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{{short description|Chemical compound}}
{{Use dmy dates|date=July 2020}}
{{Chembox {{Chembox
| Watchedfields = changed
| verifiedrevid = 442062973
| verifiedrevid = 450619714
| ImageFile = Palytoxin.png
| ImageFile = Palytoxin.svg
| ImageSize =
| ImageAlt = | ImageSize = 250px
| ImageAlt =
| IUPACName = (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
| PIN = <small>(2''S'',3''R'',5''R'',6''E'',8''R'',9''S'')-10-octana)henheptacontaphane-8,19,26,28,43-pentaen-71<sup>6</sup>-yl]-''N''-{(1''E'')-3--3-oxoprop-1-en-1-yl}-2,5,8,9-tetrahydroxy-3,7-dimethyldec-6-enamide</small>
| IUPACName_hidden = yes
|Section1={{Chembox Identifiers
| OtherNames =
| Abbreviations = PTX
| Section1 = {{Chembox Identifiers
| CASNo_Ref = {{cascite|correct|??}}
| CASNo = 77734-91-9
| PubChem = 11105289 | CASNo = 77734-91-9
| UNII_Ref = {{fdacite|correct|FDA}}
| SMILES = CC1CC2(C(OC(C1)(O2)CCCCCCCC(CC3C(C(C(C(O3)(CC(C(C)C=CC(CCC(C(C4CC(C(C(O4)CC(C(CC5C(C(C(C(O5)CC(C=CC=CCC(C(C(CC=CC(=C)CCC(C(C(C(C)CC6C(C(C(C(O6)C=CC(C(CC7CC8CC(O7)C(O8)CCC9C(CC(O9)CN)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)CC(C)CCCCCC(C(C(C(C(C1C(C(C(C(O1)CC(C(C(=CC(CC(C)C(C(=O)NC=CC(=O)NCCCO)O)O)C)O)O)O)O)O)O)O)O)O)O)C
| UNII = OQ17NC0MOV
| InChI = 1/C129H223N3O54/c1-62(29-33-81(143)108(158)103(153)68(7)47-93-111(161)117(167)110(160)91(180-93)36-35-76(138)82(144)51-73-50-74-53-92(178-73)90(177-74)38-37-89-85(147)52-75(61-130)179-89)23-20-28-78(140)105(155)77(139)26-18-13-16-25-70(135)48-94-112(162)118(168)113(163)97(181-94)55-84(146)83(145)54-95-107(157)87(149)57-96(182-95)106(156)80(142)34-32-69(134)31-30-65(4)88(150)60-129(176)125(174)123(173)115(165)99(184-129)49-71(136)24-15-10-9-11-19-40-128-59-64(3)58-127(8,186-128)100(185-128)44-63(2)22-14-12-17-27-79(141)109(159)116(166)120(170)122(172)124-121(171)119(169)114(164)98(183-124)56-86(148)102(152)66(5)45-72(137)46-67(6)104(154)126(175)132-42-39-101(151)131-41-21-43-133/h13,16,18,20,23,25,30-31,35-36,39,42,45,63-65,67-100,102-125,133-150,152-174,176H,1,9-12,14-15,17,19,21-22,24,26-29,32-34,37-38,40-41,43-44,46-61,130H2,2-8H3,(H,131,151)(H,132,175)/b18-13+,23-20-,25-16-,31-30+,36-35-,42-39+,66-45+/t63-,64-,65-,67+,68+,69+,70+,71-,72-,73-,74+,75-,76+,77+,78+,79+,80+,81-,82+,83+,84+,85+,86-,87+,88-,89+,90+,91+,92-,93+,94-,95+,96-,97+,98+,99+,100+,102+,103+,104-,105-,106+,107-,108+,109-,110+,111-,112-,113+,114-,115-,116-,117-,118+,119+,120+,121-,122-,123+,124-,125+,127+,128-,129-/m0/s1
| PubChem = 11105289
| InChIKey = CWODDUGJZSCNGB-HQNRRURTBU
