河鲀毒素 | 4368-28-9

• 物质功能分类: 分析化学 - 标准品 - 中药标准品
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 河鲀毒素
• 中文别名: 河豚毒；河豚毒素
• 英文名称: (+/-)-Tetrodotoxin
• 英文别名: (1R,5R,6R,7R,9S,11S,13S,14S)-3-amino-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.17,11.01,6]tetradec-3-ene-5,9,12,13,14-pentol
• CAS: 4368-28-9
• 化学式: C₁₁H₁₇N₃O₈
• 分子量: 319.27
• InChiKey: CFMYXEVWODSLAX-HUILCFQTSA-N

物化性质

• 熔点：
  280 °C (decomp)
• 比旋光度：
  D25 -8.64° (c = 8.55 in dil acetic acid)
• 沸点：
  458.31°C (rough estimate)
• 密度：
  1.3768 (rough estimate)
• 溶解度：
  H2O：如果冷冻储存，在pH4-5时稳定可溶
• 物理描述：
  Colorless crystalline solid that darkens when heated above 428°F (220°C).
• 颜色/状态：
  Crystals
• 稳定性/保质期：

  Stable to boiling except in an alkaline solution.

• 旋光度：
  Specific optical rotation at 25 °C/D: -8.64 deg (c = 8.55 in dilute acetic acid)
• 分解：
  When heated to decomposition it emits toxic fumes of /Nitrogen oxide/.
• 解离常数：
  pKa: 8.76 (water), 9.4 (50% alcohol)

计算性质

• 辛醇/水分配系数(LogP)：
  -5.9
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  190
• 氢给体数：
  8
• 氢受体数：
  9

ADMET

代谢

四箭毒的代谢来源尚不确定。尚未确定藻类来源，直到最近，四箭毒被认为是宿主的代谢产物。然而，最近的报告显示，包括弧菌科菌株、假单胞菌和发光杆菌属细菌在内的几种细菌能够产生四箭毒/无水四箭毒，这一发现指向了这一毒素家族的细菌来源。

The metabolic source of tetrodotoxin is uncertain. No algal source has been identified, and until recently tetrodotoxin was assumed to be a metabolic product of the host. However, recent reports of the production of tetrodotoxin/anhydrotetrodotoxin by several bacterial species, including strains of the family Vibrionaceae, Pseudomonas sp., and Photobacterium phosphoreum, point toward a bacterial origin of this family of toxins.

来源:Hazardous Substances Data Bank (HSDB)

代谢

为了研究与河豚鱼体内四氢喃毒（TTX）生物合成或积累相关的基因，通过mRNA任意引物反转录聚合酶链反应（RAP RT-PCR）比较了携带不同浓度TTX及其衍生物的河豚鱼肝脏中的mRNA表达模式。RAP RT-PCR提供了一个383 bp的cDNA片段，其在有毒河豚鱼肝脏中的转录本水平高于无毒河豚鱼。其推导的氨基酸序列与其他脊椎动物报告的纤维蛋白原样蛋白相似。Northern blot分析和cDNA末端快速扩增（RACE）揭示，383 bp的cDNA片段由至少三个纤维蛋白原样蛋白（flp）基因组成，分别是flp-1、flp-2和flp-3。flp-1、flp-2和flp-3的相对mRNA水平与两种河豚鱼肝脏的毒性呈线性相关。

To investigate the genes related to the biosynthesis or accumulation of tetrodotoxin (TTX) in pufferfish, mRNA expression patterns in the liver from pufferfish, akamefugu Takifugu chrysops and kusafugu Takifugu niphobles, were compared by mRNA arbitrarily primed reverse transcription-polymerase chain reaction (RAP RT-PCR) with fish bearing different concentrations of TTX and its derivatives. RAP RT-PCR provided a 383 bp cDNA fragment and its transcripts were higher in toxic than non-toxic pufferfish liver. Its deduced amino acid sequence was similar to those of fibrinogen-like proteins reported for other vertebrates. Northern blot analysis and rapid amplification of cDNA ends (RACE) revealed that the cDNA fragment of 383 bp was composed of at least three fibrinogen-like protein (flp) genes, flp-1, flp-2 and flp-3. Relative mRNA levels of flp-1, flp-2 and flp-3 showed a linear correlation with toxicity of the liver for two pufferfish species.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 暴露途径

曝光是由于摄入含有河豚毒素的鱼类或其他食物所致。

Exposure occurs due to ingestion of fish or other food containing tetrodotoxin.

