(1R,5R,6R,9S,11R,13S)-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

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: (1R,5R,6R,9S,11R,13S)-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
• 化学式: C₁₁H₁₇N₃O₈
• 分子量: 319.27
• InChiKey: CFMYXEVWODSLAX-CKYAAQHSSA-N

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

四度otoxin的代谢来源尚不确定。没有发现藻类来源，直到最近，四度otoxin还被认为是宿主的代谢产物。然而，最近有报道称，包括Vibrionaceae家族的菌株、Pseudomonas sp.和Photobacterium phosphoreum在内的几种细菌能够产生四度otoxin/无水四度otoxin，这一发现指向了这类毒素的细菌来源。

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）比较了含有不同浓度TTX及其衍生物的河豚鱼，包括红鳍东方鲀Takifugu chrysops和黑斑东方鲀Takifugu niphobles的肝脏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，flp-1、flp-2和flp-3组成。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是否能够通过被动免疫提供对致命TTX挑战的保护。T20G10单克隆抗体对TTX的亲和力估计约为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中不发生反应。T20G10在体外放射性配体受体结合分析中特异性地抑制TTX的结合，但对麻痹毒素在大鼠脑膜上钠通道的结合没有影响。在预防研究中，小鼠在腹腔注射TTX挑战（10 ug/kg）前30分钟通过尾静脉给予T20G10。在这些条件下，100微克的T20G10保护了6/6只小鼠，而50微克的T20G10保护了3/6只小鼠。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只小鼠在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只小鼠的死亡。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毫克/千克，静脉注射）和河豚毒素（2微克/千克，静脉注射）显示出显著的抗心律失常活性。在剂量降低2倍时，单独使用这两种物质对心律失常没有影响，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，只有迈门辛标本的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)在海生和陆生动物中广泛分布，可引起危险的中毒。这些高潜能的毒素也被认为是河豚鱼中毒的致病因素。在孟加拉国的海洋河豚，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

为了研究中国渤海海域收集的红鳍东方鲀（河豚鱼）体内河豚毒素产生细菌的分布与其毒性之间的关系，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，并筛选河豚毒素（TTX）的产生。在分离的36株细菌中，有20株在体外能够产生TTX。在毒性较强的卵巢和肝脏中，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离子化质谱分析，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)