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| tetrodotoxin |
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| CHEBI:9506 |
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| A quinazoline alkaloid that is a marine toxin isolated from fish such as puffer fish. It has been shown to exhibit potential neutotoxicity due to its ability to block voltage-gated sodium channels. |
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This entity has been manually annotated by the ChEBI Team.
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| ZINC000035941545 |
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Molfile
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SDF
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more structures >>
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0 M END): 17 ms reading 39 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. 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| Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an order that includes pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Although tetrodotoxin was discovered in these fish, it is found in several other animals (e.g., in blue-ringed octopuses, rough-skinned newts, and moon snails). It is also produced by certain infectious or symbiotic bacteria like Pseudoalteromonas, Pseudomonas, and Vibrio as well as other species found in symbiotic relationships with animals and plants.
Although it produces thousands of intoxications annually and several deaths, it has shown efficacy for the treatment of cancer-related pain in phase II and III clinical trials.
Tetrodotoxin is a sodium channel blocker. It inhibits the firing of action potentials in neurons by binding to the voltage-gated sodium channels in nerve cell membranes and blocking the passage of sodium ions (responsible for the rising phase of an action potential) into the neuron. This prevents the nervous system from carrying messages and thus muscles from contracting in response to nervous stimulation.
Its mechanism of action – selective blocking of the sodium channel – was shown definitively in 1964 by Toshio Narahashi and John W. Moore at Duke University, using the sucrose gap voltage clamp technique.
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Read full article at Wikipedia
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InChI=1S/C11H17N3O8/c12- 8-13-6(17)2-4-9(19,1-15)5-3(16)10(2,14-8)7(18)11(20,21-4)22-5/h2-7,15-20H,1H2,(H3,12,13,14)/t2-,3+,4-,5+,6-,7+,9+,10-,11+/m1/s1 |
| CFMYXEVWODSLAX-QYIGHCJRSA-N |
| OC[C@@]1(O)[C@H]2O[C@@]3(O)O[C@@H]1[C@@H]1[C@@H](O)NC(=N)N[C@]1([C@H]2O)[C@@H]3O |
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Lagocephalus sceleratus
(NCBI:txid229057)
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See:
PubMed
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Crassostrea gigas
(NCBI:txid29159)
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See:
PubMed
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marine metabolite
Any metabolite produced during a metabolic reaction in marine macro- and microorganisms.
animal metabolite
Any eukaryotic metabolite produced during a metabolic reaction in animals that include diverse creatures from sponges, insects to mammals.
bacterial metabolite
Any prokaryotic metabolite produced during a metabolic reaction in bacteria.
voltage-gated sodium channel blocker
Any sodium channel blocker that interferes with the activity of voltage-gated sodium channels.
neurotoxin
A poison that interferes with the functions of the nervous system.
metabolite
Any intermediate or product resulting from metabolism. The term 'metabolite' subsumes the classes commonly known as primary and secondary metabolites.
(via alkaloid )
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View more via ChEBI Ontology
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Outgoing
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tetrodotoxin
(CHEBI:9506)
has role
animal metabolite
(CHEBI:75767)
tetrodotoxin
(CHEBI:9506)
has role
bacterial metabolite
(CHEBI:76969)
tetrodotoxin
(CHEBI:9506)
has role
marine metabolite
(CHEBI:76507)
tetrodotoxin
(CHEBI:9506)
has role
neurotoxin
(CHEBI:50910)
tetrodotoxin
(CHEBI:9506)
has role
voltage-gated sodium channel blocker
(CHEBI:38634)
tetrodotoxin
(CHEBI:9506)
is a
azatetracycloalkane
(CHEBI:39266)
tetrodotoxin
(CHEBI:9506)
is a
oxatetracycloalkane
(CHEBI:39267)
tetrodotoxin
(CHEBI:9506)
is a
quinazoline alkaloid
(CHEBI:36470)
tetrodotoxin
(CHEBI:9506)
is conjugate base of
tetrodotoxin(1+)
(CHEBI:180459)
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Incoming
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(+/-)-tetrodotoxin
(CHEBI:209255)
has functional parent
tetrodotoxin
(CHEBI:9506)
(11s,13s)-3-amino-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.1~7,11~.0~1,6~]tetradec-3-ene-5,9,12,13,14-pentol
(CHEBI:229828)
has functional parent
tetrodotoxin
(CHEBI:9506)
(11S,13S)-3-Amino-5,12,13,14-tetrahydroxy-14-(hydroxymethyl)-8,10-dioxa-2-aza-4-azoniatetracyclo[7.3.1.17,11.01,6]tetradec-3-en-9-olate
(CHEBI:182163)
has functional parent
tetrodotoxin
(CHEBI:9506)
Anhydrotetrodotoxin
(CHEBI:221694)
has functional parent
tetrodotoxin
(CHEBI:9506)
tetrodotoxin(1+)
(CHEBI:180459)
is conjugate acid of
tetrodotoxin
(CHEBI:9506)
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(1R,5R,6R,7R,9S,11R,12R,13S,14S)-14-(hydroxymethyl)-3-imino-8,10-dioxa-2,4-diazatetracyclo[7.3.1.17,11.01,6]tetradecane-5,9,12,13,14-pentol
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Babylonia japonica toxin 1
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ChemIDplus
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BJT 1
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ChemIDplus
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fugu poison
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ChemIDplus
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maculotoxin
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ChemIDplus
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octahydro-12-(hydroxymethyl)-2-imino-5,9:7,10a-dimethano-10aH-[1,3]dioxocino[6,5-d]pyrimidine-4,7,10,11,12-pentol
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ChEBI
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spheroidine
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ChemIDplus
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tarichatoxin
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ChemIDplus
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tetrodontoxin
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ChemIDplus
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Tetrodotoxin
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KEGG COMPOUND
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tetrodotoxine
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ChemIDplus
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TTX
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KEGG COMPOUND
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4156319
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Beilstein Registry Number
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Beilstein
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4368-28-9
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CAS Registry Number
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KEGG COMPOUND
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4368-28-9
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CAS Registry Number
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ChemIDplus
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6072946
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Reaxys Registry Number
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Reaxys
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Alhatali B, Al Lawatia S, Khamis F, Kantur S, Al-Abri S, Kapil V, Thomas J, Johnson R, Hamelin EI, Coleman RM, Kazzi Z (2022)
A cluster of tetrodotoxin poisoning in Oman.
Clinical toxicology (Philadelphia, Pa.) 60, 262-266 [PubMed:33913398]
[show Abstract]
IntroductionTetrodotoxin (TTX) is a potent sodium channel blocker, with significant neurotoxicity, found in marine animals like pufferfish and blue-ringed octopus. The severity of toxicity depends on the amount of toxin ingested and the outcome depends on the time-lapse to appropriate medical care.Cases reportWe report five patients who presented with tetrodotoxin poisoning after consuming fried internal organs of local pufferfish from the coast of Oman. The patients' clinical manifestations were consistent with the expected TTX toxidrome of perioral and generalized paresthesia, weakness of upper and lower extremities, gastrointestinal manifestations, dyspnea, dysarthria, ascending paralysis, hypotension, bradycardia and coma. The severity varied among the patients who recovered completely except one patient who developed a subarachnoid hemorrhage without underlying aneurysms on computed tomography-angiogram. This complication was potentially related to TTX poisoning and has not been previously reported. In addition to standard supportive management, patients with severe illness should potentially receive the intravenous acetylcholinesterase inhibitor neostigmine, and intermittent dialysis. Urine specimens were sent to CDC in Atlanta, where they were analyzed using online solid phase extraction (SPE) with LC-MS/MS and confirmed the diagnosis in all five cases.DiscussionIn general, the patients' clinical manifestations were consistent with the expected TTX toxidrome except patient 3 who developed a subarachnoid hemorrhage early during his clinical course. Two patients received neostigmine and underwent dialysis with complete recovery. | Okabe T, Saito R, Yamamoto K, Watanabe R, Kaneko Y, Yanaoka M, Furukoshi S, Yasukawa S, Ito M, Oyama H, Suo R, Suzuki M, Takatani T, Arakawa O, Sugita H, Itoi S (2021)
The role of toxic planocerid flatworm larvae on tetrodotoxin accumulation in marine bivalves.
