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| Names | |
|---|---|
| IUPAC name (E,2S,3R,5R,8R,9S)-10-ethyl]-2,6-dioxabicyclooctan-3-yl]-3,4-dihydroxy-pent-1-enyl]-3,4,5-trihydroxy-tetrahydropyran-2-yl]-2,8,9,10,17,18,19-heptahydroxy-20-methyl-14-methylene-henicosa-3,5,12-trienyl]-3,4,5-trihydroxy-tetrahydropyran-2-yl]-2,3-dihydroxy-butyl]-4,5-dihydroxy-tetrahydropyran-2-yl]-2,6,9,10-tetrahydroxy-3-methyl-dec-4-enyl]-3,4,5,6-tetrahydroxy-tetrahydropyran-2-yl]-8-hydroxy-nonyl]-1,3-dimethyl-6,8-dioxabicyclooctan-7-yl]-1,2,3,4,5-pentahydroxy-11-methyl-dodecyl]-3,4,5-trihydroxy-tetrahydropyran-2-yl]-2,5,8,9-tetrahydroxy-N--3,7-dimethyl-dec-6-enamide | |
| Identifiers | |
| CAS Number | |
| 3D model (JSmol) | |
| ChemSpider | |
| ECHA InfoCard | 100.162.538 
|
| PubChem CID | |
| CompTox Dashboard (EPA) | |
InChI
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SMILES
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| Properties | |
| Chemical formula | C129H223N3O54 |
| Molar mass | 2680.13 g.mol |
| Hazards | |
| Occupational safety and health (OHS/OSH): | |
| Main hazards | chest pains, asthma-like breathing difficulties, tachycardia, unstable blood pressure, hemolysis. |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa).
 Y verify (what is ?)
Infobox references
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Palytoxin is a very dangerous toxin; it is considered to be one of the most toxic non-peptide substances known, second only to maitotoxin in terms of toxicity in mice. Palytoxin is a natural compound that is produced by several marine species and can be found in many more species due to accumulation. Palytoxin was originally isolated in 1971 in Hawaii from the seaweed-like coral "Limu make o hana (Seaweed of Death from Hana)". Later, in 1982 its full chemical structure was published by Prof. Daisuke Uemura and co-workers at Nagoya University. Professor Yoshito Kishi's group at Harvard University first synthesized palytoxin in 1994. This feat is still considered today by many to be the greatest synthetic accomplishment ever, due to its complexity in structure. Palytoxin targets the sodium-potassium pump protein by binding to the molecule in such a way that the molecule is locked in a position where it allows passive transport of both the sodium and potassium ions, thereby destroying the ion gradient that is essential for most cells. Because palytoxin affects every cell in the body, the symptoms are very different for the different ways of exposure. The most common way of exposure in humans is oral. The onset of symptoms in a palytoxin poisoning is rapid, and death usually follows quickly.
History
Legend
According to an ancient Hawaiian legend, (Malo 1951) on the island of Maui near the harbour of Hana there was a village of fishermen haunted by a curse. Upon their return from the sea one of the fishermen went missing. One day, enraged by another loss, the fishermen assaulted a hunchbacked hermit deemed culprit of the town's misery. While ripping of the cloak from 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 harbour 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. 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.
Discovery
Palytoxin was first isolated in 1971, by Moore and Scheuer. It was then assessed that the limu-make-o-Hana was not a seaweed but an animal, a soft coral (Walsh and Bowers 1971). The molecule responsible for its high toxicity was named palytoxin.
Synthesis
Because palytoxin is such a huge molecule, it took some time before the complete structure (including stereochemistry) was elucidated. In 1982, this problem was solved almost simultaneously by Moore and Hirata. Palytoxin is a huge molecule with chemical formula C129H223N3O54. To accomplish this, it was synthesized in eight separate parts and then joined together to form the entire molecule. First, palytoxin carboxylic acid was synthesized in 1989 by the group of Harvard professor Yushito Kishi, and in 1994 they succeeded in making palytoxin from this carboxylic acid. The accomplishment of this synthesis has been named "the Mount Everest of organic synthesis, the largest single molecule that anyone has ever even thought about making" by Crawford in 1989.
Incidents
A new type of palytoxin, ovatoxin-a, produced as a marine aerosol by the tropical microalga O. ovata caused hundreds of people in Genoa, Italy, to fall ill. In 2005 and 2006 enormous blooms of these algae occurred in the Mediterranean sea. All those affected needed medical attention. Symptoms were high fever, coughs and wheezes.
Mechanism
The toxicity of palytoxin is due to its binding to Na,K-ATPase (sodium pump), where it interacts with the natural binding site of ouabain with very high affinity. Na,K-ATPase is a transmembranal protein, which is found on the surface of every vertebrate cell. Also, the sodium pump is necessary for viability of all cells, and this explains the fact that palytoxin affects all cells. Palytoxin is the first toxic compound found to cause formation of a channel. Through this channel, which it forms within the sodium pump, monovalent positive ions such as sodium and potassium can diffuse freely thereby destroying the ion gradient of the cell. Once palytoxin is bound to the pump, it flips constantly between open and normal conformations. The open conformation is more likely (>90% probability). If palytoxin disscociates, 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 are transported through a normal functioning transporter.
