ABSTRACT
BACKGROUND: Oxidant molecules and nitric oxide (NO) have each been implicated as mediators of endothelial cell damage, but the biologic effect of these molecules acting in concert is incompletely understood. MATERIALS AND METHODS: We studied the effects of an NO donor, S-nitroso-acetyl-D,L-penicillamine (SNAP), in combination with the peroxidants tert-butyl hydroperoxide (TBH) and hydrogen peroxide (H2O2) on rabbit aortic endothelial cells in culture. Cell viability was assessed using Alamar blue, a nontoxic dye indicator of cell metabolism. Lipid peroxidation was assessed using a chemiluminescent single-photon counting technique. RESULTS: After 90 min exposure to test reagents, there was concentration-dependent cytotoxicity for both TBH and H2O2. Peroxidant-induced cytotoxicity was significantly ameliorated by SNAP (10(-4)-10(-3)M). N-Acetylpenicillamine and NO-depleted SNAP failed to demonstrate a cytoprotective effect against peroxidant cellular injury, thus implicating NO as the agent responsible for the protective effect. SNAP reduced lipid peroxidation caused by 10(-3) M TBH in a dose-dependent manner. Preincubation of cells with SNAP before exposure to peroxidants alone had no effect on toxicity. CONCLUSIONS: NO is cytoprotective to the endothelium in the presence of peroxidants through a reduction of lipid peroxidation.
Subject(s)
Endothelium, Vascular/drug effects , Hydrogen Peroxide/poisoning , Nitric Oxide/pharmacology , Oxidants/poisoning , Peroxides/poisoning , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Endothelium, Vascular/cytology , Enzyme Inhibitors/pharmacology , Hydrogen Peroxide/antagonists & inhibitors , Lipid Peroxides/antagonists & inhibitors , Lipid Peroxides/metabolism , Oxidants/antagonists & inhibitors , Penicillamine/analogs & derivatives , Penicillamine/pharmacology , Peroxides/antagonists & inhibitors , Rabbits , S-Nitroso-N-Acetylpenicillamine , tert-ButylhydroperoxideSubject(s)
Burns, Chemical/etiology , Butanones/poisoning , Chemical and Drug Induced Liver Injury/etiology , Dibutyl Phthalate/analogs & derivatives , Digestive System/injuries , Pentanols/poisoning , Pentanones/poisoning , Peroxides/poisoning , Accidents , Administration, Oral , Dibutyl Phthalate/poisoning , Glass , Humans , Male , Middle AgedABSTRACT
Fatal massive peripheral zonal hepatic necrosis developed in a 47-year-old man who accidentally ingested a solution of methyl ethyl ketone peroxide (MEKP) in dimethyl phthalate. Such solutions contain about 10% active oxygen. The clinical course was characterized by temporary cardiac arrest, abdominal burns, severe metabolic acidosis, rapid hepatic failure, rhabdomyolysis and respiratory insufficiency. A fatal outcome resulted 4 d afterwards from hepatic coma associated with blood coagulation disorders. Microscopical examination revealed massive periportal hepatic necrosis accompanied by atypical pseudoductular proliferation. The proliferating cells were probably of bile duct origin and exhibited atypia and mitoses. The pathogenetic mechanism may involve lipid peroxidation caused by free oxygen radicals derived from MEKP.
Subject(s)
Butanones/poisoning , Chemical and Drug Induced Liver Injury , Peroxides/poisoning , Humans , Liver/pathology , Male , Middle Aged , Necrosis , Oxygen/metabolismABSTRACT
Rats fed a vitamin E-deficient diet from age 3-10 weeks were either maintained on a vitamin E-deficient diet or fed a vitamin E-enriched diet for 8 subsequent weeks. The content of vitamin E, endoperoxide-derived malonaldehyde, lipofluorescent material and polyunsaturated fatty acids, and the activities of catalase, glutathione reductase, and glutathione peroxidase were then measured in cerebral tissues, with or without intoxication with methyl ethyl ketone peroxide (MEKP). For this purpose, one half of the animals in each vitamin E group received an ip injection of 5 mg MEKP per kg of body weight, which was followed 44 hours later, i.e., 4 hours before sample collection, by a second ip injection of 15 mg MEKP per kg of body weight. Despite the fact that the vitamin E concentration was 12-times lower in the brain of vitamin E-deficient rats, no significant change in other cerebral parameters was found between the two groups of animals. In contrast, the activity of selenium-glutathione peroxidase was markedly decreased in the liver of 10-week old vitamin E-deficient rats. Unexpectedly, acute systemic intoxication with MEKP caused only a small, albeit significant, decrease in glutathione reductase activity in the brain of vitamin E-sufficient rats, while no significant change in other cerebral parameters was observed in either group of animals. These results suggest that the central nervous system (CNS) is still substantially protected when its vitamin E content has been decreased to 3 micrograms/g fresh weight, and that systemic intoxication with MEKP may not cause lipid peroxidation in the CNS.
Subject(s)
Brain/metabolism , Butanones/poisoning , Peroxides/poisoning , Vitamin E Deficiency/metabolism , Animals , Brain/enzymology , Fatty Acids, Unsaturated/metabolism , Female , Glutathione Peroxidase/metabolism , Glutathione Reductase/metabolism , Liver/enzymology , Malondialdehyde/metabolism , Rats , Rats, Inbred Strains , Vitamin E/metabolism , Vitamin E Deficiency/enzymologyABSTRACT
Methyl ethyl ketone peroxide (MEKP) is a free radical-generating compound used as a fiberglass resin hardener. A 41-year-old Haitian man developed severe metabolic acidosis, hemolysis, esophageal and gastric necrosis, and perforation of the stomach after drinking an undetermined amount of MEKP in a successful suicide attempt. The biochemical effects of free radicals explain the necrosis and hemolysis observed.