Aquatic toxicology (Amsterdam, Netherlands) 237, 105908 [PubMed:34273772]
[show Abstract]
Tetrodotoxin (TTX), also known as pufferfish toxin, has been detected in marine edible bivalves worldwide. In this study, several bivalve species, Azumapecten farreri subsp. akazara, Patinopecten yessoensis and Mytilus galloprovincialis, collected from the Pacific side of the northern Japanese Islands, were studied for the accumulation of TTX in the presence of toxic planocerid larvae. LC-MS/MS analysis demonstrated that TTX was detected only in the midgut gland of A. farreri subsp. akazara. Toxic flatworm-specific PCR and direct sequencing of the amplicons showed that the DNA fragments of the Planocera multitentaculata COI gene were detected in the gut contents of the toxified bivalves. The planocerid larvae were also detected in the environmental seawaters. Toxification experiments in the aquarium demonstrated that the mussel M. galloprovincialis was also toxified by feeding on the toxic flatworm larvae. These results suggest that the source of TTX accumulation in edible bivalves is toxic flatworm larvae. | Nakamura M, Jang IS (2021)
Propranolol modulation of tetrodotoxin-resistant Na+ channels in dural afferent neurons.
European journal of pharmacology 910, 174449 [PubMed:34454925]
[show Abstract]
Propranolol, a representative adrenergic β-receptor antagonist, is widely used to prevent migraine attacks. Although propranolol is well known to inhibit tetrodotoxin-resistant (TTX-R) Na+ channels in cardiac myocytes, it is unclear whether the drug modulates these channels expressed in dural afferent neurons. In this study, we examined the effects of propranolol on TTX-R Na+ channels in medium-sized dural afferent neurons identified by the fluorescent dye DiI. The TTX-R Na+ currents (INa) were recorded from acutely isolated DiI-positive neurons using a whole-cell patch clamp technique under voltage-clamp conditions. Propranolol inhibited the noninactivating steady-state component more potently than the peak component of transient TTX-R INa. Propranolol also potently inhibited the slow voltage ramp-induced TTX-R INa in a concentration-dependent manner, suggesting that it preferentially inhibited the noninactivating or persistent INa in DiI-positive neurons. Propranolol had little effect on voltage dependence, but it increased the extent of the use-dependent inhibition of TTX-R Na+ channels. Propranolol also accelerated the onset of inactivation and retarded recovery from inactivation in these channels. Under current-clamp conditions, propranolol decreased the number of action potentials elicited by depolarizing current stimuli. In conclusion, the propranolol-mediated preferential inhibition of persistent INa and modulation of the inactivation kinetics of TTX-R Na+ channels might represent additional mechanisms for migraine prophylaxis. | Dhanji-Rapkova M, Turner AD, Baker-Austin C, Huggett JF, Ritchie JM (2021)
Distribution of Tetrodotoxin in Pacific Oysters (Crassostrea gigas).
Marine drugs 19, 84 [PubMed:33540777]
[show Abstract]
A potent and heat-stable tetrodotoxin (TTX) has been found to accumulate in various marine bivalve species, including Pacific oysters (Crassostrea gigas), raising a food safety concern. While several studies on geographical occurrence of TTX have been conducted, there is a lack of knowledge about the distribution of the toxin within and between bivalves. We, therefore, measured TTX in the whole flesh, mantle, gills, labial palps, digestive gland, adductor muscle and intravalvular fluid of C. gigas using liquid chromatography-tandem mass spectrometry. Weekly monitoring during summer months revealed the highest TTX concentrations in the digestive gland (up to 242 µg/kg), significantly higher than in other oyster tissues. Intra-population variability of TTX, measured in the whole flesh of each of twenty animals, reached 46% and 32% in the two separate batches, respectively. In addition, an inter-population study was conducted to compare TTX levels at four locations within the oyster production area. TTX concentrations in the whole flesh varied significantly between some of these locations, which was unexplained by the differences in weight of flesh. This is the first study examining TTX distribution in C. gigas and the first confirmation of the preferential accumulation of TTX in oyster digestive gland. | Biessy L, Smith KF, Wood SA, Tidy A, van Ginkel R, Bowater JRD, Hawes I (2021)
A Microencapsulation Method for Delivering Tetrodotoxin to Bivalves to Investigate Uptake and Accumulation.
Marine drugs 19, 33 [PubMed:33450969]
[show Abstract]
Most marine biotoxins are produced by microalgae. The neurotoxin tetrodotoxin (TTX) has been reported in many seafood species worldwide but its source is unknown, making accumulation and depuration studies in shellfish difficult. Tetrodotoxin is a water-soluble toxin and cannot be directly ingested by shellfish. In the present study, a method was developed which involved binding TTX to solid particles of humic acid and encapsulating them in agar-gelatin capsules. A controlled quantity of TTX-containing microcapsules (size range 20-280 μm) was fed to Paphies australis, a bivalve known to accumulate TTX in the wild. The TTX-containing microcapsules were fed to P. australis every second day for 13 days. Ten P. australis (including five controls fed non-toxic microalgae) were harvested after 7 days and ten after 13 days. Paphies australis accumulated TTX, reaching concentrations of up to 103 µg kg-1 by day 13, exceeding the European Food Safety Authority recommended concentration of 44 μg kg-1 in shellfish. This novel method will allow future studies to explore the effects, accumulation and depuration rates of TTX in different animals and document how it is transferred through food webs. | Boullot F, Fabioux C, Hégaret H, Boudry P, Soudant P, Benoit E (2021)
Electrophysiological Evaluation of Pacific Oyster (Crassostrea gigas) Sensitivity to Saxitoxin and Tetrodotoxin.
Marine drugs 19, 380 [PubMed:34209313]
[show Abstract]
Pacific oysters (Crassostrea gigas) may bio-accumulate high levels of paralytic shellfish toxins (PST) during harmful algal blooms of the genus Alexandrium. These blooms regularly occur in coastal waters, affecting oyster health and marketability. The aim of our study was to analyse the PST-sensitivity of nerves of Pacific oysters in relation with toxin bio-accumulation. The results show that C. gigas nerves have micromolar range of saxitoxin (STX) sensitivity, thus providing intermediate STX sensitivity compared to other bivalve species. However, theses nerves were much less sensitive to tetrodotoxin. The STX-sensitivity of compound nerve action potential (CNAP) recorded from oysters experimentally fed with Alexandrium minutum (toxic-alga-exposed oysters), or Tisochrysis lutea, a non-toxic microalga (control oysters), revealed that oysters could be separated into STX-resistant and STX-sensitive categories, regardless of the diet. Moreover, the percentage of toxin-sensitive nerves was lower, and the STX concentration necessary to inhibit 50% of CNAP higher, in recently toxic-alga-exposed oysters than in control bivalves. However, no obvious correlation was observed between nerve sensitivity to STX and the STX content in oyster digestive glands. None of the nerves isolated from wild and farmed oysters was detected to be sensitive to tetrodotoxin. In conclusion, this study highlights the good potential of cerebrovisceral nerves of Pacific oysters for electrophysiological and pharmacological studies. In addition, this study shows, for the first time, that C. gigas nerves have micromolar range of STX sensitivity. The STX sensitivity decreases, at least temporary, upon recent oyster exposure to dinoflagellates producing PST under natural, but not experimental environment. | Wang XN, Niu MT, Fan JX, Chen QW, Zhang XZ (2021)
Photoelectric Bacteria Enhance the In Situ Production of Tetrodotoxin for Antitumor Therapy.