| SMILES = NC1C((O1)CC1O2C(O1C2)C((\C=C/2((((O2)C((((CCC(\C=C/C(((C/C=C/C=C\(C2((((O2)C((C2((C(O2)((CC(/C=C/((C2(((((O2)C(CCCCCCC21C(C((O2)C(CCCCC(((((O)2((((O2)C((/C(=C/(C((C(O)=N\C=C\C(=NCCCO)O)O)C)O)/C)O)O)O)O)O)O)O)O)O)C)(O1)C)C)O)O)O)O)O)O)C)O)O)O)O)O)O)O)O)O)O)O)O)O)O)=C)O)O)O)C)O)O)O)O)O)O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| InChI = 1/C129H223N3O54/c1-62(29-33-81(143)108(158)103(153)68(7)47-93-111(161)117(167)110(160)91(180-93)36-35-76(138)82(144)51-73-50-74-53-92(178-73)90(177-74)38-37-89-85(147)52-75(61-130)179-89)23-20-28-78(140)105(155)77(139)26-18-13-16-25-70(135)48-94-112(162)118(168)113(163)97(181-94)55-84(146)83(145)54-95-107(157)87(149)57-96(182-95)106(156)80(142)34-32-69(134)31-30-65(4)88(150)60-129(176)125(174)123(173)115(165)99(184-129)49-71(136)24-15-10-9-11-19-40-128-59-64(3)58-127(8,186-128)100(185-128)44-63(2)22-14-12-17-27-79(141)109(159)116(166)120(170)122(172)124-121(171)119(169)114(164)98(183-124)56-86(148)102(152)66(5)45-72(137)46-67(6)104(154)126(175)132-42-39-101(151)131-41-21-43-133/h13,16,18,20,23,25,30-31,35-36,39,42,45,63-65,67-100,102-125,133-150,152-174,176H,1,9-12,14-15,17,19,21-22,24,26-29,32-34,37-38,40-41,43-44,46-61,130H2,2-8H3,(H,131,151)(H,132,175)/b18-13+,23-20-,25-16-,31-30+,36-35-,42-39+,66-45+/t63-,64-,65-,67+,68+,69+,70+,71-,72-,73-,74+,75-,76+,77+,78+,79+,80+,81-,82+,83+,84+,85+,86-,87+,88-,89+,90+,91+,92-,93+,94-,95+,96-,97+,98+,99+,100+,102+,103+,104-,105-,106+,107-,108+,109-,110+,111-,112-,113+,114-,115-,116-,117-,118+,119+,120+,121-,122-,123+,124-,125+,127+,128-,129-/m0/s1
| InChIKey = CWODDUGJZSCNGB-HQNRRURTBU
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C129H223N3O54/c1-62(29-33-81(143)108(158)103(153)68(7)47-93-111(161)117(167)110(160)91(180-93)36-35-76(138)82(144)51-73-50-74-53-92(178-73)90(177-74)38-37-89-85(147)52-75(61-130)179-89)23-20-28-78(140)105(155)77(139)26-18-13-16-25-70(135)48-94-112(162)118(168)113(163)97(181-94)55-84(146)83(145)54-95-107(157)87(149)57-96(182-95)106(156)80(142)34-32-69(134)31-30-65(4)88(150)60-129(176)125(174)123(173)115(165)99(184-129)49-71(136)24-15-10-9-11-19-40-128-59-64(3)58-127(8,186-128)100(185-128)44-63(2)22-14-12-17-27-79(141)109(159)116(166)120(170)122(172)124-121(171)119(169)114(164)98(183-124)56-86(148)102(152)66(5)45-72(137)46-67(6)104(154)126(175)132-42-39-101(151)131-41-21-43-133/h13,16,18,20,23,25,30-31,35-36,39,42,45,63-65,67-100,102-125,133-150,152-174,176H,1,9-12,14-15,17,19,21-22,24,26-29,32-34,37-38,40-41,43-44,46-61,130H2,2-8H3,(H,131,151)(H,132,175)/b18-13+,23-20-,25-16-,31-30+,36-35-,42-39+,66-45+/t63-,64-,65-,67+,68+,69+,70+,71-,72-,73-,74+,75-,76+,77+,78+,79+,80+,81-,82+,83+,84+,85+,86-,87+,88-,89+,90+,91+,92-,93+,94-,95+,96-,97+,98+,99+,100+,102+,103+,104-,105-,106+,107-,108+,109-,110+,111-,112-,113+,114-,115-,116-,117-,118+,119+,120+,121-,122-,123+,124-,125+,127+,128-,129-/m0/s1 | StdInChI = 