Different role of carboxylesterases in toxicity and tolerance to paraoxon and DFP.
The contribution of carboxylesterase (CarbE) to toxicity and tolerance to the organophosphorus anticholinesterases (OP-antiChE) paraoxon (diethyl p-nitrophenyl phosphate) and DFP (diisopropylphosphorofluoridate) was investigated in rats. Daily injections (20 days) of paraoxon (0.33 micromol/kg) or DFP (2.72 micromol/kg) reduced AChE activity in brain to 29 or 16% and in diaphragm to 58 or 54%, respectively. The animals tolerated an accumulated 6-fold LD50 dose and survived an LD90 dose of carbachol, indicating tolerance to this cholinergic agonist. A single dose of paraoxon or DFP significantly reduced CarbE activity of plasma, lung and liver. After paraoxon, rapid recovery was seen of plasma and liver CarbE while recovery after DFP was much slower. Daily pretreatment with the CarbE inhibitors CBDP (2-[o-cresyl]-4H-1,2,3-benzodioxa- phosphorin-2-oxide) (7.22 micromol/kg, s.c.) or iso-OMPA (tetraisopropylpyrophosphoramide) (8.76 micromol/kg, i.p.), followed by paraoxon (0.33 micromol/kg, s.c.) 30 min later, prevented the development of tolerance to paraoxon and potentiated its toxicity. Rats died on day four of the combined treatment. The CarbE inhibitors neither potentiated the DFP toxicity, nor prevented tolerance development to DFP. We conclude that rat plasma CarbE provides a significant protection against paraoxon toxicity because its rapid reactivation can reduce the toxicity of repeated paraoxon applications and thus contribute to tolerance development. This same mechanism does not apply to DFP toxicity, as inhibition of CarbE of plasma, liver and lung neither potentiated its toxicity, nor prevented tolerance development. These findings confirm previous observations that CarbE detoxification is of greater importance for highly toxic OP-antiChEs such as nerve agents and paraoxon than for less toxic ones such as DFP.
Department of Pharmacology and Neurology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
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Dettbarn
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Yang
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Milatovic
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004357:Drug Synergism; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007531:Isoflurophate / Q000633:toxicity*; D007700:Kinetics; D007928:Lethal Dose 50; D008297:Male; D009943:Organophosphorus Compounds / Q000633:toxicity; D010261:Paraoxon / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; C000516:2-(2-cresyl)-4H-1-3-2-benzodioxaphosphorin-2-oxide; D007531:Isoflurophate; C008705:octamethyl pyrophosphoramide; D002265:Carboxylic Ester Hydrolases; D000110:Acetylcholinesterase; D010261:Paraoxon