Different role of carboxylesterases in toxicity and tolerance to paraoxon and DFP
Different role of carboxylesterases in toxicity and tolerance to paraoxon and DFP
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DOI：
10.1016/s0009-2797(99)00057-5
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发表时间：
1999-05-14
影响因子：
5.1
通讯作者：
Milatovic, D
中科院分区：
文献类型：
--
作者：
Dettbarn, WD;Yang, ZP;Milatovic, D
本文研究了羧酸酯酶（CarbE）对有机磷抗胆碱酯酶（OP-antiChE）、对氧磷（diethyl p-nitrophenyl phosphate）和氟磷酸二异丙酯（DFP）的毒性和耐受性的影响。每日注射对氧磷（0.33 μ mol/kg）或DFP（2.72 μ mol/kg）（20天），脑中AChE活性分别降低至29%或16%，膈肌中AChE活性分别降低至58%或54%。动物耐受累积的6倍LD 50剂量，并在LD 90剂量的卡巴胆碱中存活，表明对这种胆碱能激动剂的耐受性。单剂量对氧磷或DFP显著降低血浆、肺和肝的CarbE活性。对氧磷后，血浆和肝脏CarbE迅速恢复，而DFP后恢复慢得多。每日用CarbE抑制剂CBDP（2-[邻甲苯基]-4H-1，2，3-苯并二氧杂磷杂环戊烷-2-氧化物）（7.22 μ mol/kg，s.c.）或异-OMPA（四异丙基焦磷酰胺）（8.76 μ mol/kg，腹膜内），然后用对氧磷（0.33 μ mol/kg，s.c.）30 min后，阻止对氧磷耐受的发展，并增强其毒性。大鼠在联合给药的第4天死亡。CarbE抑制剂既不增强DFP毒性，也不阻止对DFP的耐受性发展。我们的结论是，大鼠血浆CarbE提供了一个显着的保护对氧磷毒性，因为它的快速再活化可以减少重复应用对氧磷的毒性，从而有助于耐受性的发展。这种相同的机制不适用于DFP毒性，因为血浆、肝脏和肺的CarbE抑制既不增强其毒性，也不阻止耐受性的发展。这些研究结果证实了以前的观察，即CarbE解毒是更重要的高毒性的OP-抗胆碱酯酶，如神经毒剂和对氧磷比毒性较低的，如DFP。(C)1999爱思唯尔科学爱尔兰有限公司保留所有权利。
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 mu mol/kg) or DFP (2.72 mu mol/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 mu mol/kg, s.c.) or iso-OMPA (tetraisopropylpyrophosphoramide) (8.76 mu mol/kg, i.p.), followed by paraoxon (0.33 mu mol/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. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.