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. Therefore, there were some alternative hypotheses, which were reviewed by Frelin and van Renterghem in 1995. The breakthrough research which is seen as proof for the sodium pump mechanism was performed in yeast cells. These cells do not have the sodium 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.
Toxicity
An early toxicological characterization classified palytoxin as "relatively non-toxic" after intragastric administration to rats. The lethal dose (LD50) was greater than 40µg/kg. The LD50 after parenteral administration was lower than 1µg/kg. 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). More recently a study discovered an LD50 of 510µg/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 200µg/kg. It was also found that palytoxin is very toxic after intraperitoneal injection. The LD50 in mice was less than 1µg/kg. Because toxin-producing organisms spread to temperate climates and palytoxin-contaminated shellfish were discovered in the Mediterranean Sea a study was done to better define the toxic effects of palytoxin after oral exposure in mice. Palytoxin was lethal from 600µg/kg doses. The number of deaths were dose-dependent and the LD50 calculated to be 767µg/kg. This is comparable to the LD50 of 510µg/kg referred by Munday (2008). The toxicity was not different if the mice had some food in their stomach. The oral toxicity is three times lower than the intraperitoneal toxicity. This is because palytoxin is a very big hydrophilic molecule and therefore the absorption is less efficient through the gastrointestinal tract than through the peritoneum. Palytoxin is most toxic after intravenous injection. The LD50 in mice is 0.045µg/kg and in rats 0.089µg/kg. In other mammals (rabbits, dogs, monkeys and guinea pigs) the LD50 is ranged between 0.025 and 0.45µg/kg. They all died in several minutes to heart failure. The lethal dose for mice by the intra-tracheal route is above 2µg/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. There are cases where humans died after consumption of palytoxin. In the Philippines people died after eating Demania reynaudii, a crab species. After eating the sardine species Herklotsichthys quadrimaculatus some people died in Madagascar. Near fatal cases took place in Hawaii and Japan. In these cases people had eaten smoked fish and parrotfish respectively. There are also cases known that persons were poisoned by palytoxin through dermal absorption. Those people, in Germany and the USA , touched zoanthid corals in their aquariums at home. Another person was exposed to palytoxin via inhalation when he tried to kill a Palythoa in his aquarium with boiling water. Combining all animal studies, the toxic dose for humans was estimated to be between 2.3 and 31.5µg palytoxin. An acute reference dose was suggested to be 64µg for a person with weight of 60 kg.
| Exposure | LD50 in animals |
|---|---|
| Intravenous | Mice 0.054 μg/kg |
| Rats 0.089 μg/kg | |
| Intratracheal | Mice >2 μg/kg |
| Intraperitoneal | Mice <1 μg/kg |
| Oral | Mice 767 μg/kg |
Symptoms
Palytoxin could be related to ciguatera seafood poisoning and thus give rise to a number of symptoms related to this poisoning. Clupeotoxism, poisoning after consuming clupeoid fish, is also suggested to be caused by palytoxin. Neurological and gastrointestinal disturbances are associated with clupeotoxism. The most common complication of palytoxin poisoning is rhabdomyolysis. This involves skeletal muscle breakdown and the leakage of intracellular contents into the blood plasma. Other symptoms associated with palytoxin poisoning in humans are characterized by a bitter/metallic taste, abdominal cramps, nausea, vomiting, diarrhea, mild to acute lethargy, paresthesia, bradycardia, renal failure, impairment of sensation, muscle spasms, tremor myalgia, cyanosis, and respiratory distress. In the fatal cases of palytoxin poisoning, the poisoning mostly results in death due to myocardial injury. Exposure to aerosols, as happened in Italy in 2005 and 2006 (see Incidents section), results mainly in respiratory illness. Other symptoms caused by these aerosols include fever associated with serious respiratory disturbs, such as bronchoconstriction, mild dyspnea, and wheezes, while conjunctivitis was observed in some cases. Palytoxin is also classified as a non-TPAtype tumor promoter.
Treatment
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. Treatment in humans is symptomatic and supportive.
References
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- Clayden, J., Greeves, N. (2000), pages 19-21
- Chemical Society of Japan, et al. (2005). "CSJ Award-2005 Prof. Daisuke Uemura" Retrieved on 24 July 2007 from http://www.chemistry.or.jp/csj-en/membership/awards/achieve/2005-uemura.html Chemical Soc. of Japan, Prof. D. Uemura
- Chemical Society of Japan, et al. (2005), -- "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 origin."
