Palytoxin
Names | |
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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 ) |
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Abbreviations | PTX |
ChemSpider | |
ECHA InfoCard
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100.162.538 |
PubChem CID
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UNII | |
CompTox Dashboard (EPA)
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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 | |
Occupational safety and health (OHS/OSH): | |
Main hazards
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Extremely toxic, symptoms of poisoning include: chest pains, breathing difficulties, tachycardia, unstable blood pressure and hemolysis.[2] |
GHS labelling: | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Palytoxin, PTX
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
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
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
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
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
Such crabs are
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
Loss of ion gradient leads to death and
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
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
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
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]
Treatment
There is no antidote for palytoxin. Only the symptoms can be alleviated.[41]
Animal studies have shown that
Poisoning incidents
Ingestion
There have been cases where people died after eating foods containing palytoxin or poisons similar to it. In the
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
- Maitotoxin
- Botulinum toxin
- Tetrodotoxin
- Tetanospasmin
- Saxitoxin
- Algal bloom
References
- ^ ISBN 0911910131
- ^ PMID 19505494.
- ^ PMID 20714422.
- PMID 26861356.
- ^ PMID 23702624.
- ^ PMID 18986966.
- ^ .
- ^ .
- ^ ISSN 0002-7863.
- ^ .
- ^ .
- ISBN 0-910240-15-9.
- ^ S2CID 26030596.
- ^ S2CID 10098874.
- .
- .
- ^ "CSJ Award 2005-Prof. Daisuke Uemura". www.csj.jp. Chemical Society of Japan, et al. Archived from the original on 28 March 2018. Retrieved 26 April 2018.
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.
- .
- .
- .
- S2CID 239849185.
- PMID 37034718.
- ^ McKenna, Amy; Erickson, Kevin (21 August 2016). "The Power of Palytoxin". masna.org. Marine Aquarium Societies of North America. Retrieved 25 May 2023.
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.
- ^ PMID 19269304.
- PMID 2575806.
- PMID 8569711.
- S2CID 12069168.
- PMID 7713364.
- PMID 7912814.
- ISSN 0003-2670.
- ^ "Guidance for the Setting of an Acute Reference Dose (ARfD)" (PDF). European Commission. 5 July 2001. Archived (PDF) from the original on 30 April 2018.
- ^ PMID 4155146.
- ^ PMID 19376151.
- S2CID 84191389.
- PMID 18067938.
- PMID 8817810.
- S2CID 30378906.
- PMID 21070802.
- S2CID 46427496.
- ^ PMID 19016862.
- PMID 27843763.
- PMID 2894726.
- PMID 9920480.
- PMID 2572075.
- PMID 9617874.
- PMID 18433818.
- ^ Majlesi N, Su MK, Chan GM, Lee DC, Greller HA (2008). "A case of inhalational exposure to palytoxin". Clin. Toxicol. 46: 637.
- ^ "Fish tank fumes leave 10 in hospital". BBC News. 27 March 2018. Archived from the original on 15 April 2018. Retrieved 27 April 2018.
- ^ Perez P (27 April 2018). "Cedar Park mother warning others after aquarium coral nearly kills her family". KENS. Archived from the original on 29 April 2018. Retrieved 29 April 2018.
- ^ "Telford mum 'nearly died' after cleaning fish tank coral". BBC News. 7 August 2019.