1S/C129H223N3O54/c1-62(29-33-81(143)108(158)103(153)68(7)47-93-111(161)117(167)110(160)91(180-93)36-35-76(138)82(144)51-73-50-74-53-92(178-73)90(177-74)38-37-89-85(147)52-75(61-130)179-89)23-20-28-78(140)105(155)77(139)26-18-13-16-25-70(135)48-94-112(162)118(168)113(163)97(181-94)55-84(146)83(145)54-95-107(157)87(149)57-96(182-95)106(156)80(142)34-32-69(134)31-30-65(4)88(150)60-129(176)125(174)123(173)115(165)99(184-129)49-71(136)24-15-10-9-11-19-40-128-59-64(3)58-127(8,186-128)100(185-128)44-63(2)22-14-12-17-27-79(141)109(159)116(166)120(170)122(172)124-121(171)119(169)114(164)98(183-124)56-86(148)102(152)66(5)45-72(137)46-67(6)104(154)126(175)132-42-39-101(151)131-41-21-43-133/h13,16,18,20,23,25,30-31,35-36,39,42,45,63-65,67-100,102-125,133-150,152-174,176H,1,9-12,14-15,17,19,21-22,24,26-29,32-34,37-38,40-41,43-44,46-61,130H2,2-8H3,(H,131,151)(H,132,175)/b18-13+,23-20-,25-16-,31-30+,36-35-,42-39+,66-45+/t63-,64-,65-,67+,68+,69+,70+,71-,72-,73-,74+,75-,76+,77+,78+,79+,80+,81-,82+,83+,84+,85+,86-,87+,88-,89+,90+,91+,92-,93+,94-,95+,96-,97+,98+,99+,100+,102+,103+,104-,105-,106+,107-,108+,109-,110+,111-,112-,113+,114-,115-,116-,117-,118+,119+,120+,121-,122-,123+,124-,125+,127+,128-,129-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = CWODDUGJZSCNGB-HQNRRURTSA-N | StdInChIKey = CWODDUGJZSCNGB-HQNRRURTSA-N
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 9280425 | ChemSpiderID = 9280425
}} }}
| Section2 = {{Chembox Properties |Section2={{Chembox Properties
| Formula = | C=129 | H=223 | N=3 | O=54 | Formula = | C=129 | H=223 | N=3 | O=54
| MolarMass = 2680.13 g.mol<sup>-1</sup> | MolarMass = 2680.1386 grams/mol
| Appearance = white amorphous hygroscopic solid<ref name="Merck">Budavari, Susan, ed. (2001), The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals (13th ed.), Merck, {{ISBN|0911910131}}</ref>
| Appearance =
| MeltingPt = decomposes at 300&nbsp;°C<ref name="Merck"/>
| Density =
| MeltingPt = | BoilingPt =
| SolubleOther= Very soluble in ], ], ]; slightly soluble in methanol and ethanol; insoluble in ] and ]<ref name="Merck"/>}}
| BoilingPt =
|Section3={{Chembox Hazards
| Solubility = }}
| GHSPictograms = {{GHS skull and crossbones}}
| Section3 = {{Chembox Hazards
| MainHazards = chest pains, asthma-like breathing difficulties, tachycardia, unstable blood pressure, hemolysis.<ref name="deeds"/> | MainHazards = Extremely toxic, symptoms of poisoning include: chest pains, breathing difficulties, tachycardia, unstable blood pressure and hemolysis.<ref name="deeds"/>
| FlashPt = | FlashPt =
| Autoignition = }} | AutoignitionPt = }}
}} }}
'''Palytoxin''', '''PTX'''<ref name="vasconcelos">{{cite journal | vauthors = Ramos V, Vasconcelos V | title = Palytoxin and analogs: biological and ecological effects | journal = Marine Drugs | volume = 8 | issue = 7 | pages = 2021–37 | date = June 2010 | pmid = 20714422 | pmc = 2920541 | doi = 10.3390/md8072021 | doi-access = free }}</ref> or '''PLTX'''<ref>{{cite journal | vauthors = Pelin M, Brovedani V, Sosa S, Tubaro A | title = Palytoxin-Containing Aquarium Soft Corals as an Emerging Sanitary Problem | journal = Marine Drugs | volume = 14 | issue = 2 | pages = 33 | date = February 2016 | pmid = 26861356 | pmc = 4771986 | doi = 10.3390/md14020033 | doi-access = free }}</ref> is an intense ],<ref name="Merck"/> and is considered to be one of the most poisonous non-] substances known, second only to ] in terms of toxicity in mice.