Palytoxin

Palytoxin
Names
IUPAC name
(2S,3R,5R,6E,8R,9S)-10-[(2R,3R,4R,5S,6R)-6-[(1S,2R,3S,4S,5R,11S)-11-{[(1R,3S,5S,7R)-5-[(8S)-9-[(2R,3R,4R,5R,6S)-6-[(2S,3S,4E,6S,9R,10R)-10-[(2S,4R,5S,6R)-6-[(2R,3R)-4-[(2R,3S,4R,5R,6S)-6-[(2S,3Z,5E,8R,9S,10R,12Z,17S,18R,19R,20R)-20-{[(2R,3R,4R,5S,6R)-6-[(1Z,3R,4R)-5-[(1S,3R,5R,7R)-7-{2-[(2R,3R,5S)-5-(aminomethyl)-3-hydroxyoxolan-2-yl]ethyl}-2,6-dioxabicyclo[3.2.1]octan-3-yl]-3,4-dihydroxypent-1-en-1-yl]-3,4,5-trihydroxyoxan-2-yl]methyl}-2,8,9,10,17,18,19-heptahydroxy-14-methylidenehenicosa-3,5,12-trien-1-yl]-3,4,5-trihydroxyoxan-2-yl]-2,3-dihydroxybutyl]-4,5-dihydroxyoxan-2-yl]-2,6,9,10-tetrahydroxy-3-methyldec-4-en-1-yl]-3,4,5,6-tetrahydroxyoxan-2-yl]-8-hydroxynonyl]-1,3-dimethyl-6,8-dioxabicyclo[3.2.1]octan-7-yl]methyl}-1,2,3,4,5-pentahydroxydodecyl]-3,4,5-trihydroxyoxan-2-yl]-2,5,8,9-tetrahydroxy-N-[(1E)-2-[(3-hydroxypropyl)-C-hydroxycarbonimidoyl]eth-1-en-1-yl]-3,7-dimethyldec-6-enimidic acid
Identifiers
77734-91-9 YesY
ChemSpider 9280425 YesY
Jmol interactive 3D Image
PubChem 11105289
Properties
C129H223N3O54
Molar mass 2690.22 g.mol−1[1]
Appearance white amorphous hygroscopic solid[1]
Melting point decomposes at 300°C [1]
Very soluble in water, dimethyl sulfoxide, pyridine; slightly soluble in methanol and ethanol; insoluble in chloroform and diethyl ether[1]
Hazards
Main hazards Highly toxic, symptoms of poisoning include: chest pains, breathing difficulties, tachycardia, unstable blood pressure and hemolysis.[2]
GHS pictograms
T+
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

Palytoxin is an intense vasoconstrictor,[1] and is considered to be one of the most toxic non-protein substances known, second only to maitotoxin in terms of toxicity in mice. Palytoxin is a natural compound, (chemically a fatty alcohol) that is produced by several marine species and can be found in many more species due to a process known as biomagnification. Palytoxin was originally isolated in 1971 in Hawaii from the seaweed-like coral "limu-make-o-Hana" (Seaweed of Death from Hana).[3] Later, in 1982 its full chemical structure was published by Prof. Daisuke Uemura and co-workers at Nagoya University.[4][5][6] Yoshito Kishi's group at Harvard University first synthesized palytoxin in 1994.[7][8] 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 most cells. Because palytoxin affects every cell in the body, the symptoms are very different for the various routes of exposure. The most common exposure in humans is by ingestion or inhalation. The onset of symptoms 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 off 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."[3] The Hawaiians believed that an ill curse came over them if they tried to collect the deadly seaweed.[9]

Discovery

Palytoxin was first isolated in 1971, by Moore and Scheuer.[10] 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.[9]

Total synthesis

Because palytoxin is such a large molecule, it took some time before the complete structure (including stereochemistry) was elucidated. In 1982, this problem was solved almost simultaneously by Moore[11] and Hirata.[12] Palytoxin's structure being established, 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 Yoshito Kishi, and in 1994 they succeeded in making palytoxin from this carboxylic acid.[13][14] 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.[15]

Incidents

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 enormous blooms of these algae occurred in the Mediterranean sea. All those affected needed hospitalization. Symptoms were high fever, coughs and wheezes.[9]

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.[16] 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.[17][18] 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.[19] 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.[19]

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.[16] Therefore, there were some alternative hypotheses, which were reviewed by Frelin and van Renterghem in 1995.[20] 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.[21]