Nano letters 21, 4270-4279 [PubMed:33955768]
[show Abstract]
Engineered bacteria are promising bioagents to synthesize antitumor drugs at tumor sites with the advantages of avoiding drug leakage and degradation during delivery. Here, we report an optically controlled material-assisted microbial system by biosynthesizing gold nanoparticles (AuNPs) on the surface of Shewanella algae K3259 (S. algae) to obtain Bac@Au. Leveraging the dual directional electron transport mechanism of S. algae, the hybrid biosystem enhances in situ synthesis of antineoplastic tetrodotoxin (TTX) for a promising antitumor effect. Because of tumor hypoxia-targeting feature of facultative anaerobic S. algae, Bac@Au selectively target and colonize at tumor. Upon light irradiation, photoelectrons produced by AuNPs deposited on bacterial surface are transferred into bacterial cytoplasm and participate in accelerated cell metabolism to increase the production of TTX for antitumor therapy. The optically controlled material-assisted microbial system enhances the efficiency of bacterial drug synthesis in situ and provides an antitumor strategy that could broaden conventional therapy boundaries. | Kudo Y, Hanifin CT, Yotsu-Yamashita M (2021)
Identification of Tricyclic Guanidino Compounds from the Tetrodotoxin-Bearing Newt Taricha granulosa.
Organic letters 23, 3513-3517 [PubMed:33830775]
[show Abstract]
The biosynthesis of the potent neurotoxin tetrodotoxin (TTX, 1) is still unresolved. We used MS-guided screening and nuclear magnetic resonance analyses including long-range HSQMBC to characterize two novel skeletal tricyclic guanidino compounds, Tgr-288 (2a and 2b) and Tgr-210 (3), from the TTX-bearing newt, Taricha granulosa. The presence of these compounds in toxic newts is congruent with a previously proposed pathway for TTX biosynthesis in terrestrial organisms that includes a monoterpene precursor and the production of structurally diversified guanidino compounds. | Martinez-Espinosa PL, Yang C, Xia XM, Lingle CJ (2021)
Nav1.3 and FGF14 are primary determinants of the TTX-sensitive sodium current in mouse adrenal chromaffin cells.
The Journal of general physiology 153, e202012785 [PubMed:33651884]
[show Abstract]
Adrenal chromaffin cells (CCs) in rodents express rapidly inactivating, tetrodotoxin (TTX)-sensitive sodium channels. The resulting current has generally been attributed to Nav1.7, although a possible role for Nav1.3 has also been suggested. Nav channels in rat CCs rapidly inactivate via two independent pathways which differ in their time course of recovery. One subpopulation recovers with time constants similar to traditional fast inactivation and the other ∼10-fold slower, but both pathways can act within a single homogenous population of channels. Here, we use Nav1.3 KO mice to probe the properties and molecular components of Nav current in CCs. We find that the absence of Nav1.3 abolishes all Nav current in about half of CCs examined, while a small, fast inactivating Nav current is still observed in the rest. To probe possible molecular components underlying slow recovery from inactivation, we used mice null for fibroblast growth factor homology factor 14 (FGF14). In these cells, the slow component of recovery from fast inactivation is completely absent in most CCs, with no change in the time constant of fast recovery. The use dependence of Nav current reduction during trains of stimuli in WT cells is completely abolished in FGF14 KO mice, directly demonstrating a role for slow recovery from inactivation in determining Nav current availability. Our results indicate that FGF14-mediated inactivation is the major determinant defining use-dependent changes in Nav availability in CCs. These results establish that Nav1.3, like other Nav isoforms, can also partner with FGF subunits, strongly regulating Nav channel function. | Goldlust SA, Kavoosi M, Nezzer J, Kavoosi M, Korz W, Deck K (2021)
Tetrodotoxin for Chemotherapy-Induced Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Dose Finding Trial.
Toxins 13, 235 [PubMed:33805908]
[show Abstract]
Tetrodotoxin (TTX) has emerged as a potentially efficacious agent for chemotherapy-induced neuropathic pain (CINP), a prevalent, debilitating condition often resistant to analgesics. This randomized, double-blind, dose-finding study was undertaken to explore safety and trends in efficacy of four TTX doses and to identify a dose for further study. One hundred and twenty-five patients with taxane- or platinum-related CINP received subcutaneous placebo or TTX (7.5 µg twice daily (BID), 15 µg BID, 30 µg once daily (QD), 30 µg BID) for four consecutive days. Primary outcome measure was average patient-reported Numeric Pain Rating Scale (NPRS) score during Days 21-28 post-treatment. Changes in mean NPRS score were not statistically different between cohorts, due to small trial size and influence of a few robust placebo responders. Cumulative responder analysis showed significant difference from placebo with 30 µg BID cohort using the maximum response at any timepoint (p = 0.072), 5-day (p = 0.059), 10-day (p = 0.027), and 20-day (p = 0.071) rolling averages. In secondary quality of life (QOL) outcomes, 30 µg BID cohort also differed significantly from placebo in a number of SF-36 and CIPN20 subscales. Most adverse events (AE) were mild or moderate with oral paresthesia (29.6%) and oral hypoesthesia (24.8%) as most common. | Costa PR, Giráldez J, Rodrigues SM, Leão JM, Pinto E, Soliño L, Gago-Martínez A (2021)
High Levels of Tetrodotoxin (TTX) in Trumpet Shell Charonia lampas from the Portuguese Coast.
Toxins 13, 250 [PubMed:33807311]
[show Abstract]
Tetrodotoxin (TTX) is a potent neurotoxin, considered an emerging toxin in Europe where recently a safety limit of 44 µg TTX kg-1 was recommended by authorities. In this study, three specimens of the large gastropod trumpet shell Charonia lampas bought in a market in south Portugal were analyzed using a neuroblastoma cell (N2a) based assay and by LC-MS/MS. N2a toxicity was observed in the viscera of two individuals analyzed and LC-MS/MS showed very high concentrations of TTX (42.1 mg kg-1) and 4,9-anhydroTTX (56.3 mg kg-1). A third compound with m/z 318 and structurally related with TTX was observed. In the edible portion, i.e., the muscle, toxin levels were below the EFSA recommended limit. This study shows that trumpet shell marine snails are seafood species that may reach the markets containing low TTX levels in the edible portion but containing very high levels of TTX in non-edible portion raising concerns regarding food safety if a proper evisceration is not carried out by consumers. These results highlight the need for better understanding TTX variability in this gastropod species, which is critical to developing a proper legal framework for resources management ensuring seafood safety, and the introduction of these gastropods in the markets. | Li CL, Yang R, Sun Y, Feng Y, Song YB (2021)
N58A Exerts Analgesic Effect on Trigeminal Neuralgia by Regulating the MAPK Pathway and Tetrodotoxin-Resistant Sodium Channel.