<ref name=":6">{{cite journal | vauthors = Sud P, Su MK, Greller HA, Majlesi N, Gupta A | title = Case series: inhaled coral vapor--toxicity in a tank | journal = Journal of Medical Toxicology | volume = 9 | issue = 3 | pages = 282–6 | date = September 2013 | pmid = 23702624 | pmc = 3770997 | doi = 10.1007/s13181-013-0307-x }}</ref>
'''Palytoxin''' is a very dangerous toxin; it is considered to be one of the most toxic non-peptide substances known, second only to ] 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 ] from the seaweed-like coral "]".<ref>Clayden, J., Greeves, N. (2000), pages 19-21</ref> Later, in 1982 its full chemical structure was published by Prof. Daisuke Uemura and co-workers at ].<ref>Chemical Society of Japan, et al. (2005). "CSJ Award-2005 Prof. Daisuke Uemura" Retrieved on 24 July 2007 from Chemical Soc. of Japan, Prof. D. Uemura</ref><ref>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.''"</ref><ref>{{cite journal |title=Stereochemistry of Palytoxin. 4. Complete Structure |author=J. K. Cha, W. J. Christ, J. M. Finan, H. Fujioka, ], L. L. Klein, S. S. Ko, J. Leder, W. W. McWhorter, Jr., K. -P. Pfaff, M. Yonaga, D. Uemura, and Y. Hirata |journal=J. Am. Chem. Soc. |volume=104 |pages=7369–7371 |year=1982 |doi=10.1021/ja00389a101 |issue=25}}</ref> Professor ]'s group at ] first synthesized palytoxin in 1994.<ref>{{cite journal |title=Total Synthesis of Palytoxin Carboxylic Acid and Palytoxin Amide |author=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, ], 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 |journal=J. Am. Chem. Soc. |volume=111 |page=7530 |year=1989}}</ref><ref>{{cite journal |title=Synthesis of Palytoxin from Palytoxin Carboxylic Acid |author=Suh EM and Kishi Y |journal=J. Am. Chem. Soc. |volume=116 |page=11205 |year=1994}}</ref> This feat is still considered today by many to be the greatest synthetic accomplishment ever, due to its complexity in structure. {{Citation needed|date=April 2011}}
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 ]s and 64 ]. Due to ] and possible ] ], it has over ] alternative ]. It is ], 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 ]ic or ] solutions. It has multiple ] with a similar structure like ostreocin-D, mascarenotoxin-A and -B.<ref name="vasconcelos" />
Palytoxin targets the ] ] by binding to the molecule in such a way that the molecule is locked in a position where it allows ] of both the ] and ] ions, thereby destroying the ] that is essential for most ].

