Toxicity of 1,2-dibromoethane in isolated hepatocytes: role of lipid peroxidation.
Treatment of isolated hepatocytes with 1,2-dibromoethane (DBE) caused a concentration dependent depletion of cellular glutathione (GSH) content and a parallel increase in the covalent binding of reactive intermediates to cell proteins, as a consequence of the haloalkane activation. The reduction of the hepatocyte GSH content, induced by DBE, stimulated the onset of lipid peroxidation, as measured by malondialdehyde (MDA) accumulation. N-Acetylcysteine (1 mM) was found to partially prevent GSH loss and to inhibit MDA formation, whereas equal concentrations of cysteine and methionine were ineffective on these respects. The stimulation of the peroxidative reactions appeared to be also associated with an increase in the leakage of lactate dehydrogenase (LDH) from the cells, indicative of a severe hepatocyte injury. Antioxidants such as alpha-tocopherol, N,N'-phenyl-phenylenediamine (DPPD) and promethazine, as well as N-acetylcysteine reduced MDA formation to various extents and also protect against LDH release, yet without interfering with the covalent binding of DBE reactive intermediates to hepatocyte proteins. These results suggest the involvement of lipid peroxidation, consequent to GSH depletion, in the pathogenesis of liver cell necrosis due to DBE.
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D015946:Ethylene Dibromide / Q000378:metabolism / Q000633:toxicity*; D005025:Ethylene Dichlorides / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D006842:Hydrocarbons, Brominated / Q000633:toxicity*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008054:Lipid Peroxides / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000494:pharmacology
D000975:Antioxidants; D005025:Ethylene Dichlorides; D006842:Hydrocarbons, Brominated; D008054:Lipid Peroxides; D013438:Sulfhydryl Compounds; D015946:Ethylene Dibromide; D008315:Malondialdehyde; C024565:ethylene dichloride; D007770:L-Lactate Dehydrogenase; D005978:Glutathione