Toxicity

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.[22] 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.[23] It was also found that palytoxin is very toxic after intraperitoneal injection. The LD50 in mice was less than 1 µg/kg.[24] Because toxin-producing organisms spread to temperate climates and palytoxin-contaminated shellfish were discovered in the Mediterranean Sea[25] 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.[26] A recent study by Fernandez et al [27] 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 to heart failure.[2] The lethal dose for mice by the intra-tracheal 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.[23] There are cases where humans died after consumption of palytoxin. In the Philippines people died after eating Demania reynaudii, a crab species.[28] After eating the sardine species Herklotsichthys quadrimaculatus some people died in Madagascar.[29] Near fatal cases took place in Hawaii[30] and Japan.[31] 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[32] and the USA,[2] touched zoanthid corals in their aquariums at home. Another person was exposed to palytoxin via inhalation[33] 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 31.5 µg palytoxin.[34] An acute reference dose was suggested to be 64 µg for a person with weight of 60 kg.[35]

There has been reported cases where individuals have been presumably poisoned from cleaning organisms containing palytoxin under steaming water. Precautions should be taken as the palytoxin can travel in water vapor and cause poisoning by inhalation.

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

In this context despite the increasing 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 the last years, many methodologies has been described with particular attention on the develop of new techniques for the ultrasensitive detection of palytoxin in real matrix such as mussels and microalgae (based on LC-MS-MS[36] or immunoassay[37]).

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.[38] The most common complication of palytoxin poisoning is rhabdomyolysis. This involves skeletal muscle breakdown and the leakage of intracellular contents into the blood plasma.[39] 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.[38][39] 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 disturbances, such as bronchoconstriction, mild dyspnea, and wheezes, while conjunctivitis was observed in some cases.[38][39] Palytoxin is also classified as a non-TPAtype tumor promoter.[9]

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.[22] Treatment in humans is symptomatic and supportive.

