氯吡硫磷一氧 | 5598-15-2

• 物质功能分类: 化学农药原药 - 杀虫剂 - 有机氯杀虫剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 氯吡硫磷一氧
• 中文别名: 陶斯松氧化物；毒死蜱代谢物
• 英文名称: chlopyrifos oxon
• 英文别名: Chlorpyrifos oxon；O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphate；O,O-diethyl-O-(3,5,6-trichloro-2-pyridyl)phosphate；O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate；O,O'-diethyl 3,5,6-trichloro-2-pyridyl phosphate；O,O-diethyl O-3,5,6-trichloro-2-pyridylphosphate；diethyl (3,5,6-trichloropyridin-2-yl) phosphate
• CAS: 5598-15-2
• 化学式: C₉H₁₁Cl₃NO₄P
• 分子量: 334.523
• InChiKey: OTMOUPHCTWPNSL-UHFFFAOYSA-N

物化性质

• 沸点：
  357.8±42.0 °C(Predicted)
• 密度：
  1.461±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）
• 保留指数：
  1936;1940;1920;1926;1956;1966;1982;1970.1;1950;1962.1;1953.7;1952.9;1958.7;1957.5;1955.3;1952.2;1938.7;1935.8;1949

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  57.6
• 氢给体数：
  0
• 氢受体数：
  5

ADMET

代谢

氯吡硫磷-氧硫已知的代谢物包括硫代磷酸二乙酯和3,5,6-三氯-2-吡啶醇。

Chlorpyrifos-oxon has known human metabolites that include Diethyl phosphorothioate and 3,5,6-Trichloro-2-pyridinol.

来源:NORMAN Suspect List Exchange

代谢

有机磷化合物的代谢主要通过氧化、通过酯酶的水解以及与谷胱甘肽的反应进行。去甲基化和葡萄糖苷酸化也可能发生。有机磷农药的氧化可能导致产生中等毒性的产物。一般来说，磷硫代酸盐本身并不直接有毒，但需要经过氧化代谢转化为近端毒素。谷胱甘肽转移酶反应产生的产物在大多数情况下毒性较低。对氧磷酶（PON1）是有机磷化合物代谢中的关键酶。PON1可以通过水解使一些有机磷化合物失活。PON1水解多种有机磷杀虫剂以及神经毒剂（如梭曼、沙林和VX）的活性代谢物。PON1的多态性导致这种酯酶的酶水平和催化效率不同，这反过来表明不同个体可能更容易受到有机磷暴露的毒性影响。

Metabolism of organophosphates occurs principally by oxidation, by hydrolysis via esterases and by reaction with glutathione. Demethylation and glucuronidation may also occur. Oxidation of organophosphorus pesticides may result in moderately toxic products. In general, phosphorothioates are not directly toxic but require oxidative metabolism to the proximal toxin. The glutathione transferase reactions produce products that are, in most cases, of low toxicity. Paraoxonase (PON1) is a key enzyme in the metabolism of organophosphates. PON1 can inactivate some organophosphates through hydrolysis. PON1 hydrolyzes the active metabolites in several organophosphates insecticides as well as, nerve agents such as soman, sarin, and VX. The presence of PON1 polymorphisms causes there to be different enzyme levels and catalytic efficiency of this esterase, which in turn suggests that different individuals may be more susceptible to the toxic effect of organophosphate exposure.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

氯吡硫磷是一种胆碱酯酶或乙酰胆碱酯酶（AChE）抑制剂。胆碱酯酶抑制剂（或“抗胆碱酯酶”）抑制乙酰胆碱酯酶的作用。由于其基本功能，干扰乙酰胆碱酯酶作用的化学物质是强大的神经毒素，低剂量时会导致过度流涎和眼泪，随后是肌肉痉挛，最终导致死亡。神经气体和许多用于杀虫剂的物质已被证明通过结合乙酰胆碱酯酶活性位点的丝氨酸，完全抑制该酶。乙酰胆碱酯酶分解神经递质乙酰胆碱，该递质在神经和肌肉接头处释放，以使肌肉或器官放松。乙酰胆碱酯酶抑制的结果是乙酰胆碱积聚并继续发挥作用，使得任何神经冲动不断传递，肌肉收缩不会停止。最常见的乙酰胆碱酯酶抑制剂之一是基于磷的化合物，它们被设计用来结合到酶的活性位点上。结构要求是一个带有两个亲脂性基团的磷原子，一个离去基团（如卤素或硫氰酸盐）以及一个末端的氧。