来源:The National Institute for Occupational Safety and Health (NIOSH)

毒理性

• 皮肤症状

消毒

Decontamination

来源:The National Institute for Occupational Safety and Health (NIOSH)

毒理性

• 摄入症状

第一阶段：嘴唇和舌头麻木以及刺痛和麻刺感（感觉异常），随后面部和四肢出现感觉异常和麻木，头痛，感觉轻飘飘或漂浮，大量出汗（出汗），头晕，流涎（多涎症），恶心，呕吐（呕吐），腹泻，上腹部（胃部）疼痛，运动困难（运动功能障碍），乏力（不适），以及言语困难。

First stage: Numbness and sensation of prickling and tingling (paresthesia) of the lips and tongue, followed by facial and extremity paresthesias and numbness, headache, sensations of lightness or floating, profuse sweating (diaphoresis), dizziness, salivation (ptyalism), nausea, vomiting (emesis), diarrhea, abdominal (epigastric) pain, difficulty moving (motor dysfunction), weakness (malaise), and speech difficulties.

来源:The National Institute for Occupational Safety and Health (NIOSH)

毒理性

• 相互作用

一项研究调查了一种对河豚毒素（TTX）特异性的单克隆抗体T20G10能否通过被动免疫保护来对抗致命的TTX挑战。T20G10与TTX的亲和力估计为大约10^-9 M，并且与无水河豚毒素的亲和力低大约50倍，并且与河豚酸的竞争免疫分析没有反应。T20G10在体外放射性配体受体结合分析中特异性地抑制了TTX的结合，但对麻痹性贝毒在鼠脑膜上的钠通道结合没有影响。在预防研究中，小鼠在腹腔注射TTX挑战（10 ug/kg）前30分钟通过尾静脉给药T20G10。在这些条件下，100微克的T20G10保护了6/6的小鼠，而50微克的T20G10保护了3/6的小鼠。非特异性对照单克隆抗体没有提供对致命剂量的保护。模拟口服中毒的治疗研究是使用小鼠通过灌胃给予致命剂量的TTX进行的，TTX悬浮在非脂肪干牛奶中，用磷酸盐缓冲盐水。在没有给予T20G10的情况下，6/6的小鼠在25-35分钟内死亡。然而，口服TTX暴露后10-15分钟通过尾静脉给予500微克的T20G10预防了6/6的小鼠死亡。较低剂量的单克隆抗体提供了较少的保护。

The ability of a tetrodotoxin (TTX)-specific monoclonal antibody to confer passive protection against lethal TTX challenge was investigated. The monoclonal antibody, T20G10, has an estimated affinity for TTX of approximately 10-9 M and is about 50-fold less reactive with anhydrotetrodotoxin and unreactive with tetrodonic acid by competitive immunoassay. T20G10 specifically inhibited TTX binding in an in vitro radioligand receptor binding assay, but had no effect on the binding of saxitoxin to the sodium channel on rat brain membranes. In prophylaxis studies, mice were administered T20G10 via the tail vein 30 min prior to i.p. TTX challenge (10 ug/kg). Under these conditions, 100 micrograms T20G10 protected 6/6 mice, whereas 3/6 mice were protected with 50 micrograms T20G10. Non-specific control monoclonal antibody did not protect against lethality. Therapy studies simulating oral intoxication were performed with mice given a lethal dose of TTX by gavage in a suspension of non-fat dry milk in phosphate-buffered saline. Death occurred within 25-35 min in 6/6 mice not treated with T20G10. However, 500 ug T20G10 administered via the tail vein 10-15 min after oral TTX exposure prevented death in 6/6 mice. Lower doses of mAb conferred less protection.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在犬冠状动脉闭塞24小时后，利多卡因（4 mg/kg，静脉注射）和河豚毒素（2 ug/kg，静脉注射）显示出显著的抗心律失常活性。在剂量减半的情况下，单独使用这两种物质对心律失常没有效果，但一起使用时，它们几乎完全恢复了心脏节律。