References

  1. 1 2 3 4 5 Budavari, Susan, ed. (2001), The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals (13th ed.), Merck, ISBN 0911910131
  2. 1 2 3 Deeds JR, Schwartz MD (2009). "Human risk associated with palytoxin exposure". Toxicon 56 (2): 150–162. doi:10.1016/j.toxicon.2009.05.035. PMID 19505494.
  3. 1 2 Clayden, Jonathan; Greeves, Nick; Warren, Stuart; Wothers, Peter (2001). Organic Chemistry (1st ed.). Oxford University Press. pp. 19–21. ISBN 978-0-19-850346-0.
  4. ↑ 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
  5. ↑ 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[n] origin."
  6. ↑ 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.
  7. ↑ 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. doi:10.1021/ja00201a038.
  8. ↑ Suh EM and Kishi Y (1994). "Synthesis of Palytoxin from Palytoxin Carboxylic Acid". J. Am. Chem. Soc. 116: 11205. doi:10.1021/ja00103a065.
  9. 1 2 3 4 Forino M, Ciminiello P, et al. (2010). "Palytoxins: A still haunting Hawaiian curse". Phytochemistry Reviews 9 (4): 491–500. doi:10.1007/s11101-010-9185-x.
  10. ↑ Moore RE and Scheuer PJ (1971). "Palytoxin - New Marine Toxin from a Coelenterate". Science 172 (3982): 495–498. doi:10.1126/science.172.3982.495.
  11. ↑ Moore RE, Bartolini G, et al. (1982). "Absolute Stereochemistry of Palytoxin". Journal of the American Chemical Society 104 (13): 3776–3779. doi:10.1021/ja00377a064.
  12. ↑ Cha JK, Christ WJ, et al. (1982). "Stereochemistry of Palytoxin .4. Complete Structure". Journal of the American Chemical Society 104 (25): 7369–7371. doi:10.1021/ja00389a101.
  13. ↑ Armstrong RW, Beau JM, et al. (1989). "Total Synthesis of Palytoxin Carboxylic-Acid and Palytoxin Amide". Journal of the American Chemical Society 111 (19): 7530–7533. doi:10.1021/ja00201a038.
  14. ↑ Suh EM and Kishi Y (1994). "Synthesis of Palytoxin from Palytoxin Carboxylic-Acid". Journal of the American Chemical Society 116 (24): 11205–11206. doi:10.1021/ja00103a065.
  15. ↑ Crawford MH (1989). "Harvard Synthesizes Palytoxin Molecule". Science 246 (4926): 34–34. doi:10.1126/science.246.4926.34-c.
  16. 1 2 Wu CH (2009). "Palytoxin: Membrane mechanisms of action". Toxicon 54 (8): 1183–1189. doi:10.1016/j.toxicon.2009.02.030. PMID 19269304.
  17. ↑ Habermann E (1989). "Palytoxin Acts through Na+,K+-Atpase". Toxicon 27 (11): 1171–1187. doi:10.1016/0041-0101(89)90026-3. PMID 2575806.
  18. ↑ Redondo J, Fiedler B, et al. (1996). "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. PMID 8569711.
  19. 1 2 Gadsby DC, Takeuchi A, et al. (2009). "Peering into an ATPase ion pump with single-channel recordings". Philosophical Transactions of the Royal Society B 364 (1514): 229–238. doi:10.1098/rstb.2008.0243.
  20. ↑ Frelin C and Vanrenterghem C (1995). "Palytoxin - Recent Electrophysiological and Pharmacological Evidence for Several Mechanisms of Action". General Pharmacology 26 (1): 33–37. doi:10.1016/0306-3623(94)00133-8. PMID 7713364.
  21. ↑ Scheiner-Bobis G, Meyer zu Heringdorf D, et al. (1994). "Palytoxin Induces K+ Efflux from Yeast-Cells Expressing the Mammalian Sodium-Pump". Molecular Pharmacology 45 (6): 1132–1136. PMID 7912814.
  22. 1 2 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.
  23. 1 2 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.
  24. ↑ Rhodes LL, Towers N, Briggs L, Munday R, Adamson JE (2002). "Uptake of palytoxin like compounds by shellfish fed Ostreopsis siamensis (Dinophyceae)". New Zealand J. Med. Freshwater Res. 36 (3): 631–636. doi:10.1080/00288330.2002.9517118.
  25. ↑ Aligizaki K, Panagiota K, Nikolaidis G, Panou A (2008). "First episode of shellfish contamination by palytoxin-like compounds from Ostreopsis species (Aegean Sea, Greece)". Toxicon 51 (3): 418–427. doi:10.1016/j.toxicon.2007.10.016. PMID 18067938.
  26. ↑ Ito E, Ohkusu M, Yasumoto T (1996). "Intestinal injuries caused by experimental palytoxicosis in mice". Toxicon 34 (6): 643–652. doi:10.1016/0041-0101(96)00005-0. PMID 8817810.
  27. ↑ Fernandez DA, Louzao MC, Vilarino N, Espina B, Fraga M, Vieytes MR, Roman A, Poli M, Botana LM (2013). "The kinetic, mechanistic and cytomorphological effects of palytoxin in human intestinal cells (Caco-2) explain its lower-than-parenteral oral toxicity". FEBS Journal 280 (16): 3906–3919. doi:10.1111/febs.12390. PMID 23773601.
  28. ↑ Alcala AC, Alcala LC, Garth JS, Yasumura D, Yasumoto T (1988). "Human fatality due to ingestion of the crab Demania reynaudii that contained a palytoxin-like toxin". Toxicon 26 (1): 105–107. doi:10.1016/0041-0101(88)90142-0. PMID 2894726.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ Majlesi N, Su MK, Chan GM, Lee DC, Greller HA (2008). "A case of inhalational exposure to palytoxin". Clin. Toxicol. 46: 637.
  34. ↑ 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.
  35. ↑ 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
  36. ↑ Ciminiello,, P.; Dell'Aversano, C.; Dello Iacovo, E.; Fattorusso, E.; Forino, M.; Tartaglione, L. (2011). "LC-MS of Palytoxin and Its Analogues: State of the Art and Future Perspectives.". Toxicon 57: 376–389. doi:10.1016/j.toxicon.2010.11.002.
  37. ↑ Zamolo, V.; Valenti, G.; Venturelli, E.; Chaloin, O.; Marcaccio, M.; Boscolo, S.; Castagnola, V.; Sosa, S.; Berti, F.; Fontanive, G.; Poli, M.; Tubaro, A.; Bianco, A.; Paolucci, F.; Prato, M. (August 2012). "Highly Sensitive Electrochemiluminescent Nanobiosensor for the Detection of Palytoxin". ACS Nano 6 (9): 7989–7997. doi:10.1021/nn302573c.
  38. 1 2 3 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.
  39. 1 2 3 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.
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