toxicology Study Section (TOX)
Project Start
1984-04-01
Project End
1987-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Michigan State University
Department
Type
Earth Sciences/Resources
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Minotti, G; Aust, S D (1989) The role of iron in oxygen radical mediated lipid peroxidation. Chem Biol Interact 71:1-19
Krause, G S; White, B C; Aust, S D et al. (1988) Brain cell death following ischemia and reperfusion: a proposed biochemical sequence. Crit Care Med 16:714-26
Samokyszyn, V M; Thomas, C E; Reif, D W et al. (1988) Release of iron from ferritin and its role in oxygen radical toxicities. Drug Metab Rev 19:283-303
Reif, D W; Beales, I L; Thomas, C E et al. (1988) Effect of diquat on the distribution of iron in rat liver. Toxicol Appl Pharmacol 93:506-10
Morehouse, L A; Aust, S D (1988) Reconstituted microsomal lipid peroxidation: ADP-Fe3+-dependent peroxidation of phospholipid vesicles containing NADPH-cytochrome P450 reductase and cytochrome P450. Free Radic Biol Med 4:269-77
Minotti, G; Aust, S D (1987) The requirement for iron (III) in the initiation of lipid peroxidation by iron (II) and hydrogen peroxide. J Biol Chem 262:1098-104
Minotti, G; Aust, S D (1987) The role of iron in the initiation of lipid peroxidation. Chem Phys Lipids 44:191-208
Minotti, G; Aust, S D (1987) Superoxide-dependent redox cycling of citrate-Fe3+: evidence for a superoxide dismutaselike activity. Arch Biochem Biophys 253:257-67
Thomas, C E; Aust, S D (1986) Reductive release of iron from ferritin by cation free radicals of paraquat and other bipyridyls. J Biol Chem 261:13064-70
Aust, S D; Thomas, C E; Morehouse, L A et al. (1986) Active oxygen and toxicity. Adv Exp Med Biol 197:513-26

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