Toxins 13, 357 [PubMed:34067828]
[show Abstract]
The primary studies have shown that scorpion analgesic peptide N58A has a significant effect on voltage-gated sodium channels (VGSCs) and plays an important role in neuropathic pain. The purpose of this study was to investigate the analgesic effect of N58A on trigeminal neuralgia (TN) and its possible mechanism. The results showed that N58A could significantly increase the threshold of mechanical pain and thermal pain and inhibit the spontaneous asymmetric scratching behavior of rats. Western blotting results showed that N58A could significantly reduce the protein phosphorylation level of ERK1/2, P38, JNK, and ERK5/CREB pathways and the expression of Nav1.8 and Nav1.9 proteins in a dose-dependent manner. The changes in current and kinetic characteristics of Nav1.8 and Nav1.9 channels in TG neurons were detected by the whole-cell patch clamp technique. The results showed that N58A significantly decreased the current density of Nav1.8 and Nav1.9 in model rats, and shifted the activation curve to hyperpolarization and the inactivation curve to depolarization. In conclusion, the analgesic effect of N58A on the chronic constriction injury of the infraorbital (IoN-CCI) model rats may be closely related to the regulation of the MAPK pathway and Nav1.8 and Nav1.9 sodium channels. | Melnikova DI, Nijland R, Magarlamov TY (2021)
The First Data on the Complete Genome of a Tetrodotoxin-Producing Bacterium.
Toxins 13, 410 [PubMed:34207879]
[show Abstract]
Tetrodotoxin (TTX)-producing bacteria have attracted great interest as a model system for study of the TTX biosynthetic route. Here, we report the complete genome of the TTX-producing bacterium Bacillus sp. 1839. The genome of the strain Bacillus sp. 1839, previously isolated from the TTX-bearing marine ribbon worm Cephalothrix cf. simula, was obtained using second generation Illumina and third generation nanopore sequencing technologies. Phylogenetic analysis has classified this strain as Cytobacillus gottheilii. | González-Cano R, Ruiz-Cantero MC, Santos-Caballero M, Gómez-Navas C, Tejada MÁ, Nieto FR (2021)
Tetrodotoxin, a Potential Drug for Neuropathic and Cancer Pain Relief?
Toxins 13, 483 [PubMed:34357955]
[show Abstract]
Tetrodotoxin (TTX) is a potent neurotoxin found mainly in puffer fish and other marine and terrestrial animals. TTX blocks voltage-gated sodium channels (VGSCs) which are typically classified as TTX-sensitive or TTX-resistant channels. VGSCs play a key role in pain signaling and some TTX-sensitive VGSCs are highly expressed by adult primary sensory neurons. During pathological pain conditions, such as neuropathic pain, upregulation of some TTX-sensitive VGSCs, including the massive re-expression of the embryonic VGSC subtype NaV1.3 in adult primary sensory neurons, contribute to painful hypersensitization. In addition, people with loss-of-function mutations in the VGSC subtype NaV1.7 present congenital insensitive to pain. TTX displays a prominent analgesic effect in several models of neuropathic pain in rodents. According to this promising preclinical evidence, TTX is currently under clinical development for chemo-therapy-induced neuropathic pain and cancer-related pain. This review focuses primarily on the preclinical and clinical evidence that support a potential analgesic role for TTX in these pain states. In addition, we also analyze the main toxic effects that this neurotoxin produces when it is administered at therapeutic doses, and the therapeutic potential to alleviate neuropathic pain of other natural toxins that selectively block TTX-sensitive VGSCs. | Campos-Ríos A, Rueda-Ruzafa L, Herrera-Pérez S, Rivas-Ramírez P, Lamas JA (2021)
Tetrodotoxin: A New Strategy to Treat Visceral Pain?
Toxins 13, 496 [PubMed:34357968]
[show Abstract]
Visceral pain is one of the most common symptoms associated with functional gastrointestinal (GI) disorders. Although the origin of these symptoms has not been clearly defined, the implication of both the central and peripheral nervous systems in visceral hypersensitivity is well established. The role of several pathways in visceral nociception has been explored, as well as the influence of specific receptors on afferent neurons, such as voltage-gated sodium channels (VGSCs). VGSCs initiate action potentials and dysfunction of these channels has recently been associated with painful GI conditions. Current treatments for visceral pain generally involve opioid based drugs, which are associated with important side-effects and a loss of effectiveness or tolerance. Hence, efforts have been intensified to find new, more effective and longer-lasting therapies. The implication of VGSCs in visceral hypersensitivity has drawn attention to tetrodotoxin (TTX), a relatively selective sodium channel blocker, as a possible and promising molecule to treat visceral pain and related diseases. As such, here we will review the latest information regarding this toxin that is relevant to the treatment of visceral pain and the possible advantages that it may offer relative to other treatments, alone or in combination. | Bucciarelli GM, Lechner M, Fontes A, Kats LB, Eisthen HL, Shaffer HB (2021)
From Poison to Promise: The Evolution of Tetrodotoxin and Its Potential as a Therapeutic.
Toxins 13, 517 [PubMed:34437388]
[show Abstract]
Tetrodotoxin (TTX) is a potent neurotoxin that was first identified in pufferfish but has since been isolated from an array of taxa that host TTX-producing bacteria. However, determining its origin, ecosystem roles, and biomedical applications has challenged researchers for decades. Recognized as a poison and for its lethal effects on humans when ingested, TTX is primarily a powerful sodium channel inhibitor that targets voltage-gated sodium channels, including six of the nine mammalian isoforms. Although lethal doses for humans range from 1.5-2.0 mg TTX (blood level 9 ng/mL), when it is administered at levels far below LD50, TTX exhibits therapeutic properties, especially to treat cancer-related pain, neuropathic pain, and visceral pain. Furthermore, TTX can potentially treat a variety of medical ailments, including heroin and cocaine withdrawal symptoms, spinal cord injuries, brain trauma, and some kinds of tumors. Here, we (i) describe the perplexing evolution and ecology of tetrodotoxin, (ii) review its mechanisms and modes of action, and (iii) offer an overview of the numerous ways it may be applied as a therapeutic. There is much to be explored in these three areas, and we offer ideas for future research that combine evolutionary biology with therapeutics. The TTX system holds great promise as a therapeutic and understanding the origin and chemical ecology of TTX as a poison will only improve its general benefit to humanity. | Murakami K, Toma T, Fukuyama T, Yokoshima S (2020)
Total Synthesis of Tetrodotoxin.
Angewandte Chemie (International ed. in English) 59, 6253-6257 [PubMed:31985136]
[show Abstract]
A total synthesis of tetrodotoxin was accomplished. A Diels-Alder reaction between a known enone and a siloxy diene gave a tricyclic product, the steric bias of which was used to construct the remaining stereogenic centers. A nitrogen atom was introduced either by a four-step sequence involving a Curtius rearrangement, or a three-step sequence featuring a newly developed transformation of a terminal alkyne into a nitrile. Introduction of the guanidine moiety followed by the formation of the heterocyclic system by cascade reactions led to tetrodotoxin. | Thuy LV, Yamamoto S, Kawaura R, Takemura N, Yamaki K, Yasumoto K, Takada K, Watabe S, Sato S (2020)
Tissue distribution of tetrodotoxin and its analogs in Lagocephalus pufferfish collected in Vietnam
Fisheries science : FS 86, 1101-1110 [Agricola:IND607175662]
[show Abstract]
Pufferfish belonging to Lagocephalus are composed of several species, some of which have been recognized to be non-toxic. Although fish belonging to this genus inhabit a wide variety of seawaters from temperate to tropical, toxin distribution has remained unclear. The present study was conducted to thoroughly survey the presence of tetrodotoxin (TTX) and its analogs (TTXs) in the extracts from various tissues of Lagocephalus pufferfish, including L. spadiceus, L. cheesemanii, L. lunaris, and L. inermis collected in Vietnam, by using the TTX enzyme-linked immunosorbent assay (ELISA) kit. Analyses using the TTX-ELISA kit demonstrated the presence of a considerable amount of TTXs in the extracts prepared from various tissues and organs of Lagocephalus pufferfish. TTX was detected in gonads and intestine of L. cheesemanii as well as L. lunaris by high performance liquid chromatography with fluorescence detection, but not in any tissues and organs of L. spadiceus. The extract from muscle of L. spadiceus was further subjected to liquid chromatography-mass spectrometry analyses to investigate toxin components, revealing the presence of a high amount of 5,6,11-trideoxyTTX (TDT), but no TTX. Since the toxicity of TDT is very weak, L. spadiceus muscle was regarded to be non-toxic as far as samples collected in the present study are concerned. | Biessy L, Pearman JK, Smith KF, Hawes I, Wood SA (2020)
Seasonal and Spatial Variations in Bacterial Communities From Tetrodotoxin-Bearing and Non-tetrodotoxin-Bearing Clams.
