Cyanide-induced lipid peroxidation in different organs: subcellular distribution and hydroperoxide generation in neuronal cells.
To evaluate hydroperoxide generation as a potential mechanism of cyanide neurotoxicity, mice were treated with KCN (7 mg/kg, subcutaneously (s.c.)) and the level of lipid peroxidation (expressed as conjugated dienes) was measured later in various organs. Brain showed elevated conjugated diene levels after cyanide but the liver, which is not considered a target for cyanide toxicity, showed no increase. The heart also showed no increase, whereas kidney conjugated dienes slowly increased to a peak 1 h after cyanide. In vitro studies show elevation of peroxidized lipids in mouse brain cortical slices following incubation with KCN (0.1 mM). Omission of calcium from the medium or pretreatment of brain slices with diltiazem (a calcium channel blocker) prevented formation of conjugated dienes by KCN. Calcium thus appears to play a critical role in cyanide-induced generation of peroxidized lipids in neuronal cells. Subcellular fractionation of brains from mice treated with cyanide showed that lipid peroxidation increased in the microsomal fraction but not in the mitochondrial fraction. Fluorescent studies using 2,7-dichlorofluorescein (a hydroperoxide sensitive fluorescent dye) show that hydroperoxides are generated rapidly after cyanide treatment of PC12 cells, a neuron-like cell, and hydroperoxide levels remain elevated for many minutes in the presence of cyanide. These results suggest that hydroperoxide generation with subsequent peroxidation of lipids may lead to changes in structure and function of certain membranes and contribute to the neurotoxic damage produced by cyanide.
Ardelt
B K
BK
Department of Pharmacology and Toxicology, Purdue University, West Lafayette, IN 47907-1334.
Borowitz
J L
JL
Maduh
E U
EU
Swain
S L
SL
Isom
G E
GE
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002118:Calcium / Q000502:physiology; D002460:Cell Line; D004110:Diltiazem / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007279:Injections, Subcutaneous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011190:Potassium Cyanide / Q000633:toxicity*
D006861:Hydrogen Peroxide; D004110:Diltiazem; D011190:Potassium Cyanide; D002118:Calcium