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.
Palytoxin occurs at least in ] and ] where it is made by '']'' corals and '']'' ]s, or possibly by ] occurring in these organisms. It can be found in many more species like ] and ]s due to the process of ]. It can also be found in organisms living close to palytoxin producing organisms like ]s, ]s, ] and ].<ref name="vasconcelos" />

People are rarely exposed to palytoxin. Exposures have happened in people who have eaten sea animals like fish and crabs, but also in ] hobbyists who have handled ''Palythoa'' corals incorrectly and in those who have been exposed to certain ]s.<ref name="deeds" />

Palytoxin targets the ] ] by locking it into a position where it allows ] of both ] and ] ions, thereby destroying the ] that is essential for life.<ref name="gadsby" /> As palytoxin can affect every type of cell in the body, the symptoms can be very different for the various routes of exposure.<ref name="deeds" />

Palytoxin's planar chemical structure was solved in 1981 by two research groups independently from each other.<ref name="vasconcelos" /> ] was solved in 1982.<ref name="moore82">{{cite journal|vauthors=Moore RE, Bartolini G, et al|date=June 1982|title=Absolute Stereochemistry of Palytoxin |journal=Journal of the American Chemical Society|volume=104|issue=13|pages=3776–3779|doi=10.1021/ja00377a064 |bibcode=1982JAChS.104.3776M }}</ref><ref name=":4">{{Cite journal| vauthors = Klein LL, McWhorter WW, Ko SS, Pfaff KP, KishiB Y, Uemura D, Hirata Y | date=December 1982|title=Stereochemistry of palytoxin. Part 1. C85-C115 segment |journal=Journal of the American Chemical Society|volume=104|issue=25|pages=7362–7364|doi=10.1021/ja00389a098 | bibcode=1982JAChS.104.7362K}}</ref><ref name=":3">{{Cite journal | vauthors = Cha JK, Christ WJ, Finan JM, Fujioka H, Kishi Y, Klein LL, Ko SS, Leder J, McWhorter WW | display-authors=6|date=December 1982|title=Stereochemistry of palytoxin. Part 4. Complete structure |journal=Journal of the American Chemical Society|volume=104|issue=25|pages=7369–7371|doi=10.1021/ja00389a101| bibcode=1982JAChS.104.7369C|issn=0002-7863 }}</ref> Palytoxin ] was synthesized by ] and colleagues in 1989<ref name=":1">{{cite journal| vauthors = Armstrong RW, Beau JM, Cheon SH, Christ WJ, Fujioka H, Ham WH, Hawkins LD, Jin H, Kang SH, Kishi Y, Martinelli MJ, McWhorter WW, Mizuno M, Nakata M, Stutz AE, Talamas FX, Taniguchi M, Tino JA, Ueda K, Uenishi J, White JB, Yonaga M
| display-authors = 6 |year=1989|title=Total Synthesis of Palytoxin Carboxylic Acid and Palytoxin Amide |journal=J. Am. Chem. Soc.|volume=111| issue = 19 |page=7530|doi=10.1021/ja00201a038 | bibcode = 1989JAChS.111.7530A }}</ref> and actual palytoxin in 1994 by Kishi and Suh.<ref name=":2">{{cite journal |vauthors=Suh EM, Kishi Y|year=1994|title=Synthesis of Palytoxin from Palytoxin Carboxylic Acid |journal=J. Am. Chem. Soc.|volume=116|issue=24|page=11205|doi=10.1021/ja00103a065 |bibcode=1994JAChS.11611205S }}</ref>


==History== ==History==

===Legend=== ===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. According to an ancient Hawaiian legend, on the island of ] near the harbor of ] 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.<ref>{{cite book|url=https://books.google.com/books?id=k0ZCAAAAIAAJ|title=Moolelo Hawaii| first= David | last = Malo | name-list-style = vanc |date=1 July 1987|publisher=Bishop Museum Press|isbn=0-910240-15-9|edition=2nd|pages=201|language=Hawaiian|translator=Nathaniel Bright Emerson|trans-title=Hawaiian Antiquities|author-link=David Malo|orig-year=1898|translator-link=Nathaniel Bright Emerson}}</ref><ref name="fo" /> The moss growing in the cursed tide pool became known as "]" 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".<ref name="moore71" /><ref name="fo">{{cite journal |vauthors = Ciminiello P, Dell'Aversano C, Fattorusso E, Forino M |year=2010|title=Palytoxins: A still haunting Hawaiian curse |journal=Phytochemistry Reviews|volume=9|issue=4|pages=491–500|doi=10.1007/s11101-010-9185-x |bibcode=2010PChRv...9..491C |s2cid=26030596}}</ref>
The moss growing in the cursed tide pool became known as "]" which literally means "seaweed of death from Hana."<ref name="clayden">Clayden, J., Greeves, N. (2000), pages 19-21</ref> The Hawaiians believed that an ill curse came over them if they tried to collect the deadly seaweed.<ref name="fo" >{{cite journal |author=Forino M, Ciminiello P, ''et al.'' |year=2010 |title=Palytoxins: A still haunting Hawaiian curse |journal=Phytochemistry Reviews |volume=9 |issue=4 |pages=491–500 |doi=10.1007/s11101-010-9185-x}}</ref>