Frontiers in microbiology 11, 1860 [PubMed:32849450]
[show Abstract]
Tetrodotoxin (TTX) is one of the most potent naturally occurring compounds and is responsible for many human intoxications worldwide. Paphies australis are endemic clams to New Zealand which contain varying concentrations of TTX. Research suggests that P. australis accumulate the toxin exogenously, but the source remains uncertain. The aim of this study was to identify potential bacterial TTX-producers by exploring differences in bacterial communities in two organs of P. australis: the siphon and digestive gland. Samples from the digestive glands of a non-toxic bivalve Austrovenus stutchburyi that lives amongst toxic P. australis populations were also analyzed. Bacterial communities were characterized using 16S ribosomal RNA gene metabarcoding in P. australis sourced monthly from the Hokianga Harbor, a site known to have TTX-bearing clams, for 1 year, from ten sites with varying TTX concentrations around New Zealand, and in A. stutchburyi from the Hokianga Harbor. Tetrodotoxin was detected in P. australis from sites all around New Zealand and in all P. australis collected monthly from the Hokianga Harbor. The toxin averaged 150 μg kg-1 over the year of sampling in the Hokianga Harbor but no TTX was detected in the A. stutchburyi samples from the same site. Bacterial species diversity differed amongst sites (p < 0.001, F = 5.9) and the diversity in siphon samples was significantly higher than in digestive glands (p < 0.001, F = 65.8). Spirochaetaceae (4-60%) and Mycoplasmataceae (16-78%) were the most abundant families in the siphons and the digestive glands, respectively. The bacterial communities were compared between sites with the lowest TTX concentrations and the Hokianga Harbor (site with the highest TTX concentrations), and the core bacterial communities from TTX-bearing individuals were analyzed. The results from both spatial and temporal studies corroborate with previous hypotheses that Vibrio and Bacillus could be responsible for the source of TTX in bivalves. The results from this study also indicate that marine cyanobacteria, in particular picocyanobacteria (e.g., Cyanobium, Synechococcus, Pleurocapsa, and Prochlorococcus), should be investigated further as potential TTX producers. | Kashitani M, Okabe T, Oyama H, Noguchi K, Yamazaki H, Suo R, Mori T, Sugita H, Itoi S (2020)
Taxonomic Distribution of Tetrodotoxin in Acotylean Flatworms (Polycladida: Platyhelminthes).
Marine biotechnology (New York, N.Y.) 22, 805-811 [PubMed:32415408]
[show Abstract]
Tetrodotoxin (TTX), also known as pufferfish toxin, causes a respiratory disorder by blocking neurotransmission, with voltage-gated sodium channel inhibition on muscle and nerve tissues. The toxin is widely distributed across vertebrates, invertebrates and bacteria. Therefore, it is generally thought that TTX in pufferfish accumulates via the food webs, beginning with marine bacteria as a primary producer. Polyclad flatworms in the genus Planocera are also known to be highly toxic, TTX-bearing organisms. Unlike the case of pufferfish, the source of TTX in these flatworms is unknown. In this study, taxonomical distribution patterns of TTX were investigated for acotylean flatworms from coastal waters using molecular phylogenetic analysis and high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). A maximum likelihood tree based on the 28S rRNA gene sequence showed that the flatworms belonged to several different lineages among the genera Planocera, Stylochus, Paraplanocera, Discocelis, Notocomplana, Notoplana, Callioplana and Peudostylochus. After LC-MS/MS analysis, the distribution of TTX was mapped onto the molecular phylogenetic tree. TTX-bearing flatworm species were seen to be restricted to specific Planocera lineages, suggesting that the TTX-bearing flatworm species have common genes for TTX-accumulating mechanisms. | Melnikova DI, Magarlamov TY (2020)
The Microbial Community of Tetrodotoxin-Bearing and Non-Tetrodotoxin-Bearing Ribbon Worms (Nemertea) from the Sea of Japan.
Marine drugs 18, E177 [PubMed:32210160]
[show Abstract]
A potent marine toxin, tetrodotoxin (TTX), found in a great variety of marine and some terrestrial species, leaves intriguing questions about its origin and distribution in marine ecosystems. TTX-producing bacteria were found in the cultivable microflora of many TTX-bearing hosts, thereby providing strong support for the hypothesis that the toxin is of bacterial origin in these species. However, metagenomic studies of TTX-bearing animals addressing the whole microbial composition and estimating the contribution of TTX-producing bacteria to the overall toxicity of the host were not conducted. The present study is the first to characterize and compare the 16S rRNA gene data obtained from four TTX-bearing and four non-TTX-bearing species of marine ribbon worms. The statistical analysis showed that different nemertean species harbor distinct bacterial communities, while members of the same species mostly share more similar microbiomes. The bacterial species historically associated with TTX production were found in all studied samples but predominated in TTX-bearing nemertean species. This suggests that deeper knowledge of the microbiome of TTX-bearing animals is a key to understanding the origin of TTX in marine ecosystems. | Akbora HD, Kunter İ, Erçeti N T, Elagöz AM, Çi Çek BA (2020)
Determination of tetrodotoxin (TTX) levels in various tissues of the silver cheeked puffer fish (Lagocephalus sceleratus (Gmelin, 1789)) in Northern Cyprus Sea (Eastern Mediterranean).
Toxicon : official journal of the International Society on Toxinology 175, 1-6 [PubMed:31833474]
[show Abstract]
Lagocephalus sceleratus from the family Tetraodontidae, which is originated from the Red Sea, started to migrate to Mediterranean waters after the opening of the Suez Channel in 1869. Since they do not have any predators in the Mediterranean Sea, their population increased in number very fast. Different tissues of L. sceleratus have tetrodotoxin (TTX). TTX is a non-protein, heat resistant molecule which binds to voltage-gated sodium channels of musculatory and nervous system. Ingestion of the fish can cause a wide variety of effects from mild toxications to death. This study is the first toxicity report of L. sceleratus for Cyprus. Due to the lack of data on toxicity levels of L. sceleratus, and some cases of poising after the ingestion of the fish were the reasons for the start of this work. 24 L. sceleratus were sampled from 3 different areas to represent Northern Cyprus, during one year period. 16 fish samples selected and grouped into 4 fishes per season for toxicity assay. TTX levels from liver, gonad, intestine, muscle and skin tissue homogenate were analyzed with TTX ELISA. Totally 80 tissues were analyzed, 40% of them were above the toxic limit (2.2 μg/g). Most toxic tissue, according to the seasonal average, was found in the summer season and was determined as; Liver = 13.48 μg/g. Most toxic three fishes were found to be female with a length of 45-60 cm. TTX distribution among tissues have similarities with previously published studies from different regions. | Zou S (2020)
Comparative Transcriptome Analysis of Toxic and Non-Toxic Nassarius Communities and Identification of Genes Involved in TTX-Adaptation.
