Effects of novel antioxidants on carbon tetrachloride-induced lipid peroxidation and toxicity in precision-cut rat liver slices.
Previous studies in rat liver microsomes have demonstrated the effectiveness of the 21-aminosteroid, U-74,006F, the troloxamine, U-78,517G, and N,N'-diphenyl-p-phenylenediamine (DPPD) in preventing carbon tetrachloride (CCl4)-induced lipid peroxidation. Studies reported here utilized liver slices to assess whether these antioxidants could prevent lipid peroxidation and ensuing toxicity in a more complete/complex system. Liver slices prepared from Aroclor 1254-induced SD rats were incubated in Dulbecco's modified eagle media, 37 degrees C, for up to 9 hr. Slices were preincubated with test compounds for 30 min prior to addition of CCl4. Lipid peroxidation, as measured by the formation of thiobarbituric acid-reactive substances and ethane evolution, was decreased by U-74,006F (100 microM), U-78,517G (100 microM), and DPPD (1 microM). CCl4 (2.5 microliters) decreased intracellular K+ content, intracellular lactate dehydrogenase (LDH), and intracellular isocitrate dehydrogenase (ICD) activities over a 9-hr incubation period. Despite the marked effects on lipid peroxidation, U-74,006F showed no protection against K+ or LDH loss and only moderate protection against ICD loss. U-78,517G showed no protection against K+ loss but substantial protection against enzyme loss. DPPD demonstrated slight protection against K+ and marked protection against enzyme loss. All three compounds inhibited CCl4-induced lipid peroxidation; U-78,517G being most effective, followed by DPPD and U-74,006F. Inhibition of lipid peroxidation provided protection to the membrane structure as indicated by inhibition of LDH and ICD loss. The antioxidants failed to protect against CCl4-induced toxicity (K+ loss). These results suggest that CCl4-induced lipid peroxidation and toxicity may be dissociable.
Wolfgang
G H
GH
Investigative Toxicology, Upjohn Company, Kalamazoo, Michigan 49001.
Donarski
W J
WJ
Petry
T W
TW
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002839:Chromans / Q000494:pharmacology*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010655:Phenylenediamines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000975:Antioxidants; D002839:Chromans; D010655:Phenylenediamines; D010879:Piperazines; D011281:Pregnatrienes; C066382:U 78517F; D002251:Carbon Tetrachloride; C004845:N,N'-diphenyl-4-phenylenediamine; D007770:L-Lactate Dehydrogenase; D011188:Potassium