- J. K. Cha, W. J. Christ, J. M. Finan, H. Fujioka, Y. Kishi, L. L. Klein, S. S. Ko, J. Leder, W. W. McWhorter, Jr., K. -P. Pfaff, M. Yonaga, D. Uemura, and Y. Hirata (1982). "Stereochemistry of Palytoxin. 4. Complete Structure". J. Am. Chem. Soc. 104 (25): 7369–7371. doi:10.1021/ja00389a101.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - R.W. Armstrong, J.-M. Beau, S.H. Cheon, W.J. Christ, H. Fujioka, W.-H. Ham, L.D. Hawkins, H. Jin, S.H. Kang, Y. Kishi, M.J. Martinelli, W.W. McWhorter, Jr., M. Mizuno, M. Nakata, A.E. Stutz, F.X. Talamas, M. Taniguchi, J.A. Tino, K. Ueda, J. Uenishi, J.B. White, and M. Yonaga (1989). "Total Synthesis of Palytoxin Carboxylic Acid and Palytoxin Amide". J. Am. Chem. Soc. 111: 7530.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Suh EM and Kishi Y (1994). "Synthesis of Palytoxin from Palytoxin Carboxylic Acid". J. Am. Chem. Soc. 116: 11205.
- Clayden, J., Greeves, N. (2000), pages 19-21
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{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Gadsby DC, Takeuchi A; et al. (2009). "Peering into an ATPase ion pump with single-channel recordings". Philosophical Transactions of the Royal Society B-Biological Sciences. 364 (1514): 229–238. doi:10.1098/rstb.2008.0243.
{{cite journal}}: Explicit use of et al. in:|author=(help) - Frelin C and Vanrenterghem C (1995). "Palytoxin - Recent Electrophysiological and Pharmacological Evidence for Several Mechanisms of Action". General Pharmacology. 26 (1): 33–37. PMID 7713364.
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{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Wiles JS, Vick JA, Christensen MK (1974). "Toxicological evaluation of palytoxin in several animal species". Toxicon. 12 (4): 427–433. doi:10.1016/0041-0101(74)90011-7. PMID 4155146.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Ito E, Yasumoto T (2009). "Toxicological studies on palytoxin and ostreocin-d administered to mice by three different routes". Toxicon. 54 (3): 244–251. doi:10.1016/j.toxicon.2009.04.009. PMID 19376151.
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{{cite journal}}: CS1 maint: multiple names: authors list (link) - Onuma Y, Satake M, Ukena T, Roux J, Chanteau S, Rasolofonirina N, Ratsimaloto M, Naoki H, Yasumoto T (1999). "Identification of putative palytoxin as the cause of clupeotoxism". Toxicon. 37 (1): 55–65. doi:10.1016/S0041-0101(98)00133-0. PMID 9920480.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Kodama AM, Hokama Y, Yasumoto T, Fukui M, Manea SJ, Sutherland N (1989). "Clinical and laboratory findings implicating palytoxin as cause of ciguatera poisoning due to Decapterus macrosoma (mackerel)". Toxicon. 27 (9): 1051–1053. doi:10.1016/0041-0101(89)90156-6. PMID 2572075.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Okano H, Masuoka H, Kamei S, Seko T, Koyabu S, Tsuneoka K, Tamai T, Ueda K, Nakazawa S, Sugawa M, Suzuki H, Watanabe M, Yatani R, Nakano T (1998). "Rhabdomyolysis and myocardial damage induced by palytoxin, a toxin of blue humphead parrotfish". Internal Med. 37 (3): 330–333. doi:10.2169/internalmedicine.37.330.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Hoffmann K, Hermanns-Clausen M, Buhl C, Buchler MW, Schemmer P, Mebs D, Kauferstein S (2008). "A case of palytoxin poisoning due to contact with zoanthid corals through a skin injury". Toxicon. 51 (8): 1535–1537. doi:10.1016/j.toxicon.2008.03.009. PMID 18433818.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Majlesi N, Su MK, Chan GM, Lee DC, Greller HA (2008). "A case of inhalational exposure to palytoxin". Clin. Toxicol. 46: 637.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Riobó P, Paz B, Franco JM (2006). "Analysis of palytoxin-like in Ostreopsis cultures by liquid chromatography with precolumn derivatization and fluorescence detection". Anal. Chim. Acta. 566 (2): 217–223. doi:10.1016/j.aca.2006.03.013.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Rhodes, L., Munday, R., Briggs, L., 2008. Ostreopsis siamensis and palytoxin-related compounds in New Zealand: a risk to human health? In: Moestrup, Ø. (Ed.), Proceedings of the 12th International Conference on Harmful Algae. ISSHA and Intergovernmental Oceanographic Commission of UNESCO. Copenhagen, Denmark, pp. 326–329
- ^ Louzao MC, Ares IR; et al. (2008). "Marine toxins and the cytoskeleton: a new view of palytoxin toxicity". FEBS Journal. 275 (24): 6067–6074. doi:10.1111/j.1742-4658.2008.06712.x. PMID 19016862.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Vasconcelos V, Ramos V (2010). "Palytoxin and Analogs: Biological and Ecological Effects". Marine Drugs. 8 (7): 2021–2037. doi:10.3390/md8072021. PMC 2920541. PMID 20714422.
{{cite journal}}: CS1 maint: unflagged free DOI (link)
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