Chlorpyrifos oxon is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

急性接触胆碱酯酶抑制剂可能会导致胆碱能危象，表现为严重的恶心/呕吐、流涎、出汗、心动过缓、低血压、晕厥和抽搐。肌肉无力可能性增加，如果呼吸肌受累，可能会导致死亡。在运动神经积累的乙酰胆碱会导致神经肌肉接头处烟碱受体的过度刺激。当这种情况发生时，可能会看到肌肉无力、疲劳、肌肉痉挛、肌束震颤和麻痹的症状。当自主神经节积累乙酰胆碱时，这会导致交感系统中烟碱受体的过度刺激。与此相关的症状是高血压和低血糖。由于乙酰胆碱积累而在中枢神经系统中过度刺激烟碱乙酰胆碱受体，会导致焦虑、头痛、抽搐、共济失调、呼吸和循环抑制、震颤、全身无力，甚至可能昏迷。当由于副交感乙酰胆碱受体上乙酰胆碱过多而导致毒蕈碱过度刺激时，可能会出现视力障碍、胸部紧绷、由于支气管收缩引起的喘息、支气管分泌物增加、唾液分泌增加、流泪、出汗、肠蠕动和排尿的症状。对于男性和女性的生育、生长和发育，已经特别将与有机磷农药暴露联系起来。关于生殖影响的大多数研究都是在农村地区使用杀虫剂和杀虫剂的农民进行的。在女性中，月经周期紊乱、怀孕时间延长、自然流产、死产以及后代的一些发育效应与有机磷农药暴露有关。产前暴露与胎儿生长和发育受损有关。神经毒性效应也与人因接触有机磷农药而中毒引起的四种神经毒性效应有关：胆碱能综合症、中间综合症、有机磷诱导的迟发性多发性神经病（OPIDP）和慢性有机磷诱导的神经精神障碍（COPIND）。这些综合症在急性接触和慢性接触有机磷农药后出现。

Acute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

低剂量暴露的症状包括过度流涎和眼泪。急性剂量症状包括严重恶心/呕吐、流涎、出汗、心动过缓、低血压、虚脱和抽搐。肌肉无力可能会逐渐加剧，如果呼吸肌肉受影响，可能会导致死亡。还可能出现高血压、低血糖、焦虑、头痛、震颤和共济失调。

Symptoms of low dose exposure include excessive salivation and eye-watering. Acute dose symptoms include severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Hypertension, hypoglycemia, anxiety, headache, tremor and ataxia may also result.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露处理

如果已经摄入该化合物，应使用5%碳酸氢钠进行快速洗胃。对于皮肤接触，应用肥皂和水清洗皮肤。如果化合物进入眼睛，应用大量等渗盐水或水清洗。在严重情况下，应给予阿托品和/或普瑞洛辛。抗胆碱能药物作用是拮抗过量的乙酰胆碱并重新激活乙酰胆碱酯酶。阿托品可以与普瑞洛辛或其他吡啶季铵盐（如三甲氧胺或欧比多辛）联合使用作为解毒剂，尽管至少有两项荟萃分析发现使用“-氧胺”没有益处，甚至可能有害。阿托品是一种毒蕈碱拮抗剂，因此可以阻断乙酰胆碱的外周作用。

If the compound has been ingested, rapid gastric lavage should be performed using 5% sodium bicarbonate. For skin contact, the skin should be washed with soap and water. If the compound has entered the eyes, they should be washed with large quantities of isotonic saline or water. In serious cases, atropine and/or pralidoxime should be administered. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime), though the use of '-oximes' has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally.