===Discovery=== ===Discovery===
Palytoxin was first isolated in 1971, by Moore and Scheuer.<ref name="moore71">{{cite journal |author=Moore RE and Scheuer PJ |year=1971 |title=Palytoxin - New Marine Toxin from a Coelenterate |journal=Science |volume=172 |pages=495–498 |issue=3982 |doi=10.1126/science.172.3982.495}}</ref> 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.<ref name="fo" /> Palytoxin was first isolated, named and described from '']'' by Moore and ] in a study published in 1971. They measured that its ] 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.<ref name="moore71">{{cite journal | vauthors = Moore RE, Scheuer PJ| title = Palytoxin: a new marine toxin from a coelenterate | journal = Science | volume = 172 | issue = 3982 | pages = 495–8 | date = April 1971 | pmid = 4396320 | doi = 10.1126/science.172.3982.495 | bibcode = 1971Sci...172..495M | s2cid = 10098874 }}</ref> It was then assessed by Walsh and Bowers that the limu-make-o-Hana was not a seaweed but a ] coral, subsequently described as ''Palythoa toxica''.<ref>{{Cite journal | vauthors = Walsh GE, Bowers RL |date=May 1971|title=A review of Hawaiian zoanthids with descriptions of three new species|journal=Zoological Journal of the Linnean Society|volume=50|issue=2|pages=161–180|doi=10.1111/j.1096-3642.1971.tb00757.x }}</ref> Moore and Scheuer were aware of the study that Walsh and Bowers were writing.<ref name="moore71" />


===Structure and total synthesis===
===Synthesis===
In 1978 by ] the mass of the palytoxin was measured to be 2861 g/mol and that it had 8 ]s.<ref>{{Cite journal | vauthors = Macfarlane RD, Uemura D, Ueda K, Hirata Y |date=January 1980|title=Californium-252 plasma desorption mass spectrometry of palytoxin |journal=Journal of the American Chemical Society|volume=102|issue=2|pages=875–876|doi=10.1021/ja00522a088 |bibcode=1980JAChS.102..875M }}</ref> As palytoxin is such a large molecule, it took some time before the complete structure (including ]) was elucidated. Uemura ] solved its planar chemical structure first and published their results in January 1981.<ref>{{Cite web|url=http://www.csj.jp/csj-en/membership/awards/achieve/2005-uemura.html|title=CSJ Award 2005-Prof. Daisuke Uemura |website=www.csj.jp|publisher=Chemical Society of Japan, et al.|archive-url=https://web.archive.org/web/20180328165752/http://www.csj.jp/csj-en/membership/awards/achieve/2005-uemura.html|archive-date=2018-03-28|url-status=live|access-date=2018-04-26|quote=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.}}</ref><ref>{{Cite journal| vauthors = Uemura D, Ueda K, Hirata Y, Naoki H, Iwashita T | date=January 1981|title=Further studies on palytoxin. I. |journal=Tetrahedron Letters|volume=22|issue=20|pages=1909–1912|doi=10.1016/s0040-4039(01)90475-7}}</ref><ref>{{Cite journal| vauthors = Uemura D, Ueda K, Hirata Y, Naoki H, Iwashita T | date = January 1981|title=Further studies on palytoxin. II.|journal=Tetrahedron Letters|volume=22|issue=20|pages=2781–2784 | doi = 10.1016/S0040-4039(01)90551-9}}</ref> Shortly afterwards Moore and Bartolini solved the same structure and published their results in May 1981.<ref>{{Cite journal | vauthors = Moore RE, Bartolini G | date=May 1981|title=Structure of palytoxin |journal=Journal of the American Chemical Society|volume=103|issue=9|pages=2491–2494|doi=10.1021/ja00399a093 | bibcode=1981JAChS.103.2491M}}</ref> Forementioned groups solved the structure independently from each other.<ref name="vasconcelos" /> Palytoxin's stereochemistry was solved first by Moore et al. in June 1982<ref name="moore82" /> and then by Uemura et al. in December in a study of four parts.<ref name=":4" /><ref name=":3" />
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<ref name="moore82">{{cite journal |author=Moore RE, Bartolini G, ''et al.'' |year=1982 |title=Absolute Stereochemistry of Palytoxin |journal=Journal of the American Chemical Society |volume=104 |issue=13 |pages=3776–3779 |doi=10.1021/ja00377a064}}</ref> and Hirata.<ref name="cha">{{cite journal |author=Cha JK, Christ WJ, ''et al.'' |year=1982 |title=Stereochemistry of Palytoxin .4. Complete Structure |journal=Journal of the American Chemical Society |volume=104 |issue=25 |pages=7369–7371 |doi=10.1021/ja00389a101}}</ref>
Palytoxin is a huge molecule with chemical formula C<sub>129</sub>H<sub>223</sub>N<sub>3</sub>O<sub>54</sub>. 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.<ref name="armstrong">{{cite journal |author=Armstrong RW, Beau JM, ''et al.'' |year=1989 |title=Total Synthesis of Palytoxin Carboxylic-Acid and Palytoxin Amide |journal=Journal of the American Chemical Society |volume=111 |issue=19 |pages=7530–7533 |doi=10.1021/ja00201a038}}</ref><ref name="suh">{{cite journal |author=Suh EM and Kishi Y |year=1994 |title=Synthesis of Palytoxin from Palytoxin Carboxylic-Acid |journal=Journal of the American Chemical Society |volume=116 |issue=24 |pages=11205–11206 |doi=10.1021/ja00103a065}}</ref> 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.<ref name="crawford">{{cite journal |author=Crawford MH |year=1989 |title=Harvard Synthesizes Palytoxin Molecule |journal=Science |volume=246 |pages=34–34 |issue=4926 |doi=10.1126/science.246.4926.34-c}}</ref>


