Inhibition of diquat-induced lipid peroxidation and toxicity in precision-cut rat liver slices by novel antioxidants.
The ability of the novel antioxidants U-74,006F and U-78,517G and a known antioxidant (N,N'-diphenyl-p-phenylenediamine, (DPPD)) to inhibit chemically induced (diquat dibromide) oxidative stress was examined in precision-cut liver slices. Previous studies in rat liver microsomes demonstrated the ability of these antioxidants to inhibit lipid peroxidation without preventing redox cycling of diquat. Diquat (1 mM) initiated lipid peroxidation in liver slices prepared from F344 rats. A 30-min preincubation with antioxidants inhibited formation of thiobarbituric acid reactive substances to control levels; ethane evolution, when elevated, was also inhibited by antioxidants. The toxicity of diquat (100 microM-3 mM) was evaluated in liver slices; 1 and 3 mM diquat caused decreases in intracellular K+ and intracellular LDH. Preincubation with antioxidants substantially decreased the toxicity of diquat as indicated by K+ and LDH. Diquat significantly decreased total glutathione levels in the slices; the antioxidants did not significantly inhibit this diquat-dependent effect. In summary, diquat, a compound which undergoes redox cycling and produces oxidative stress, was shown to produce lipid peroxidation, glutathione depletion, and toxicity in liver slices. Two experimental antioxidants, a 21-aminosteroid (U-74,006F) and a trolox-amine (U-78,517G) as well as a known antioxidant (DPPD) were shown to be effective in preventing lipid peroxidation and reducing the subsequent toxicity.
Wolfgang
G H
GH
Investigative Toxicology, Upjohn Company, Kalamazoo, Michigan 49001.
Jolly
R A
RA
Donarski
W J
WJ
Petry
T W
TW
D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D004178:Diquat / Q000633:toxicity*; D004980:Ethane / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D007424:Intracellular Fluid / Q000378:metabolism; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors*; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013858:Thiobarbiturates / Q000378:metabolism; D013997:Time Factors
D002839:Chromans; D008054:Lipid Peroxides; D010655:Phenylenediamines; D010879:Piperazines; D011281:Pregnatrienes; D013858:Thiobarbiturates; C066382:U 78517F; D004178:Diquat; C004845:N,N'-diphenyl-4-phenylenediamine; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D004980:Ethane; D011188:Potassium; D019803:Glutathione Disulfide