Toxins 12, E761 [PubMed:33276679]
[show Abstract]
Nassarius has caused serious people poisoning and death incident as a popular food due to tetrodotoxin (TTX) accumulation in their body. Understanding the genetic basis of tetrodotoxin (TTX) transformation and resistance in animals could lead to significant insights into adaptive evolution to toxins and toxin poisoning cures in medicine. Here we performed comparative transcriptome analysis for toxic and non-toxic communities in Nassarius succinctus and Nassarius variciferus to reveal their genetic expression and mutation patterns. For both species, the cellular and metabolic process, and binding and catalytic activity accounted for the top classification categories, and the toxic communities generally produced more up-regulated genes than non-toxic communities. Most unigenes and different expression genes were related to disease, e.g., heat shock protein and tissue factor pathway inhibitors, which involve detoxification and coagulation. In mutation levels, the sodium channel gene of N. succinctus had one amino acid mutation "L", which is different from that of other animals. In conclusion, the comparative transcriptome analysis of different species and populations provided an important genetic basis for adaptive evolution to toxins, health and toxin poisoning cure research for TTX in marine gastropoda mollusk. Future studies will focus on the action mechanism of the important functional gene for TTX accumulation and resistance. | Ling S, Li X, Zhang D, Wang K, Zhao W, Zhao Q, Wang R, Yuan J, Xin S, Wang S (2019)
Detection of okadaic acid (OA) and tetrodotoxin (TTX) simultaneously in seafood samples using colloidal gold immunoassay.
Toxicon : official journal of the International Society on Toxinology 165, 103-109 [PubMed:31029635]
[show Abstract]
Tetrodotoxin (TTX) is a neurotoxin mainly responsible for severe neurological illness, and okadaic acid (OA) is another important lipophilic toxin to humans. In this study, we developed a gold strip for simultaneous detection of OA and TTX in real seafood samples. In the assay, the prepared nanoparticles (about 40 nm) was applied to conjugate with specific monoclonal antibodies against OA and TTX, and the resulted mixtures were used to capture its corresponding toxin in test strip. OA and TTX conjugates were coated as two test lines on the nitrocellulose membrane, and goat anti-mouse IgG was used to form the control line, forming three lines on the test strip. The visual detection limits (vLOD) of this immunoassay for OA and TTX were 0.75 and 15 ng/mL, respectively, and no cross reactions were observed in the process of detection. The visual assay for OA and TTX detection could be finished within 10 min. This study might provide a feasible method and good understanding for rapidly simultaneous detection for toxins based on immunoassay. | EFSA Panel on Contaminants in the Food Chain (CONTAM), Knutsen HK, Alexander J, Barregård L, Bignami M, Brüschweiler B, Ceccatelli S, Cottrill B, Dinovi M, Edler L, Grasl-Kraupp B, Hogstrand C, Hoogenboom LR, Nebbia CS, Oswald IP, Rose M, Roudot AC, Schwerdtle T, Vleminckx C, Vollmer G, Wallace H, Arnich N, Benford D, Botana L, Viviani B, Arcella D, Binaglia M, Horvath Z, Steinkellner H, van Manen M, Petersen A (2017)
Risks for public health related to the presence of tetrodotoxin (TTX) and TTX analogues in marine bivalves and gastropods.
EFSA journal. European Food Safety Authority 15, e04752 [PubMed:32625458]
[show Abstract]
Tetrodotoxin (TTX) and its analogues are produced by marine bacteria and have been detected in marine bivalves and gastropods from European waters. The European Commission asked EFSA for a scientific opinion on the risks to public health related to the presence of TTX and TTX analogues in marine bivalves and gastropods. The Panel on Contaminants in the Food Chain reviewed the available literature but did not find support for the minimum lethal dose for humans of 2 mg, mentioned in various reviews. Some human case reports describe serious effects at a dose of 0.2 mg, corresponding to 4 μg/kg body weight (bw). However, the uncertainties on the actual exposure in the studies preclude their use for derivation of an acute reference dose (ARfD). Instead, a group ARfD of 0.25 μg/kg bw, applying to TTX and its analogues, was derived based on a TTX dose of 25 μg/kg bw at which no apathy was observed in an acute oral study with mice, applying a standard uncertainty factor of 100. Estimated relative potencies for analogues are lower than that of TTX but are associated with a high degree of uncertainty. Based on the occurrence data submitted to EFSA and reported consumption days only, average and P95 exposures of 0.00-0.09 and 0.00-0.03 μg/kg bw, respectively, were calculated. Using a large portion size of 400 g bivalves and P95 occurrence levels of TTX, with exception of oysters, the exposure was below the group ARfD in all consumer groups. A concentration below 44 μg TTX equivalents/kg shellfish meat, based on a large portion size of 400 g, was considered not to result in adverse effects in humans. Liquid chromatography with tandem mass spectroscopy (LC-MS/MS) methods are the most suitable for identification and quantification of TTX and its analogues, with LOQs between 1 and 25 μg/kg. | Wang R, Zeng L, Yang H, Zhong Y, Wang J, Ling S, Saeed AF, Yuan J, Wang S (2017)
Detection of okadaic acid (OA) using ELISA and colloidal gold immunoassay based on monoclonal antibody.
Journal of hazardous materials 339, 154-160 [PubMed:28648727]
[show Abstract]
Okadaic Acid (OA), a small seafood-borne toxin secreted by Dinophysis and Prorocentrum dinoflagellates, is generally distributed in various species of shellfish and has caused diarrhetic shellfish poisoning (DSP). In view of OA toxin threat to humans and animals, it is essential to develop a rapid, accurate and sensitive method for the detection and quantification of OA in real samples. In this study, a monoclonal antibody named 10E8 was screened by cells fusion of Sp2/0 with spleen cells isolated from immunized mouse, and the isotype of McAb 10E8 was belonged to IgG1. The resulted McAb 10E8 displayed higher specificity to OA antigen, with the highest affinity of 2.66×109L/moL until now. Indirect competitive ELISA (ic-ELISA) indicated that the linear range to detect OA was 20-750ng/mL. The limit of detection (LOD) was 12pg/mL, and the recovery average was (84.04±5.08)%. The LOD of colloidal gold immunoassay by naked eye and strip reader was 1ng/mL and 100pg/mL, respectively, with an average recovery of (88.0275±4.4225)%. Therefore, the developed ELISA and colloidal gold immunoassay based on this McAb can be used for OA detection in real samples. | Saeed AFUH, Ling S, Yuan J, Wang S (2017)
The Preparation and Identification of a Monoclonal Antibody against Domoic Acid and Establishment of Detection by Indirect Competitive ELISA.
Toxins 9, E250 [PubMed:28817087]
[show Abstract]
Domoic acid (DA) is a potent toxin, marine biotoxin, and primarily produced by Pseudo-nitzschia. The DA hapten was coupled with bovine serum albumin (BSA), and ovalbumin (OVA) as carrier proteins. DA-BSA conjugate was used as immunogen and DA-OVA as coating antigen. Cell fusion between spleen cells and sp2/0 myeloma cells developed 1C3 hybridoma clone producing 1C3 monoclonal antibody (mAb). Hybridoma was injected into the mice to produce ascites, and further purified by caprylic acid/ammonium sulfate method. The mAb was of IgG3 subclass, and was specific to DA with high affinity (2.5 × 10⁸ L/mol). Moreover, western blot exhibited significant specificity to the DA antigens. Indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) showed DA working range of 0.006-0.2 ng/mL. The IC50 was 0.03 ng/mL with low limit of detection (LOD) of 0.006 ng/mL. Average DA recovery from spiked shellfish extract was 100.56% ± 2.8% with the coefficient variation of 0.01-0.1%. Hence, mAb producing 1C3 hybridoma was successfully developed and could be used to detect DA in contaminated samples. | Thattiyaphong A, Unahalekhaka J, Mekha N, Nispa W, Kluengklangdon P, Rojanapantip L (2014)
Efficiency of a rapid test for detection of tetrodotoxin in puffer fish.
