 | |
| 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 |
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| ECHA InfoCard | 100.162.538 |
| UNII | |
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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 inwater,dimethyl sulfoxide,pyridine; slightly soluble in methanol and ethanol; insoluble inchloroform anddiethyl ether[1] |
| Hazards | |
| Occupational safety and health (OHS/OSH): | |
Main hazards | Extremely toxic, symptoms of poisoning include: chest pains, breathing difficulties, tachycardia, unstable blood pressure and hemolysis.[2] |
| GHS labelling: | |
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Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Palytoxin,PTX[3] orPLTX[4] is an intensevasoconstrictor,[1] and is considered to be one of the most poisonous non-protein substances known, second only tomaitotoxin 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, 40hydroxy groups and 64chiral centers. Due tochirality and possibledouble bondcis-trans isomerism, it has over1021 alternativestereoisomers. It isthermostable, and boiling contaminated seafood does not noticeably reduce toxicity. It remains stable in aqueous solutions for prolonged periods but rapidly decomposes inacidic oralkaline solutions. It has multipleanalogues such as ostreocin-D, mascarenotoxin-A and -B.[3]
Palytoxin occurs at least intropics andsubtropics where it is made byPalythoa corals andOstreopsisdinoflagellates, or possibly bybacteria occurring in these organisms. It can be found in many more species likefish andcrabs due to the process ofbiomagnification. It can also be found in varioussponges,mussels,starfish andcnidaria.[3]
People are rarely exposed to palytoxin. Exposures have happened in people who have eaten contaminated fish and crabs, but also inaquarium hobbyists who have handledPalythoa corals incorrectly and in those who have been exposed to certainalgal blooms.[2]
Palytoxin targets thesodium-potassium pumpprotein by locking it into a position where it allowspassive transport of bothsodium andpotassium ions, thereby destroying theion gradient that is essential for life.[6] As 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 chemical structure was solved in 1981 by two research groups independently from each other.[3]Stereochemistry was solved in 1982.[7][8][9] Palytoxincarboxylic acid was synthesized byYoshito Kishi and colleagues in 1989[10] and actual palytoxin in 1994 by Kishi and Suh.[11]
According to an ancient Hawaiian legend, on the island ofMaui near the harbor ofHana 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]
Palytoxin was first isolated, named and described fromPalythoa toxica by Moore andScheuer in a study published in 1971. They measured that itsmolar mass is approximately 3300 g/mol. They also identified it to be the substance that was probably responsible for the toxicity ofP. 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 azoanthidcoral, subsequently described asPalythoa toxica.[15] Moore and Scheuer were aware of the study that Walsh and Bowers were writing.[14]
In 1978 byplasmadesorption the mass of the palytoxin was measured to be 2861 g/mol and that it had 8double bonds.[16] As palytoxin is such a large molecule, it took some time before the complete structure (includingstereochemistry) was elucidated. Uemuraet 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 professorYoshito 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 "theMount 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 usingmicrocrystal 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]
Some of theorganisms that contain palytoxin or its closeanalogues are listed below. These are either able to produce these compounds or have been found to contain them in some occasions due tobioaccumulation.[23]
Such corals arePalythoa caribeaorum,P. mammilosa,P. tuberculosa,P. toxica,P. vestitus,P.aff.margaritae,Zoanthus soanderi andZ. sociatus.[24]
Suchdinoflagellates areOstreopsis lenticularis,O. siamensis,O. mascarensis andO. ovata.[24]
Such fish arescrawled filefish,pinktail triggerfish,Ypsiscarus ovifrons,Decapterus macrosoma (shortfin scad),bluestripe herring andEpinephelussp.[24]
Such crabs areLophozozymus pictor,Demania reynaudii andgaudy clown crab.[24]
Certainbacteria 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 includePseudomonas,Brevibacterium,Acinetobacter,Bacillus cereus,Vibrio sp. jaAeromonas.[3]
The toxicity of palytoxin is due to its binding to external part ofNa+/K+-ATPase (thesodium–potassium pump),[3] where it interacts with the natural binding site ofouabain with very high affinity. Na+/K+-ATPase is atransmembrane protein, which is found on the surface of everyvertebrate cell. The sodium–potassium pump is necessary for viability of allcells, and this explains the fact that palytoxin affects all cells.[24] Through this channel, which it forms within the sodium–potassium pump,monovalent positiveions such as sodium and potassium candiffuse freely, thereby destroying theion gradient of the cell.[25][26] Once palytoxin is bound to the pump, it flips constantly between open and normalconformations. 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 andhemolysis ofred blood cells, for example, and also to violent contractions ofheart and othermuscle cells.[3]
First evidence of the mechanism described above was obtained in 1981 and the proposed mechanism was published in 1982.[27] As 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 providesactive transport, could become anion 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 theDNA to encode for complete sheep Na+/K+-ATPase, they were killed by palytoxin.[29]
Fromintravenous (IV) animal studies the toxic dose (LD50) of palytoxin via IV for humans has been estimated byextrapolation to be between 2.3 and 31.5micrograms (μg) of palytoxin.[3][30] An acute oralreference 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 viaintramuscular andsubcutaneous 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 someLD50 values for partially pure palytoxin obtained from differentPalythoa. These values represent the amount of palytoxin required to kill half of the test animals. Values are inmicrograms (μg) perkilogram of the animal's weight and have been measured 24 hours after the initial exposure.[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] As 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]).
Thesymptoms 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 commoncomplication of severe palytoxin poisoning isrhabdomyolysis. This involvesskeletal muscle breakdown and the leakage ofintracellular contents into the blood. Other symptoms in humans are bitter/metallic taste, abdominal cramps, nausea, vomiting, diarrhea, mild to acutelethargy, tingling,slow heart rate,kidney failure, impairment of sensation, muscle spasms, tremormyalgia,cyanosis, and respiratory distress. In lethal cases palytoxin usually causes death bycardiac 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 asbronchoconstriction, mild dyspnea, and wheezes, whileconjunctivitis was observed in some cases.[40][3]
Clupeotoxism, poisoning after consumingclupeoid 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 tociguatoxins, palytoxin could also be a causative agent ofciguatera seafood poisoning.[2]
There is noantidote for palytoxin. Only the symptoms can be alleviated.[41]
Animal studies have shown thatvasodilators, such aspapaverine andisosorbide dinitrate, can be used asantidotes. The animal experiments only showed benefit if the antidotes were injected into theheart immediately following exposure.[32]
There have been cases where people died after eating foods containing palytoxin or poisons similar to it (possiblyciguatoxins). In thePhilippines people died after eatingDemania crabs.[42] After eatingbluestripe herring some people died in Madagascar.[43] People who had eaten smokedmackerel andparrotfish experienced near fatal poisoning in Hawaii[44] and Japan respectively.[45]
There have been palytoxin poisonings through skin absorption e.g. in people who handledPalythoa corals without gloves in their home aquariums in Germany[46] and the USA.[2]
Cases of inhalation are also known. A man inhaled palytoxin when he tried to kill aPalythoa in his aquarium with boiling water.[47] In 2018, six people fromSteventon, 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 inCedar Park, Texas was poisoned when she scraped growing algae fromPalythoa 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]
A formerly unknown derivative of palytoxin, ovatoxin-a, produced as a marine aerosol by the tropicaldinoflagellateOstreopsis ovata caused hundreds of people inGenoa, 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]
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.
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.