来源:Toxin and Toxin Target Database (T3DB)

安全信息

• 危险等级：
  6.1(b)
• 危险品运输编号：
  UN 2783
• 包装等级：
  III
• 危险类别：
  6.1(b)
• 储存条件：
  0-6°C

制备方法与用途

生物活性

氯吡硫磷肟（Chlorpyrifos-oxo）是氯吡硫磷的一种活性代谢产物，能够有效抑制乙酰胆碱酯酶（AChE）。它还能诱导微管蛋白亚基之间的交联并破坏微管功能。

体外研究

将1.5 mM 氯吡硫磷肟（CPO）与微管蛋白孵育会导致蛋白质聚集。然而，即使在1.5 μM 浓度下，也能观察到三聚体的交联。氯吡硫磷肟促进微管蛋白单体之间的异肽键交联形成多聚体。

在培养的PC12细胞中，暴露于3.0 μM 氯吡硫磷浓度（低于抑制AChE活性10倍）下24小时后，神经突生长受损；而在相同条件下，氯吡硫磷肟则在1.0 nM 浓度下即可抑制神经突生长。

体内研究

氯吡硫磷肟（CPO）在人类肝微粒体中通过依赖细胞色素P450的脱乙酰化和去芳基化迅速解毒，并由谷胱甘肽-S-转移酶代谢。此外，肝脏中的A-酯酶（如单过氧化物酶1）或B-酯酶（如羧基酯酶和丁酰胆碱酯酶）也可能快速降解或清除氯吡硫磷肟。

给野生型小鼠腹腔注射3 mg/kg 氯吡硫磷肟后，实验结果表明，与对照组相比，处理组小鼠的微管尺寸减少了约60%。这些微管表现出共价修饰的氨基酸和异常结构，提示微管功能受损。

反应信息

• 作为反应物：
  描述：

  氯吡硫磷一氧 在 sodium hydroxide 作用下， 以 aq. buffer 为溶剂， 反应 1.72h， 生成 3,5,6-三氯吡啶-2-醇
  参考文献：
  名称：

  毒死rif和其他有机磷酯在水溶液中的半衰期。

  摘要：

  毒死rif的水溶液被用来研究毒死ox催化蛋白质交联的能力。通过使用溶液中毒死的稳​​定性信息，蛋白质交联测定可以避免伪影。由于没有文献资料，我们承诺确定毒死rif的半衰期。在23°C下于20 mM TrisCl pH 8和pH 9中，通过记录毒死rif在290 nm处的吸光度损失和在380 nm下的吸光度增加来测量毒死rif oxon转化为3,5,6-三氯-2-吡啶醇的速率。对于3,5,6-三氯-2-吡啶醇为320 nm。毒死rif的半衰期在pH值为8时为20.9天，在pH值为9时为6.7天。

  DOI：

  10.1016/j.cbi.2019.108788
• 作为产物：
  描述：

  毒死蜱 在 双氧水 作用下， 以 溶剂黄146 为溶剂， 反应 3.0h， 以80%的产率得到氯吡硫磷一氧
  参考文献：
  名称：

  Fakhr, I. M. I.; Hegazi, B.; Khatab, M. S., Egyptian Journal of Chemistry, 1998, vol. 41, # 1-6, p. 145 - 154

  摘要：

  DOI：
• 作为试剂：
  描述：

  7-乙酰氧基-4-甲基香豆素 在 氯吡硫磷一氧 、 serine hydrolase KIAA₁₃₆₃ 作用下， 生成 羟甲香豆素
  参考文献：
  名称：

  Interaction of the serine hydrolase KIAA1363 with organophosphorus agents: Evaluation of potency and kinetics

  摘要：

  Oxons are bioactive metabolites of organophosphorus insecticides (OPs) that covalently inactivate serine hydrolases. KIAA1363 is one of the most abundant serine hydrolases in mouse brain. Although the physiological consequences related to the inhibition of KIAA1363 due to environmental exposures to OPs are poorly understood, the enzyme was previously shown to have a role in the detoxification of oxons. Here, we overexpressed human KIAA1363 and CES1 in COS7 cells and compared the potency of inhibition (IC(50)s, 15 min) of KIAA1363 and CES1 by chlorpyrifos oxon (CPO), paraoxon (PO), and methyl paraoxon (MPO). The order of potency was CPO > PO >> MPO for both enzymes. We also determined the bimolecular rate constants (k(inact)/K-i) for reactions of CPO and PO with KIAA1363 and CES1. KIAA1363 and CES1 were inactivated by CPO at comparable rates (4.4 x 10(6) s(-1) M-1 and 6.7 x 10(6) s(-1) M-1, respectively), whereas PO inactivated both enzymes at slower rates (0.4 x 10(6) s(-1) M-1 and 1.5 x 10(6) s(-1) M-1, respectively). Finally, the reactivation rate of KIAA1363 following inhibition by CPO was evaluated. Together, the results define the kinetics of inhibition of KIAA1363 by active metabolites of agrochemicals and indicate that KIAA1363 is highly sensitive to inhibition by these compounds. (C) 2015 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.abb.2015.11.034

文献信息

• Use of metabolic phenotyping in individualized treatment with amonafide
  申请人：McGill University

  公开号：US20030190671A1

  公开（公告）日：2003-10-09

  The invention relates to the individualization of therapy on the basis of a phenotypic profile of an individual. More specifically, the present invention relates to the use of metabolic phenotyping for the individualization of treatment with the drug, amonafide.

  该发明涉及根据个体的表型特征个性化治疗。更具体地说，本发明涉及利用代谢表型来个性化阿莫那非德药物治疗。
• Multiple determinants for metabolic phenotypes
  申请人：——

  公开号：US20030091975A1

  公开（公告）日：2003-05-15

  The invention relates to the determination of multiple phenotypic determinants for human drug metabolizing enzymes. More specifically, the present invention relates to the characterization of metabolic phenotypes based on phenotypic determinants and applications and uses thereof.

  这项发明涉及确定人类药物代谢酶的多个表型决定因素。更具体地说，本发明涉及基于表型决定因素对代谢表型进行表征以及其应用和用途。
• Individualization of therapy with anxiolitics
  申请人：McGill University

  公开号：US20030175210A1

  公开（公告）日：2003-09-18

  The invention relates to the individualization of therapy on the basis of a phenotypic profile of an individual. More specifically, the present invention relates to the use of metabolic phenotyping for the individualization of treatment with anxiolitic agents.

  本发明涉及基于个体表型特征的治疗个体化。更具体地说，本发明涉及利用代谢表型特征来个体化治疗抗焦虑药物。
• Individualization of therapy with antipsychotics
  申请人：McGill University

  公开号：US20030170176A1

  公开（公告）日：2003-09-11

  The invention relates to the individualization of therapy on the basis of a phenotypic profile of an individual. More specifically, the present invention relates to the use of metabolic phenotyping for the individualization of treatment with antipsychotic agents.

  本发明涉及基于个体表型特征进行治疗个体化的技术。更具体地说，本发明涉及利用代谢表型特征个体化抗精神病药物治疗的方法。
• Individualization of therapy with antihistamines
  申请人：Xanthus Life Sciences, Inc.

  公开号：US20030180823A1

  公开（公告）日：2003-09-25

  The invention relates to the individualization of therapy on the basis of a phenotypic profile of an individual. More specifically, the present invention relates to the use of metabolic phenotyping for the individualization of treatment with antihistamines.

  本发明涉及根据个体的表型特征进行治疗个性化的方法。更具体地说，本发明涉及利用代谢表型为抗组胺药物治疗个性化的方法。

表征谱图