Cocaine-induced biochemical changes and cytotoxicity in hepatocytes isolated from both mice and rats.
The mechanism of cocaine-induced cytotoxicity was investigated in hepatocytes isolated from both male C3H mice and male Sprague-Dawley rats. Cocaine was more cytotoxic to mouse hepatocytes than rat and induced reduced glutathione (GSH) depletion prior to marked increases in cytotoxicity in both systems. In both mouse and rat cells, GSH depletion was accompanied by GSSG production, but in rat cells, quantitative measures suggested that other mechanisms contributed to GSH depletion. No cocaine-induced depletion of protein-thiol groups or generation of protein-glutathione mixed disulfides could be detected in rat cells. Cocaine induced lipid peroxidation, using malondialdehyde (MDA) production as an index of the peroxidation process, in both mouse and rat hepatocytes. Inhibition of MDA production to below control levels using the antioxidant N,N'-diphenyl-phenylene diamine (DPPD) however, had no inhibitory effect on cocaine-induced cytotoxicity in either mouse or rat cells. These data suggest that neither generalized protein thiol depletion nor lipid peroxidation are critical determinants of cocaine-induced cytotoxicity in cellular systems.
Donnelly
D A
DA
Molecular and Environmental Toxicology Program, School of Pharmacy, University of Colorado, Boulder 80309.
Boyer
C S
CS
Petersen
D R
DR
Ross
D
D
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D010655:Phenylenediamines / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000378:metabolism
D010655:Phenylenediamines; D011506:Proteins; D013438:Sulfhydryl Compounds; D008315:Malondialdehyde; C004845:N,N'-diphenyl-4-phenylenediamine; D005978:Glutathione; D003042:Cocaine