At 24 hours after coronary artery occlusion in dogs, lidocaine (4 mg/kg, iv) and tetrodotoxin (2 ug/kg, iv) showed marked antiarrhythmic activity. At 2-fold lower doses, neither substance alone had an effect on arrhythmias, but when administered together, they induced almost complete restoration of cardiac rhythm.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

1999年，从孟加拉国的两个地点（迈门辛和巴里萨尔）收集了23只树蛙Polypedates sp.的标本，并对其毒性评分和毒素原理进行了检测。在所有组织中，只有来自迈门辛的标本皮肤在小鼠测试中被发现具有毒性，毒性评分为31-923微克/克。从皮肤中分离出的毒素通过高效液相色谱、电喷雾电离-飞行时间质谱和质子核磁共振进行分析，并被鉴定为河豚毒素，这是一种毒素原理。

Twenty-three specimens of a tree-frog Polypedates sp. were collected from two locations (Mymensingh and Barisal) of Bangladesh in 1999, and assayed for their toxicity scores and toxin principle. Among the tissues, only the skin of the Mymensingh specimens was found to be toxic in mouse test, with the toxicity scores of 31-923 ug/g. The toxin isolated from the skin was analyzed by high-performance liquid chromatography, electrospray ionization-time of flight mass spectrometry and proton nuclear magnetic resonance, and characterized as tetrodotoxin, a toxin principle.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

河豚毒素（TTX）及其类似物（TTXs）在海洋和陆生动物中广泛分布，可引起危险的中毒。这些高潜力毒素也被认为是河豚鱼中毒的致病因素。在孟加拉国海洋河豚鱼，Takifugu oblongus的不同组织中，测定了TTX、无水河豚毒素、11-脱氧河豚毒素和三脱氧河豚毒素。TTX在皮肤、肌肉和肝脏中占主导地位，而三脱氧河豚毒素在卵巢中占优势。通过小鼠生物测定法确定了各种组织的毒性。

Tetrodotoxin (TTX) and its analogs (TTXs), widely distributed among marine as well as terrestrial animals, induce dangerous intoxications. These highly potential toxins are also known as the causative agent of puffer fish poisoning. ... TTX, anhydrotetrodotoxin, 11-deoxytetrodotoxin and trideoxytetrodotoxin were determined in separated tissues of Bangladeshi marine puffers, Takifugu oblongus. TTX was predominant in skin, muscle and liver, whereas trideoxytetrodotoxin preponderated in the ovary. The toxicity of the various tissues was determined by a mouse bioassay.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

为了研究中国渤海地区收集的红鳍东方鲀的毒性与其体内产生河豚毒素的细菌分布之间的关系，从红鳍东方鲀的各个器官（卵巢、肝脏、肠道和胆囊）中分离细菌，并筛选能够产生河豚毒素（TTX）的细菌。在分离出的36株细菌中，有20株能够在体外产生TTX。在毒性更强的卵巢和肝脏器官中，产生TTX的菌株数量和毒性都大于其他器官。根据形态观察、生理生化特性和DNA的G+C含量，大多数产生TTX的细菌菌株被鉴定为芽孢杆菌属（19株）和放线菌属（1株）。通过高效液相色谱法、薄层色谱法和电喷雾电离质谱分析，纯化的毒素被确认为TTX。我们的结果表明，产生TTX的细菌与河豚鱼的毒性密切相关。需要进一步研究以阐明TTX的合成机制及其在细菌中的作用。