Journal of immunoassay & immunochemistry 35, 111-119 [PubMed:24295175]
[show Abstract]
The selling and importing of puffer fish species and their products was banned in Thailand in 2002, because of possible neurotoxic effects. However, the sale of their flesh is still happening in Thai markets. Standard methods for toxin quantification (HPLC and LC-MS) have significant limitations, therefore a lateral flow, immuno-chromatographic test (TTX-IC) was developed as a tool for rapid detection of toxin. A total of 750 puffer fishes (387 Lagocephalus lunaris(LL), and 363 Lagocephalus spadiceus (LS)) and 100 edible fishes were caught in Thailand from June 2011-February 2012. Screening of TTX from their flesh by TTX-IC revealed that 69 samples (17.8%) of LL possessed TTX at dangerous levels but LS and edible fishes did not. A selected 339 samples were quantified by LC-MS/MS, showing 50 LL possessed TTX at dangerous levels. Comparison of results with LC-MS/MS showed the TTX-IC to have 94.0% sensitivity and 92.4% specificity. The TTX-IC will be a useful tool for TTX screening of a large number of samples, reducing the testing required by LC-MS/MS, thus reducing costs. All positive cases found should be confirmed by standard methods. | Bane V, Lehane M, Dikshit M, O'Riordan A, Furey A (2014)
Tetrodotoxin: chemistry, toxicity, source, distribution and detection.
Toxins 6, 693-755 [PubMed:24566728]
[show Abstract]
Tetrodotoxin (TTX) is a naturally occurring toxin that has been responsible for human intoxications and fatalities. Its usual route of toxicity is via the ingestion of contaminated puffer fish which are a culinary delicacy, especially in Japan. TTX was believed to be confined to regions of South East Asia, but recent studies have demonstrated that the toxin has spread to regions in the Pacific and the Mediterranean. There is no known antidote to TTX which is a powerful sodium channel inhibitor. This review aims to collect pertinent information available to date on TTX and its analogues with a special emphasis on the structure, aetiology, distribution, effects and the analytical methods employed for its detection. | Nishikawa T, Isobe M (2013)
Synthesis of tetrodotoxin, a classic but still fascinating natural product.
Chemical record (New York, N.Y.) 13, 286-302 [PubMed:23661608]
[show Abstract]
Tetrodotoxin, a toxic principle of puffer fish intoxication, is one of the most famous marine natural products due to its densely functionalized structure and potent toxicity. Despite its small molecular size (MW 319 g mol⁻¹), tetrodotoxin has long been well known as a formidable molecule in natural product synthesis. We have devoted more than twenty years to developing synthetic strategies for this molecule, resulting in the preparation of a variety of analogues of tetrodotoxin for biological experiments. This account describes a brief history of tetrodotoxin research and an overview of our synthetic efforts toward tetrodotoxin with the underlying logic and strategy. | Pratheepa V, Vasconcelos V (2013)
Microbial diversity associated with tetrodotoxin production in marine organisms.
Environmental toxicology and pharmacology 36, 1046-1054 [PubMed:24121556]
[show Abstract]
Tetrodotoxin (TTX), is a potent neurotoxin found in genetically diversed organisms. Many TTX producing microorganism have also been isolated from TTX bearing animals. The TTX producing microbes found in four different phylum (Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes), the Proteobacteria are the dominating one. In most of the cases, TTX producing microbes are found in the intestine of the TTX producing vector indicating the origin of TTX through food chain. This paper reviews the TTX and its analogs and the geographic distribution of TTX in symbiotic microorganism and its production. | Sato K, Akai S, Yoshimura J (2013)
Stereocontrolled total synthesis of tetrodotoxin from myo-inositol and D-glucose by three routes: aspects for constructing complex multi-functionalized cyclitols with branched-chain structures.
Natural product communications 8, 987-998 [PubMed:23980434]
[show Abstract]
This report describes the stereocontrolled total synthesis of the multi-functionalized cyclitol derivative, tetrodotoxin, containing eight asymmetric carbons and different types of branched-chains, from myo-inositol and D-glucose using three different methods. The tetrodotoxin derivatives possess a relatively small molecular weight but unique structural and chemical properties. Selection of the appropriate synthetic method may be useful not only for compounds related to TTX (including related derivatives), but also for other highly complex multi-functionalized cyclitols containing branched-chains. | Moczydlowski EG (2013)
The molecular mystique of tetrodotoxin.
Toxicon : official journal of the International Society on Toxinology 63, 165-183 [PubMed:23261990]
[show Abstract]
In many respects tetrodotoxin (TTX) is the quintessential natural toxin. It is unequivocally toxic to mammals with LD(50) values for mice in the range of 10 μg/kg (intraperitoneal), 16 μg/kg (subcutaneous), and 332 μg/kg (oral) (Kao, 1966). Its biothreat status is recognized by its listing as a "Select Agent" by the US Department of Health and Human Services which includes regulated agents "determined to have the potential to pose a severe threat to both human and animal health" (http://www.selectagents.gov/). It has a well-defined cellular target (i.e., NaV channels) and pharmacological mode of action (i.e., block of nerve and muscle action potentials), and it is an indispensable chemical tool in neuroscience. It is widely distributed in marine and terrestrial ecosystems where it plays a role in the chemical ecology of predator-prey relationships and drives evolutionary selection of TTX-resistance (Hanifin, 2010; Williams, 2010; Zimmer and Ferrer, 2007). Lastly, TTX has acquired a certain mystique in scientific lore attributable to many fascinating aspects of its natural history and molecular interactions as presented in selected summary below. Additional information may be found in other excellent reviews (Fozzard and Lipkind, 2010; Kao, 1966; Lee and Ruben, 2008; Narahashi, 2001, 2008). | Zhang XY, Cai XX (2013)
[Determination of tetrodotoxin in seafood using graphitized carbon black clean-up with hilic ultra performance liquid chromatography-triple quadrupole mass spectrometry].
Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] 47, 274-277 [PubMed:23866757]
[show Abstract]
ObjectiveTo develop a rapid hilic ultra performance liquid chromatography (UPLC)-mass spectrum (MS)/MS method for determination of tetrodotoxin in seafood.MethodsThe sample of muscle and liver of puffer fish and nassarius were extracted with aqueous solution containing 0.2% (V/V) acetic acid (the extract of liver must be purified through HLB cartridge), and then cleanup of extract was accomplished by solid-phase extraction with a graphitized carbon black cartridge. The analysis of tetrodotoxin was carried out on a chromatographic column (Acquity UPLC BEH Amide, 100 mm×2.1 mm×1.7 µm) with gradient elution of 95% (V/V) acetonitrile-H2O both containing 0.1% (V/V) formic acid and 2.0 mmol/L ammonium formate, and detected by positive electrospray ionization tandem mass spectrometry in the multiple reaction monitoring (MRM) mode, and quantified by matrix-match standard solution.ResultsThe calibration curves were linear in the range of 30 - 10 000, 50 - 10 000 and 30 - 10 000 µg/kg of tetradotoxin in muscle and liver of puffer fish and in muscle of nassarius, respectively. The correlation coefficients were within 0.9963 - 0.9990. The limits of detection were 10, 20 and 10 µg/kg, and that of quantitation were 30, 50 and 30 µg/kg for muscle and liver of puffer fish and muscle of nassarius, respectively. The average recoveries were 81.5% - 93.1%, 82.3% - 106.0% and 83.5% - 95.2% for tetrodotoxin spiked in muscle and liver of puffer fish and in muscle of nassarius, respectively, with relative standard deviation (RSD) of 2.3% - 11%, 4.3% - 14.0% and 3.5% - 13.0% (n = 6).ConclusionThe method was simple, accurate and sensitive, and could be successfully applied to the measurement of tetrodotoxin in puffer fish and nassarius. | Savio-Galimberti E, Gollob MH, Darbar D (2012)
Voltage-gated sodium channels: biophysics, pharmacology, and related channelopathies.
Frontiers in pharmacology 3, 124 [PubMed:22798951]
[show Abstract]
Voltage-gated sodium channels (VGSC) are multi-molecular protein complexes expressed in both excitable and non-excitable cells. They are primarily formed by a pore-forming multi-spanning integral membrane glycoprotein (α-subunit) that can be associated with one or more regulatory β-subunits. The latter are single-span integral membrane proteins that modulate the sodium current (I(Na)) and can also function as cell adhesion molecules. In vitro some of the cell-adhesive functions of the β-subunits may play important physiological roles independently of the α-subunits. Other endogenous regulatory proteins named "channel partners" or "channel interacting proteins" (ChiPs) like caveolin-3 and calmodulin/calmodulin kinase II (CaMKII) can also interact and modulate the expression and/or function of VGSC. In addition to their physiological roles in cell excitability and cell adhesion, VGSC are the site of action of toxins (like tetrodotoxin and saxitoxin), and pharmacologic agents (like antiarrhythmic drugs, local anesthetics, antiepileptic drugs, and newly developed analgesics). Mutations in genes that encode α- and/or β-subunits as well as the ChiPs can affect the structure and biophysical properties of VGSC, leading to the development of diseases termed sodium "channelopathies". This review will outline the structure, function, and biophysical properties of VGSC as well as their pharmacology and associated channelopathies and highlight some of the recent advances in this field. | Nieto FR, Cobos EJ, Tejada MÁ, Sánchez-Fernández C, González-Cano R, Cendán CM (2012)
Tetrodotoxin (TTX) as a therapeutic agent for pain.
Marine drugs 10, 281-305 [PubMed:22412801]
[show Abstract]
Tetrodotoxin (TTX) is a potent neurotoxin that blocks voltage-gated sodium channels (VGSCs). VGSCs play a critical role in neuronal function under both physiological and pathological conditions. TTX has been extensively used to functionally characterize VGSCs, which can be classified as TTX-sensitive or TTX-resistant channels according to their sensitivity to this toxin. Alterations in the expression and/or function of some specific TTX-sensitive VGSCs have been implicated in a number of chronic pain conditions. The administration of TTX at doses below those that interfere with the generation and conduction of action potentials in normal (non-injured) nerves has been used in humans and experimental animals under different pain conditions. These data indicate a role for TTX as a potential therapeutic agent for pain. This review focuses on the preclinical and clinical evidence supporting a potential analgesic role for TTX. In addition, the contribution of specific TTX-sensitive VGSCs to pain is reviewed. | Leung KS, Fong BM, Tsoi YK (2011)
Analytical challenges: determination of tetrodotoxin in human urine and plasma by LC-MS/MS.
Marine drugs 9, 2291-2303 [PubMed:22163187]
[show Abstract]
Tetrodotoxin (TTX) is a powerful sodium channel blocker found in puffer fish and some marine animals. Cases of TTX poisoning most often result from puffer fish ingestion. Diagnosis is mainly from patient's signs and symptoms or the detection of TTX in the leftover food. If leftover food is unavailable, the determination of TTX in the patient's urine and/or plasma is essential to confirm the diagnosis. Although various methods for the determination of TTX have been published, most of them are for food tissue samples. Dealing with human urine and blood samples is much more challenging. Unlike in food, the amount of toxin in the urine and blood of a patient is generally extremely low; therefore a very sensitive method is required to detect it. In this regard, mass spectrometry (MS) methods are the best choice. Since TTX is a very polar compound, there will be lack of retention on conventional reverse-phase columns; use of ion pair reagent or hydrophilic interaction liquid chromatography (HILIC) can help solve this problem. The problem of ion suppression is another challenge in analyzing polar compound in biological samples. This review will discuss different MS methods and their pros and cons. | Lin SJ, Hwang DF (2001)
Possible source of tetrodotoxin in the starfish Astropecten scoparius.
Toxicon : official journal of the International Society on Toxinology 39, 573-579 [PubMed:11024497]
[show Abstract]
The seasonal variations of toxicity and stomach contents in toxic starfish Astropecten scoparius were detected. The average highest specimen toxicity, expressed as tetrodotoxin (TTX), was 16,821 mouse units (MU). The toxin was composed of TTX only, except April's sample containing mainly TTX along with minor paralytic shellfish poisons. The composition in the stomach of less and more toxic starfish was mainly Veremolpa scabra and Umborium suturale, respectively. The toxicities of U. suturale and V. scabra, found in the starfish stomach were 65 and 33 MU, respectively. For those collected from the coastal waters, U. suturale was toxic with average toxicity value of 77 MU/g, but V. scabra was nontoxic. The toxin in the specimens of U. suturale collected from either the digestive gland of starfish or the coastal waters, was TTX and anhydroTTX only. It indicates that the starfish A. scoparius might mainly accumulate high amount of TTX from U. suturale. Furthermore, both small gastropods U. suturale and Natica psuestes are first reported to contain TTX. | Schwartz DM, Fields HL, Duncan KG, Duncan JL, Jones MR (1998)
Experimental study of tetrodotoxin, a long-acting topical anesthetic.
American journal of ophthalmology 125, 481-487 [PubMed:9559733]
[show Abstract]
PurposeTo determine the effectiveness and toxicity of tetrodotoxin for use as a long-acting topical anesthetic.MethodsFour groups of six rabbits each received a 40-microl aliquot of either tetrodotoxin in one of three concentrations (10 mM, 1 mM, or 0.1 mM) or proparacaine 0.5% into the inferior conjunctival cul-de-sac of one eye, with the fellow eye of each rabbit receiving 40 microl of a 60-mM, pH 4.3 sodium citrate vehicle as a control. Corneal sensation was tested for up to 8 hours after administration of drugs, and response was noted by no blink, partial blink without full eyelid closure, and full blink. Slit-lamp examination at 12 and 24 hours after administration and pachymetry before and 24 hours after administration were performed to detect corneal toxicity.ResultsRabbits receiving all three concentrations of tetrodotoxin did not demonstrate any ocular irritation, corneal thickening, or signs of systemic toxicity. At a dose of 10 mM, tetrodotoxin produced an anesthetic effect lasting up to 8 hours. At 1 mM, tetrodotoxin was an effective but shorter-acting anesthetic. At 0.1 mM, tetrodotoxin had no significant anesthetic effect. Proparacaine-treated rabbits initially were anesthetic, but this effect was largely gone by 1 hour and completely gone by 3 hours.ConclusionsTetrodotoxin is a long-acting topical anesthetic in the rabbit cornea. Although additional toxicity studies are required, tetrodotoxin may provide an effective, long-lasting topical anesthetic for use in pain control after corneal procedures such as photorefractive keratectomy. |
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2021-09-13
