iso-OMPA-induced potentiation of soman toxicity in rat.
Male Sprague-Dawley rats, injected with the irreversible acetylcholinesterase (AChE) inhibitor soman (pinacolyl methylphosphonofluoridate) 25 micrograms/kg sc, showed no signs of toxicity. Pretreatment with iso-OMPA (tetraisopropylpyrophosphoramide) 1 mg/kg sc 1 h before the soman administration, caused severe signs of hypercholinergic activity, similar to those seen with an acute signs-producing nonlethal dosage (100 micrograms soman/kg sc). Within 1 h iso-OMPA alone significantly reduced the activity of carboxylesterases (CarbE) in all tissues studied and butyrylcholinesterase (BuChE) activity was significantly reduced in plasma (22%) and liver (27%). Soman (25 micrograms/kg) alone significantly reduced the plasma activity of CarbE (15%), BuChE (53%) and AChE (18%), but had no effect on these enzymes of liver. The combined treatment of iso-OMPA and soman, however, reduced CarbE activity in liver (0%) and produced significantly greater effects than iso-OMPA or soman alone on AChE and BuChE in all the brain areas and skeletal muscles tested. The number of necrotic lesions found in skeletal muscles was many times higher with the combined treatment than seen with soman (25 micrograms/kg) alone, and was equal to those seen with an acute toxicity signs-producing dose of soman. It is concluded that the observed iso-OMPA-induced potentiation of soman toxicity is probably caused via reduced nonspecific binding sites (BuChE and CarbE) for soman leading to greater inhibition of AChE.
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
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Gupta
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Dettbarn
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D004357:Drug Synergism; D008297:Male; D009132:Muscles / Q000187:drug effects / Q000473:pathology; D009336:Necrosis / Q000139:chemically induced; D009943:Organophosphorus Compounds / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012999:Soman / Q000633:toxicity*; D013770:Tetraisopropylpyrophosphamide / Q000633:toxicity*
D009943:Organophosphorus Compounds; D013770:Tetraisopropylpyrophosphamide; D012999:Soman; D002265:Carboxylic Ester Hydrolases; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase