Chemistry:Palytoxin

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Short description: Chemical compound
Palytoxin
Palytoxin.svg
Names
Preferred IUPAC name
(2S,3R,5R,6E,8R,9S)-10-[(12R,13R,15S,41R,43R,45S,46R,6R,7R,8Z,102R,103S,104R,105R,106R,12R,13R,14R,15S,19Z,22R,23S,24R,26E,28Z,30S,322S,323R,324R,325S,326R,34R,35R,372R,373S,374R,376S,38R,39R,42S,43E,45S,46S,482S,483R,484R,485R,486R,50S,581S,583S,585R,586R,60S,66R,67S,68S,69R,70S,712R,713S,714R,715R,716R)-15-(Aminomethyl)-13,6,7,103,104,105,13,14,15,22,23,24,30,323,324,325,34,35,373,374,38,39,42,46,482,483,484,485,50,66,67,68,69,70,713,714,715-heptatriacontahydroxy-12,45,583,585,60-pentamethyl-18-methylidene-44,47,587,588-tetraoxa-10,32,37,48(2,6),71(2)-pentakis(oxana)-1(2)-oxolana-4(6,3),58(1,6)-bis(bicyclo[3.2.1]octana)henheptacontaphane-8,19,26,28,43-pentaen-716-yl]-N-{(1E)-3-[(3-hydroxypropyl)amino]-3-oxoprop-1-en-1-yl}-2,5,8,9-tetrahydroxy-3,7-dimethyldec-6-enamide
Identifiers
3D model (JSmol)
Abbreviations PTX
ChemSpider
UNII
Properties
C129H223N3O54
Molar mass 2680.1386 grams/mol
Appearance white amorphous hygroscopic solid[1]
Melting point decomposes at 300 °C[1]
Solubility Very soluble in water, dimethyl sulfoxide, pyridine; slightly soluble in methanol and ethanol; insoluble in chloroform and diethyl ether[1]
Hazards
Main hazards Extremely toxic, symptoms of poisoning include: chest pains, breathing difficulties, tachycardia, unstable blood pressure and hemolysis.[2]
GHS pictograms GHS06: Toxic
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Tracking categories (test):

Palytoxin, PTX[3] or PLTX[4] is an intense vasoconstrictor,[1] and is considered to be one of the most poisonous non-protein substances known, second only to maitotoxin in terms of toxicity in mice.[5]

Palytoxin is a polyhydroxylated and partially unsaturated compound (8 double bonds) with a long carbon chain. It has water-soluble and fat-soluble parts, 40 hydroxy groups and 64 chiral centers. Due to chirality and possible double bond cis-trans isomerism, it has over 1021 alternative stereoisomers. It is thermostable, and treatment with boiling water does not remove its toxicity. It remains stable in aqueous solutions for prolonged periods but rapidly decomposes and loses its toxicity in acidic or alkaline solutions. It has multiple analogues with a similar structure like ostreocin-D, mascarenotoxin-A and -B.[3]

Palytoxin occurs at least in tropics and subtropics where it is made by Palythoa corals and Ostreopsis dinoflagellates, or possibly by bacteria occurring in these organisms. It can be found in many more species like fish and crabs due to the process of biomagnification. It can also be found in organisms living close to palytoxin producing organisms like sponges, mussels, starfish and cnidaria.[3]

People are rarely exposed to palytoxin. Exposures have happened in people who have eaten sea animals like fish and crabs, but also in aquarium hobbyists who have handled Palythoa corals incorrectly and in those who have been exposed to certain algal blooms.[2]

Palytoxin targets the sodium-potassium pump protein by locking it into a position where it allows passive transport of both sodium and potassium ions, thereby destroying the ion gradient that is essential for life.[6] Because palytoxin can affect every type of cell in the body, the symptoms can be very different for the various routes of exposure.[2]

Palytoxin's planar chemical structure was solved in 1981 by two research groups independently from each other.[3] Stereochemistry was solved in 1982.[7][8][9] Palytoxin carboxylic acid was synthesized by Yoshito Kishi and colleagues in 1989[10] and actual palytoxin in 1994 by Kishi and Suh.[11]

History

Legend

According to an ancient Hawaiian legend, on the island of Maui near the harbor of Hana there was a village of fishermen haunted by a curse. Upon their return from the sea, one of the fishermen would go missing. One day, enraged by another loss, the fishermen assaulted a hunchbacked hermit deemed to be the culprit of the town's misery. While ripping the cloak off the hermit the villagers were shocked because they uncovered rows of sharp and triangular teeth within huge jaws. A shark god had been caught. It was clear that the missing villagers had been eaten by the god on their journeys to the sea. The men mercilessly tore the shark god into pieces, burned him and threw the ashes into a tide pool near the harbor of Hana. Shortly after, a thick brown "moss" started to grow on the walls of the tide pool causing instant death to victims hit by spears smeared with the moss. Thus was the evil of the demon.[12][13] The moss growing in the cursed tide pool became known as "limu-make-o-Hana" which literally means "seaweed of death from Hana." The Hawaiians believed that an ill curse came over them if they tried to collect the deadly "seaweed".[14][13]

Discovery

Palytoxin was first isolated, named and described from Palythoa toxica by Moore and Scheuer in a study published in 1971. They measured that its molar mass is approximately 3300 g/mol. They also identified it to be the substance that was probably responsible for the toxicity of P. toxica, but it was uncertain at the time if the coral also had other toxic compounds in it.[14] It was then assessed by Walsh and Bowers that the limu-make-o-Hana was not a seaweed but a zoanthid coral, subsequently described as Palythoa toxica.[15] Moore and Scheuer were aware of the study that Walsh and Bowers were writing.[14]

Structure and total synthesis

In 1978 by plasmadesorption the mass of the palytoxin was measured to be 2861 g/mol and that it had 8 double bonds.[16] Because palytoxin is such a large molecule, it took some time before the complete structure (including stereochemistry) was elucidated. Uemura et al. solved its planar chemical structure first and published their results in January 1981.[17][18][19] Shortly afterwards Moore and Bartolini solved the same structure and published their results in May 1981.[20] Forementioned groups solved the structure independently from each other.[3] Palytoxin's stereochemistry was solved first by Moore et al. in June 1982[7] and then by Uemura et al. in December in a study of four parts.[8][9]

Palytoxin carboxylic acid was synthesized in 1989 by the group of Harvard professor Yoshito Kishi. Synthesis happened in 8 parts and then the parts were joined to form the carboxylic acid.[10] In 1994 Kishi et al. succeeded in making the actual palytoxin from this carboxylic acid.[11] The accomplishment of palytoxin carboxylic acid synthesis was described as "the Mount Everest of organic synthesis, the largest single molecule that anyone has ever even thought about making" by Crawford in 1989.[21]

Direct observation of the crystal structure of palytoxin was made in 2022 using microcrystal electron diffraction and an antibody named scFv. Palytoxin is found to fold into a hairpin structure which, according to simulation, would facilitate its binding with the Na+/K+-ATPase.[22]

Occurrence

Some of the organisms that contain palytoxin or its close analogues are listed below. These are either able to produce these compounds or have been found to contain them in some occasions due to bioaccumulation.[23]

Such corals are Palythoa caribeaorum, P. mammilosa, P. tuberculosa, P. toxica, P. vestitus, P. aff. margaritae, Zoanthus soanderi and Z. sociatus.[24]

Such dinoflagellates are Ostreopsis lenticularis, O. siamensis, O. mascarensis and O. ovata.[24]

Such fish are scrawled filefish, pinktail triggerfish, Ypsiscarus ovifrons, Decapterus macrosoma (shortfin scad), bluestripe herring and Epinephelus sp.[24]

Such crabs are Lophozosimus pictor, Demania reynaudii and gaudy clown crab.[24]

Certain bacteria might be able to produce palytoxin and may be the actual producers in some of the organisms listed above. Bacteria that have some evidence of palytoxin or its analogue production include Pseudomonas, Brevibacterium, Acinetobacter, Bacillus cereus, Vibrio sp. ja Aeromonas.[3]

Mechanism

The toxicity of palytoxin is due to its binding to external part of Na+/K+-ATPase (the sodium–potassium pump),[3] where it interacts with the natural binding site of ouabain with very high affinity. Na+/K+-ATPase is a transmembrane protein, which is found on the surface of every vertebrate cell. The sodium–potassium pump is necessary for viability of all cells, and this explains the fact that palytoxin affects all cells.[24] Through this channel, which it forms within the sodium–potassium pump, monovalent positive ions such as sodium and potassium can diffuse freely, thereby destroying the ion gradient of the cell.[25][26] Once palytoxin is bound to the pump, it flips constantly between open and normal conformations. The open conformation is more likely (over 90% probability). If palytoxin detaches, the pump will return to closed conformation. In open conformation, millions of ions diffuse through the pump per second, whereas only about one hundred ions per second are transported through a normally functioning transporter.[6]

Loss of ion gradient leads to death and hemolysis of red blood cells, for example, and also to violent contractions of heart and other muscle cells.[3]

First evidence of the mechanism described above was obtained in 1981 and the proposed mechanism was published in 1982.[27] Because the mechanism of action of palytoxin was so unlike any other, it was initially not widely accepted. This was primarily because it was not expected that a pump which provides active transport, could become an ion channel by binding of a compound such as palytoxin.[24] Therefore, there were some alternative hypotheses, which were reviewed by Frelin and van Renterghem in 1995.[28] The breakthrough research which is seen as proof for the sodium–potassium pump mechanism was performed in yeast cells (Saccharomyces cerevisiae). These cells do not have the sodium–potassium pump, and hence palytoxin does not affect them. But once they were given the DNA to encode for complete sheep Na+/K+-ATPase, they were killed by palytoxin.[29]

Toxicity

From intravenous (IV) animal studies the toxic dose (LD50) of palytoxin via IV for humans has been estimated by extrapolation to be between 2.3 and 31.5 micrograms (µg) of palytoxin.[3][30] An acute oral reference dose has been suggested to be 64 µg for a person with weight of 60 kg.[3] Acute reference dose means a dose that can be safely ingested over a short period of time, usually during one meal or one day.[31]

In comparison to IV injection, the toxicity of palytoxin in various animals via intramuscular and subcutaneous injections are 2.5 and 4–30 times higher, respectively. Upon ingestion the toxicity in animals has been 200 times less than via IV.[2] In the table below, there are listed some LD50 values for partially pure palytoxin obtained from different Palythoa. These values represent the amount of palytoxin required to kill half of the test animals. Values are in micrograms (µg) per kilogram of the animal's weight and have been measured 24 hours after the initial exposure.[3]

LD50 values for palytoxin[3]
Exposure Animal LD50 (µg/kg)
Intravenous Mouse 0.045
Rat 0.089
Intratracheal Rat 0.36
Intraperitoneal Mouse 0.295
Rat 0.63
Oral Mouse 510 or 767

An early toxicological characterization classified palytoxin as "relatively non-toxic" after intragastric administration to rats. The lethal dose (LD50) was greater than 40 µg/kg. The LD50 after parenteral administration was lower than 1 µg/kg.[32] However the doubtful purity of this study increased because of uncertainty concerning the toxicological data. In 1974, the structure of palytoxin was not completely elucidated and the molecular weight was a lot higher (3300 Da instead of 2681 Da). A 2004 study discovered an LD50 of 510 µg/kg after intragastric administration in mice, but histological or biochemical information was missing. (Rhodes and Munday, 2004) Furthermore, palytoxin was not lethal to mice given an oral dose of 200 µg/kg.[33] It was also found that palytoxin is very toxic after intraperitoneal injection. The LD50 in mice was less than 1 µg/kg.[34] Because toxin-producing organisms spread to temperate climates and palytoxin-contaminated shellfish were discovered in the Mediterranean Sea[35] a study was done to better define the toxic effects of palytoxin after oral exposure in mice. Palytoxin was lethal from 600 µg/kg doses. The number of deaths were dose-dependent and the LD50 calculated to be 767 µg/kg. This is comparable to the LD50 of 510 µg/kg referred by Munday (2008). The toxicity was not different if the mice had some food in their stomach. The oral toxicity is several times lower than the intraperitoneal toxicity. One of the possible causes of this behavior is that palytoxin is a very big hydrophilic molecule and therefore the absorption could be less efficient through the gastrointestinal tract than through the peritoneum.[36] A recent study by Fernandez et al.[37] further investigated on this issue using an in vitro model of intestinal permeability with differentiated monolayers of human colonic Caco-2 cells, confirming that palytoxin was unable to cross the intestinal barrier significantly, despite the damage the toxin exerted on cells and on the integrity of the monolayer. The same study also revealed that palytoxin does not affect tight-junctions on such cells. Palytoxin is most toxic after intravenous injection. The LD50 in mice is 0.045 µg/kg and in rats 0.089 µg/kg. In other mammals (rabbits, dogs, monkeys and guinea pigs) the LD50 is ranged between 0.025 and 0.45 µg/kg. They all died in several minutes from heart failure.[2] The lethal dose for mice by the intratracheal route is above 2 µg/kg in 2 hours. Palytoxin is also very toxic after intramuscular or subcutaneous injection. No toxicity is found after intrarectal administration. Palytoxin is not lethal when topically applied to skin or eyes.[33] Palytoxin can travel in water vapor and cause poisoning by inhalation.

In this context, despite an increase in reports of palytoxin contaminated seafood in temperate waters (i.e., Mediterranean Sea), there are no validated and accepted protocols for the detection and quantification of this class of biomolecules. However, in recent years, many methodologies have been described with particular attention on the development of new techniques for the ultrasensitive detection of palytoxin in real matrix such as mussels and microalgae (based on LC-MS-MS[38] or immunoassay[39]).

Symptoms

The symptoms of palytoxin poisoning and how quickly they appear depend partially on how much and through what route one has been exposed, e.g. if the poison has been inhaled or if the exposure has happened via skin.[2]

In some non-lethal cases the symptoms in people have appeared in 6–8 hours after inhalation or skin exposure, and have lasted for 1–2 days.[5] In different animals the symptoms have appeared in 30–60 minutes after intravenous injection and after 4 hours of eye-exposure.[2]

The most common complication of severe palytoxin poisoning is rhabdomyolysis. This involves skeletal muscle breakdown and the leakage of intracellular contents into the blood. Other symptoms in humans are bitter/metallic taste, abdominal cramps, nausea, vomiting, diarrhea, mild to acute lethargy, tingling, slow heart rate, kidney failure, impairment of sensation, muscle spasms, tremor myalgia, cyanosis, and respiratory distress. In lethal cases palytoxin usually causes death by cardiac arrest via myocardial injury.[3][40]

Exposure to aerosols of palytoxin analogue ovatoxin-a have resulted mainly in respiratory illness. Other symptoms caused by these aerosols included fever associated with serious respiratory disturbances, such as bronchoconstriction, mild dyspnea, and wheezes, while conjunctivitis was observed in some cases.[40][3]

Clupeotoxism, poisoning after consuming clupeoid fish, is also suggested to be caused by palytoxin. Neurological and gastrointestinal disturbances are associated with clupeotoxism.[40] Haff disease might be related to palytoxin and is characterized by rhabdomyolysis and gastrointestinal problems.[5] In addition to ciguatoxin, palytoxin could be related to ciguatera seafood poisoning in some cases and thus give rise to a number of symptoms in this poisoning.[2]

Treatment

There is no antidote for palytoxin. Only the symptoms can be alleviated.[41]

Animal studies have shown that vasodilators, such as papaverine and isosorbide dinitrate, can be used as antidotes. The animal experiments only showed benefit if the antidotes were injected into the heart immediately following exposure.[32]

Poisoning incidents

Ingestion

There have been cases where people died after eating foods containing palytoxin or poisons similar to it. In the Philippines people died after eating Demania crabs.[42] After eating bluestripe herring some people died in Madagascar.[43] People who had eaten smoked mackerel and parrotfish experienced near fatal poisoning in Hawaii[44] and Japan respectively.[45]

Skin contact

There have been palytoxin poisonings through skin absorption e.g. in people who handled corals without gloves in their home aquariums in Germany[46] and the USA.[2]

Inhalation

Cases of inhalation are also known. A man inhaled palytoxin when he tried to kill a Palythoa in his aquarium with boiling water.[47] In 2018, six people from Steventon, Oxfordshire, England were hospitalized after probable exposure by inhalation to "palytoxins" which were released by coral that was being removed from a personal aquarium. Four firefighters, who responded to the incident, were also hospitalized. The patients presented "flu-like symptoms" and eye-irritation.[48] Also in 2018, a woman in Cedar Park, Texas was poisoned when she scraped growing algae from Palythoa polyps in her home aquarium. Other members of the family, including children, also reportedly fell ill. The woman described intense flu-like respiratory symptoms and high fever within hours of inhalation and was hospitalized. Confused physicians initially misdiagnosed the palytoxin poisoning to viral infection. The toxin also killed most of the fish in the aquarium. Many aquatic hobbyists purchase the coral for their bright coloring unaware of the toxins present and the danger of the toxin if it is disturbed.[49] A similar event occurred in the UK in August 2019.[50]

Mass poisonings

A formerly unknown derivative of palytoxin, ovatoxin-a, produced as a marine aerosol by the tropical dinoflagellate Ostreopsis ovata caused hundreds of people in Genoa, Italy, to fall ill. In 2005 and 2006 blooms of these algae occurred in the Mediterranean sea. All those affected needed hospitalization. Symptoms were high fever, coughs and wheezes.[13]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 Budavari, Susan, ed. (2001), The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals (13th ed.), Merck, ISBN:0911910131
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "Human risk associated with palytoxin exposure". Toxicon 56 (2): 150–62. August 2010. doi:10.1016/j.toxicon.2009.05.035. PMID 19505494. https://zenodo.org/record/1259397. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 "Palytoxin and analogs: biological and ecological effects". Marine Drugs 8 (7): 2021–37. June 2010. doi:10.3390/md8072021. PMID 20714422. 
  4. ↑ "Palytoxin-Containing Aquarium Soft Corals as an Emerging Sanitary Problem". Marine Drugs 14 (2): 33. February 2016. doi:10.3390/md14020033. PMID 26861356. 
  5. ↑ 5.0 5.1 5.2 "Case series: inhaled coral vapor--toxicity in a tank". Journal of Medical Toxicology 9 (3): 282–6. September 2013. doi:10.1007/s13181-013-0307-x. PMID 23702624. 
  6. ↑ 6.0 6.1 "Review. Peering into an ATPase ion pump with single-channel recordings". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 364 (1514): 229–38. January 2009. doi:10.1098/rstb.2008.0243. PMID 18986966. 
  7. ↑ 7.0 7.1 "Absolute Stereochemistry of Palytoxin". Journal of the American Chemical Society 104 (13): 3776–3779. June 1982. doi:10.1021/ja00377a064. 
  8. ↑ 8.0 8.1 "Stereochemistry of palytoxin. Part 1. C85-C115 segment". Journal of the American Chemical Society 104 (25): 7362–7364. December 1982. doi:10.1021/ja00389a098. 
  9. ↑ 9.0 9.1 "Stereochemistry of palytoxin. Part 4. Complete structure". Journal of the American Chemical Society 104 (25): 7369–7371. December 1982. doi:10.1021/ja00389a101. ISSN 0002-7863. 
  10. ↑ 10.0 10.1 "Total Synthesis of Palytoxin Carboxylic Acid and Palytoxin Amide". J. Am. Chem. Soc. 111 (19): 7530. 1989. doi:10.1021/ja00201a038. 
  11. ↑ 11.0 11.1 "Synthesis of Palytoxin from Palytoxin Carboxylic Acid". J. Am. Chem. Soc. 116 (24): 11205. 1994. doi:10.1021/ja00103a065. 
  12. ↑ Malo, David (1 July 1987) (in Hawaiian). Moolelo Hawaii (2nd ed.). Bishop Museum Press. pp. 201. ISBN 0-910240-15-9. https://books.google.com/books?id=k0ZCAAAAIAAJ. 
  13. ↑ 13.0 13.1 13.2 "Palytoxins: A still haunting Hawaiian curse". Phytochemistry Reviews 9 (4): 491–500. 2010. doi:10.1007/s11101-010-9185-x. Bibcode: 2010PChRv...9..491C. 
  14. ↑ 14.0 14.1 14.2 "Palytoxin: a new marine toxin from a coelenterate". Science 172 (3982): 495–8. April 1971. doi:10.1126/science.172.3982.495. PMID 4396320. Bibcode: 1971Sci...172..495M. 
  15. ↑ "A review of Hawaiian zoanthids with descriptions of three new species". Zoological Journal of the Linnean Society 50 (2): 161–180. May 1971. doi:10.1111/j.1096-3642.1971.tb00757.x. 
  16. ↑ "Californium-252 plasma desorption mass spectrometry of palytoxin". Journal of the American Chemical Society 102 (2): 875–876. January 1980. doi:10.1021/ja00522a088. 
  17. ↑ "CSJ Award 2005-Prof. Daisuke Uemura". Chemical Society of Japan, et al.. http://www.csj.jp/csj-en/membership/awards/achieve/2005-uemura.html. "Its structural determination presented many difficulties. Dr. Uemura elucidated its planar structure in 1981 by repeatedly carrying out site-specific oxidative degradation and determined the structure of the degraded products using a sample that was originally isolated from Palythoa tuberculosa of Okinawa[n] origin." 
  18. ↑ "Further studies on palytoxin. I.". Tetrahedron Letters 22 (20): 1909–1912. January 1981. doi:10.1016/s0040-4039(01)90475-7. 
  19. ↑ "Further studies on palytoxin. II.". Tetrahedron Letters 22 (20): 2781–2784. January 1981. doi:10.1016/S0040-4039(01)90551-9. 
  20. ↑ "Structure of palytoxin". Journal of the American Chemical Society 103 (9): 2491–2494. May 1981. doi:10.1021/ja00399a093. 
  21. ↑ "Harvard synthesizes palytoxin molecule". Science 246 (4926): 34. October 1989. doi:10.1126/science.246.4926.34.d. PMID 17837760. https://www.science.org/doi/10.1126/science.246.4926.34.d. 
  22. ↑ Gillman, C; Patel, K; Unge, J; Gonen, T (1 June 2023). "The structure of the neurotoxin palytoxin determined by MicroED.". BioRxiv: The Preprint Server for Biology. doi:10.1101/2023.03.31.535166. PMID 37034718. 
  23. ↑ McKenna, Amy; Erickson, Kevin (August 21, 2016). "The Power of Palytoxin". Marine Aquarium Societies of North America. https://masna.org/masna-education/palytoxin/. "There is some speculation that palytoxin is not produced by the zoanthids themselves, but by Ostreopsis dinoflagellates that the animals bioaccumulate (Violand 2008) Alternately, that the bacteria that live symbiotically in the coral are the producers of the toxin (Tartaglione et. al. 2016). More studies need to be conducted, however palytoxin poisoning does occur in dinoflagellate blooms in the Mediterranean area from aerosolization of the marine toxin." 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 24.5 "Palytoxin: membrane mechanisms of action". Toxicon 54 (8): 1183–9. December 2009. doi:10.1016/j.toxicon.2009.02.030. PMID 19269304. 
  25. ↑ "Palytoxin acts through Na+,K+-ATPase". Toxicon 27 (11): 1171–87. 1989. doi:10.1016/0041-0101(89)90026-3. PMID 2575806. 
  26. ↑ "Palytoxin-induced Na+ influx into yeast cells expressing the mammalian sodium pump is due to the formation of a channel within the enzyme". Molecular Pharmacology 49 (1): 49–57. January 1996. PMID 8569711. http://molpharm.aspetjournals.org/content/49/1/49.long. 
  27. ↑ "Ouabain inhibits the increase due to palytoxin of cation permeability of erythrocytes". Naunyn-Schmiedeberg's Archives of Pharmacology 319 (2): 101–107. 1982-05-01. doi:10.1007/BF00503920. PMID 6125898. 
  28. ↑ "Palytoxin. Recent electrophysiological and pharmacological evidence for several mechanisms of action". General Pharmacology 26 (1): 33–7. January 1995. doi:10.1016/0306-3623(94)00133-8. PMID 7713364. 
  29. ↑ "Palytoxin induces K+ efflux from yeast cells expressing the mammalian sodium pump". Molecular Pharmacology 45 (6): 1132–6. June 1994. PMID 7912814. http://molpharm.aspetjournals.org/content/45/6/1132. 
  30. ↑ Riobó, P; Paz, B; Franco, JM (2006). "Analysis of palytoxin-like in Ostreopsis cultures by liquid chromatography with precolumn derivatization and fluorescence detection". Analytica Chimica Acta 566 (2): 217–223. doi:10.1016/j.aca.2006.03.013. ISSN 0003-2670. 
  31. ↑ "Guidance for the Setting of an Acute Reference Dose (ARfD)". European Commission. 2001-07-05. https://ec.europa.eu/food/sites/food/files/plant/docs/pesticides_ppp_app-proc_guide_tox_acute-ref-dose.pdf. 
  32. ↑ 32.0 32.1 "Toxicological evaluation of palytoxin in several animal species". Toxicon 12 (4): 427–33. August 1974. doi:10.1016/0041-0101(74)90011-7. PMID 4155146. 
  33. ↑ 33.0 33.1 "Toxicological studies on palytoxin and ostreocin-D administered to mice by three different routes". Toxicon 54 (3): 244–51. September 2009. doi:10.1016/j.toxicon.2009.04.009. PMID 19376151. 
  34. ↑ "Uptake of palytoxin like compounds by shellfish fed Ostreopsis siamensis (Dinophyceae)". New Zealand J. Med. Freshwater Res. 36 (3): 631–636. 2002. doi:10.1080/00288330.2002.9517118. 
  35. ↑ "First episode of shellfish contamination by palytoxin-like compounds from Ostreopsis species (Aegean Sea, Greece)". Toxicon 51 (3): 418–27. March 2008. doi:10.1016/j.toxicon.2007.10.016. PMID 18067938. 
  36. ↑ "Intestinal injuries caused by experimental palytoxicosis in mice". Toxicon 34 (6): 643–52. June 1996. doi:10.1016/0041-0101(96)00005-0. PMID 8817810. 
  37. ↑ "The kinetic, mechanistic and cytomorphological effects of palytoxin in human intestinal cells (Caco-2) explain its lower-than-parenteral oral toxicity". The FEBS Journal 280 (16): 3906–19. August 2013. doi:10.1111/febs.12390. PMID 23773601. 
  38. ↑ "LC-MS of palytoxin and its analogues: State of the art and future perspectives". Toxicon 57 (3): 376–89. March 2011. doi:10.1016/j.toxicon.2010.11.002. PMID 21070802. 
  39. ↑ "Highly sensitive electrochemiluminescent nanobiosensor for the detection of palytoxin". ACS Nano 6 (9): 7989–97. September 2012. doi:10.1021/nn302573c. PMID 22913785. https://zenodo.org/record/3443880. 
  40. ↑ 40.0 40.1 40.2 "Marine toxins and the cytoskeleton: a new view of palytoxin toxicity". The FEBS Journal 275 (24): 6067–74. December 2008. doi:10.1111/j.1742-4658.2008.06712.x. PMID 19016862. 
  41. ↑ "Palytoxin-induced acute respiratory failure". Respiratory Medicine Case Reports 20: 4–6. 2016-10-21. doi:10.1016/j.rmcr.2016.10.014. PMID 27843763. 
  42. ↑ "Human fatality due to ingestion of the crab Demania reynaudii that contained a palytoxin-like toxin". Toxicon 26 (1): 105–7. 1988. doi:10.1016/0041-0101(88)90142-0. PMID 2894726. 
  43. ↑ "Identification of putative palytoxin as the cause of clupeotoxism". Toxicon 37 (1): 55–65. January 1999. doi:10.1016/S0041-0101(98)00133-0. PMID 9920480. 
  44. ↑ "Clinical and laboratory findings implicating palytoxin as cause of ciguatera poisoning due to Decapterus macrosoma (mackerel)". Toxicon 27 (9): 1051–3. 1989. doi:10.1016/0041-0101(89)90156-6. PMID 2572075. 
  45. ↑ "Rhabdomyolysis and myocardial damage induced by palytoxin, a toxin of blue humphead parrotfish". Intern. Med. 37 (3): 330–333. 1998. doi:10.2169/internalmedicine.37.330. PMID 9617874. 
  46. ↑ "A case of palytoxin poisoning due to contact with zoanthid corals through a skin injury". Toxicon 51 (8): 1535–7. June 2008. doi:10.1016/j.toxicon.2008.03.009. PMID 18433818. 
  47. ↑ "A case of inhalational exposure to palytoxin". Clin. Toxicol. 46: 637. 2008. 
  48. ↑ "Fish tank fumes leave 10 in hospital". BBC News. 2018-03-27. https://www.bbc.co.uk/news/uk-england-oxfordshire-43558736. 
  49. ↑ Perez, Pattrik (2018-04-27). "Cedar Park mother warning others after aquarium coral nearly kills her family". KENS. http://www.kens5.com/article/news/health/cedar-park-mother-warning-others-after-aquarium-coral-nearly-kills-her-family/546756484. 
  50. ↑ "Telford mum 'nearly died' after cleaning fish tank coral". BBC News. 7 August 2019. https://www.bbc.co.uk/news/uk-england-shropshire-49269013. 



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