To investigate the relationship between the toxicity of puffer fish and the distribution of tetrodotoxin-producing bacteria in puffer fish Fugu rubripes collected from the Bohai Sea of China, bacteria were isolated from each organ (ovaries, livers, intestines and gallbladders) and screened for tetrodotoxin (TTX) production. 20 out of 36 isolated strains were found to produce TTX in vitro. In the organs of ovaries and livers whose toxicity is more potent than other organs, the number and toxicity of TTX-producing strains was greater than that of others. Most TTX-producing bacterial strains were identified as Bacillus spp. (19 strains) and Actinomycete spp. (1 strain) based on the morphological observation, physiological and biochemical characteristics and G+C content of DNA. The purified toxin was identified to be TTX by high performance liquid chromatography assay, thin-layer chromatography assay and electrospray ionization mass spectrometry analysis. Our results suggested that TTX-producing bacteria are closely related to the toxification of the puffer fish. More research is needed to elucidate the mechanism of TTX synthesis and the role of TTX in bacteria.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

河豚肝脏匀浆通过差速离心法被分离成血细胞、核、线粒体、微粒体和胞浆组分。通过高效液相色谱（HPLC）和液相色谱-快速原子轰击质谱（LC-FABMS）分析表明，河豚毒素是每个组分中的主要有毒成分。这些结果揭示河豚毒素在肝细胞器中广泛分布，尽管主要存在于胞浆组分中。

The liver homogenate of puffer fish was fractionated into blood cell, nuclear, mitochondrial, microsomal and cytosol fractions by the differential centrifugation method. ... Analyses by HPLC and LC-FABMS demonstrated that tetrodotoxin is the major toxic principle in each fraction. These results reveal that tetrodotoxin is widely distributed in organelles in liver cells, though predominantly in the cytosol fraction.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(a)
• 危险品标志：
  T+
• 安全说明：
  S22,S36/37/39,S45
• 危险类别码：
  R26/27/28
• WGK Germany：
  3
• 海关编码：
  30029090
• 危险品运输编号：
  UN 3462 6.1/PG 1
• RTECS号：
  IO1450000
• 包装等级：
  I
• 危险类别：
  6.1(a)

制备方法与用途

河豚毒素是一种极具毒性的物质，主要存在于河豚鱼类的血液、卵巢、皮肤和肝脏等部位。它的毒性主要通过抑制神经传导来实现，特别是对神经轴索膜对钠离子的透过作用产生阻断，从而影响神经系统功能。

河豚毒素的主要特点

1. 极高的毒性：河豚毒素是目前已知自然界中最毒的非蛋白物质之一，其毒性远超许多其他剧毒物。
2. 选择性抑制钠通道：它能特异性地阻断神经细胞膜上的电压门控钠通道，阻止动作电位的产生和传导。
3. 对心脏的影响较小：虽然河豚毒素可以引起中毒者感觉障碍、运动麻痹等症状，但对心脏功能影响相对较小。

河豚毒素的临床应用

尽管河豚毒素毒性极大，但它在科学研究中有一定的应用价值：

1. 药理学研究工具：用于研究药物对神经细胞的作用机制。
2. 基础生理研究：帮助科学家更好地理解神经传导和肌肉收缩的基本原理。
3. 镇痛剂替代品：历史上曾被用作局部麻醉或轻度镇痛剂。

河豚毒素中毒的急救措施

1. 立即洗胃、催吐及导泻：使用生理盐水或其他液体清洗消化道，促使毒物尽快排出。
2. 保持呼吸道通畅并提供吸氧：对于呼吸困难者给予氧气支持。
3. 维持水电解质平衡和酸碱平衡：通过静脉输液等方式调节体内环境稳定。
4. 心血管系统的监护和支持治疗：如出现血压下降等情况，可使用升压药物进行干预。

预防措施

为了避免河豚毒素中毒事件的发生，在食用河豚鱼时应严格遵守相关法律法规，并由专业人员处理和烹饪。在民间流传着一些传统疗法用于解救河豚毒素中毒者，但这些方法缺乏科学依据，不能代替正规医疗救治。一旦怀疑或确认发生河豚毒素中毒情况，应立即寻求专业医疗机构的帮助。

总之，尽管河豚毒素具有广泛的应用前景，但由于其高度的危险性，在实际操作中必须格外谨慎，并采取严格的安全防护措施以确保人员安全。

文献信息

• SUBSTITUTED CYCLOHEXYLDIAMINES
  申请人：Zemolka Saskia

  公开号：US20090247591A1

  公开（公告）日：2009-10-01

  The invention relates to compounds that have an affinity to the μ-opioid receptor and the ORL 1-receptor, methods for their production, medications containing these compounds and the use of these compounds for the treatment of pain or other conditions.

  这项发明涉及具有亲和力与μ-阿片受体和ORL 1-受体的化合物，其生产方法，含有这些化合物的药物以及利用这些化合物治疗疼痛或其他疾病的用途。
• INDOLINONE ANALOGUES
  申请人：ENGELHARDT Harald

  公开号：US20140296229A1

  公开（公告）日：2014-10-02

  The present invention encompasses compounds of general formula (I) wherein the groups R 1 to R 4 , A 1 and A 2 have the meanings given in the claims and in the specification. The compounds of the invention are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation pharmaceutical preparations containing such compounds and their uses as a medicament.

  本发明涵盖了一般式（I）的化合物， 其中基团R1至R4，A1和A2具有权利要求和说明书中给定的含义。本发明的化合物适用于治疗以细胞过度或异常增殖为特征的疾病，包括含有这些化合物的药物制剂以及它们作为药物的用途。
• Chemical Compounds
  申请人：Brown Alan Daniel

  公开号：US20120010182A1

  公开（公告）日：2012-01-12

  The invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to new sulfonamide Nav1.7 inhibitors of formula (I): or pharmaceutically acceptable salts thereof, wherein Z 1 , R a , R b , R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the description. Nav 1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, particularly pain.

  该发明涉及磺胺衍生物，其在医学上的应用，含有它们的组合物，其制备方法以及用于这些方法的中间体。 更具体地，该发明涉及公式（I）的新磺胺基Nav1.7抑制剂： 或其药学上可接受的盐，其中Z 1 ，R a ，R b ，R 1 ，R 2 ，R 3 ，R 4 和R 5 如描述中所定义。 Nav 1.7抑制剂在治疗各种疾病，特别是疼痛方面具有潜在用途。
• [EN] QUINAZOLINES USEFUL AS MODULATORS OF ION CHANNELS<br/>[FR] QUINAZOLINES UTILISEES COMME MODULATEURS DE CANAUX IONIQUES
  申请人：VERTEX PHARMA

  公开号：WO2004078733A1

  公开（公告）日：2004-09-16

  The present invention relates to quinazoline compounds of formula (I) useful as inhibitors of voltage-gated sodium channels and calcium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. or a pharmaceutically acceptable derivative thereof, wherein R1, X, R3, x, and ring A are as defined in the present application.

  本发明涉及式（I）的喹唑啉化合物，其作为电压门控钠通道和钙通道的抑制剂。该发明还提供了包括本发明化合物的药学上可接受的组合物，以及使用这些组合物治疗各种疾病的方法。或其药学上可接受的衍生物，其中R1、X、R3、x和环A如本申请中所定义。
• TREPROSTINIL PRODRUGS
  申请人：United Therapeutics Corporation

  公开号：US20210054009A1

  公开（公告）日：2021-02-25

  Provided are novel prodrugs of treprostinil, as well as methods of making and methods of using these prodrugs.

  提供了特瑞普罗斯汀的新型前药，以及制备这些前药的方法和使用这些前药的方法。