Diquat-induced oxidative damage in hepatic microsomes: effects of antioxidants.
The ability of the redox cycling compound, diquat, to induce lipid peroxidation and oxidative damage was investigated using hepatic microsomes. Antioxidants, with demonstrated efficacy in physical models of oxidative stress, were examined in a diquat model. Diquat (10 microM-3 mM) induced lipid peroxidation (TBARS) in hepatic microsomes prepared from Fischer 344 rats. Diquat (1 mM) also increased protein carbonyl formation, NADPH oxidation and superoxide anion radical production (acetylated cytochrome c reduction). The novel antioxidants U-74,006F, U-78,517G and the known antioxidant, DPPD, decreased diquat-induced lipid peroxidation to levels below that of the control. These antioxidants also decreased protein carbonyl formation caused by diquat. U-74,006F and U-78,517G reduced NADPH oxidation slightly; although this inhibition was statistically significant, the biological significance is questionable. DPPD had no effect on this parameter. U-78,517G inhibited the reduction of acetylated cytochrome c slightly, whereas the other antioxidants had little effect. Thus overall, the increase in NADPH oxidation and the production of superoxide anion by redox cycling of diquat were not substantially affected by antioxidants. Neither did the test compounds show evidence of activity as iron chelators. This leads to the suggestion that antioxidants are preventing diquat-induced oxidative damage by scavenging lipid peroxyl radicals and preventing the propagation of the lipid peroxidation process.
Wolfgang
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Upjohn Company, Kalamazoo, MI 49001.
Jolly
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Petry
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D000818:Animals; D000975:Antioxidants; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D004178:Diquat / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010655:Phenylenediamines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D002839:Chromans; D010655:Phenylenediamines; D010879:Piperazines; D011506:Proteins; D013481:Superoxides; C066382:U 78517F; D004178:Diquat; C004845:N,N'-diphenyl-4-phenylenediamine