Differential sensitivity of plasma carboxylesterase-null mice to parathion, chlorpyrifos and chlorpyrifos oxon, but not to diazinon, dichlorvos, diisopropylfluorophosphate, cresyl saligenin phosphate, cyclosarin thiocholine, tabun thiocholine, and carbofuran
Differential sensitivity of plasma carboxylesterase-null mice to parathion, chlorpyrifos and chlorpyrifos oxon, but not to diazinon, dichlorvos, diisopropylfluorophosphate, cresyl saligenin phosphate, cyclosarin thiocholine, tabun thiocholine, and carbofuran
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DOI：
10.1016/j.cbi.2011.12.006
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发表时间：
2012-02-05
影响因子：
5.1
通讯作者：
Lockridge, Oksana
中科院分区：
文献类型：
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作者：
Duysen, Ellen G.;Cashman, John R.;Lockridge, Oksana
小鼠血液中含有四种能使有机磷化合物解毒的酯酶：羧酸酯酶、丁基胆碱酯酶、乙酰胆碱酯酶和对氧磷酶-1。相比之下，人血中含有后三种酶，但不含羧酸酯酶。有机磷化合物的毒性是由于对乙酰胆碱酯酶的抑制。大约50%的乙酰胆碱酯酶被抑制后，就会出现中毒症状。然而，完全抑制羧酸酯酶和丁基胆碱酯酶对动物的健康没有已知的影响。对氧磷酶能降解有机磷化合物，且不受其抑制。我们的目标是确定血浆羧酸酯酶缺乏对10种有机磷毒物和1种氨基甲酸酯类杀虫剂亚致死剂量反应的影响。观察了纯合子血浆羧酸酯酶缺陷ES1(-/-)小鼠和野生型仔鼠在单次亚致死剂量毒物处理后的中毒体征和体温变化。检测对血浆乙酰胆碱酯酶、丁酰胆碱酯酶和血浆羧酸酯酶的抑制作用。结果表明，皮下注射12.5 mg/kg对硫磷对野生型小鼠有保护作用。然而，这两种基因型对对氧磷、甲苯基沙利津磷酸盐、二异丙基氟磷酸盐、二氮磷、敌敌畏、环沙林硫代胆碱、塔布恩硫代胆碱和克百威的反应相似。一个意想不到的结果是，100 mg/kg的毒死蜱和14 mg/kg的毒死蜱透皮应用对野生型小鼠是致命的，但对ES1(-/-)小鼠不是，这表明在这种有机氯中，羧酸酯酶的存在是有害的，而不是保护作用。结论：小鼠血浆中的羧酸酯酶对高毒性药物具有保护作用，但其含量太低，不能保护需要高剂量抑制乙酰胆碱酯酶的低毒化合物。(C)2011爱思唯尔爱尔兰有限公司。保留所有权利。
Mouse blood contains four esterases that detoxify organophosphorus compounds: carboxylesterase, butyrylcholinesterase, acetylcholinesterase, and paraoxonase-1. In contrast human blood contains the latter three enzymes but not carboxylesterase. Organophosphorus compound toxicity is due to inhibition of acetylcholinesterase. Symptoms of intoxication appear after approximately 50% of the acetylcholinesterase is inhibited. However, complete inhibition of carboxylesterase and butyrylcholinesterase has no known effect on an animal's well being. Paraoxonase hydrolyzes organophosphorus compounds and is not inhibited by them. Our goal was to determine the effect of plasma carboxylesterase deficiency on response to sublethal doses of 10 organophosphorus toxicants and one carbamate pesticide. Homozygous plasma carboxylesterase deficient ES1(-/-) mice and wild-type littermates were observed for toxic signs and changes in body temperature after treatment with a single sublethal dose of toxicant. Inhibition of plasma acetylcholinesterase, butyrylcholinesterase, and plasma carboxylesterase was measured. It was found that wild-type mice were protected from the toxicity of 12.5 mg/kg parathion applied subcutaneously. However, both genotypes responded similarly to paraoxon, cresyl saligenin phosphate, diisopropylfluorophosphate, diazinon, dichlorvos, cyclosarin thiocholine, tabun thiocholine, and carbofuran. An unexpected result was the finding that transdermal application of chlorpyrifos at 100 mg/kg and chlorpyrifos oxon at 14 mg/kg was lethal to wild-type but not to ES1(-/-) mice, showing that with this organochlorine, the presence of carboxylesterase was harmful rather than protective. It was concluded that carboxylesterase in mouse plasma protects from high toxicity agents, but the amount of carboxylesterase in plasma is too low to protect from low toxicity compounds that require high doses to inhibit acetylcholinesterase. (C) 2011 Elsevier Ireland Ltd. All rights reserved.