Diisopropylphosphorofluoridate-induced muscle hyperactivity associated with enhanced lipid peroxidation in vivo.
Acute exposure to acetylcholinesterase (AChE) inhibitors such as organophosphates and carbamates induces functional changes at the neuromuscular junctions, leading to fasciculations that ultimately cause muscle fiber necrosis. There is recent evidence that oxygen free radical formation may be a factor in the toxicity of these insecticides. One of the targets of free radical-induced injury is lipid peroxidation. The role of lipid peroxidation in diisopropylphosphorofluoridate (DFP)-induced muscle necrosis was investigated by quantifying two products resulting from the oxidation of lipids in muscle tissue-the thiobarbituric acid-malondialdehyde complex (TBA-MDA) and F2-isoprostanes, the latter being a novel and extremely accurate marker of lipid peroxidation in vivo. When compared with control animals, significant increases in MDA of 96% and in F2-isoprostanes of 56% were found in the diaphragms of rats treated with 2.0 mg/kg DFP after 60 min (P < 0.01). In rats pretreated with the neuromuscular blocking agent d-tubocurarine or the lazaroid U-78517F, an antioxidant, no DFP-induced increases in either MDA or F2-isoprostanes were observed. It is suggested that the AChE inhibitor-induced cholinergic hyperactivity initiates that accumulation of free radicals leading to lipid peroxidation, which may be the initiator of the AChE inhibitor-induced cell injury.
Yang
Z P
ZP
Department of Pharmacology, Vanderbilt University School of Medicine, USA.
Morrow
J
J
Wu
A
A
Roberts
L J
LJ
Dettbarn
W D
WD
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002839:Chromans / Q000494:pharmacology; D015237:Dinoprost / Q000096:biosynthesis; D005207:Fasciculation / Q000139:chemically induced* / Q000378:metabolism; D007531:Isoflurophate / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D009132:Muscles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014403:Tubocurarine / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D002839:Chromans; D010879:Piperazines; D007531:Isoflurophate; C066382:U 78517F; D008315:Malondialdehyde; D015237:Dinoprost; D014403:Tubocurarine