Palytoxin carboxylic acid was synthesized in 1989 by the group of Harvard professor ]. Synthesis happened in 8 parts and then the parts were joined to form the carboxylic acid.<ref name=":1" /> In 1994 Kishi et al. succeeded in making the actual palytoxin from this carboxylic acid.<ref name=":2" /> The accomplishment of palytoxin carboxylic acid synthesis was described as "the ] of organic synthesis, the largest single molecule that anyone has ever even thought about making" by Crawford in 1989.<ref name="crawford">{{cite journal |vauthors=Crawford MH |date=October 1989 |title=Harvard synthesizes palytoxin molecule |url=https://www.science.org/doi/10.1126/science.246.4926.34.d |journal=Science |volume=246 |issue=4926 |pages=34 |doi=10.1126/science.246.4926.34.d |pmid=17837760|s2cid=239849185 }}</ref>
===Incidents===

A new type of palytoxin, ovatoxin-a, produced as a marine aerosol by the tropical ] 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.<ref name="fo"/>
Direct observation of the crystal structure of palytoxin was made in 2022 using ] 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<sup>+</sup>/K<sup>+</sup>-ATPase.<ref>{{cite journal |last1=Gillman |first1=C |last2=Patel |first2=K |last3=Unge |first3=J |last4=Gonen |first4=T |title=The structure of the neurotoxin palytoxin determined by MicroED. |journal=BioRxiv: The Preprint Server for Biology |date=1 June 2023 |doi=10.1101/2023.03.31.535166 |pmid=37034718|pmc=10081313 }}</ref>

== Occurrence ==
Some of the ]s that contain palytoxin or its close ] are listed below. These are either able to produce these compounds or have been found to contain them in some occasions due to ].<ref name="McKenna">{{cite web |url=https://masna.org/masna-education/palytoxin/ |title=The Power of Palytoxin |last1=McKenna |first1=Amy |last2=Erickson |first2=Kevin |date=August 21, 2016 |website=masna.org |publisher=Marine Aquarium Societies of North America |access-date=May 25, 2023 |quote=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.}}</ref>

Such corals are '']'', '']'', '']'', '']'', '']'', ''P.'' ] ''margaritae'', '']'' and ].<ref name="wu">{{cite journal | vauthors = Wu CH | title = Palytoxin: membrane mechanisms of action | journal = Toxicon | volume = 54 | issue = 8 | pages = 1183–9 | date = December 2009 | pmid = 19269304 | doi = 10.1016/j.toxicon.2009.02.030 | bibcode = 2009Txcn...54.1183W }}</ref>

Such ]s are '']'', '']'', '']'' and ].<ref name="wu"/>

Such fish are ], ], '']'', '']'' (shortfin scad), ] and '']'' ].<ref name="wu"/>

Such crabs are '']'', '']'' and ].<ref name="wu"/>

Certain ] 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 '']'', '']'', '']'', '']'', '']'' sp. ja '']''.<ref name="vasconcelos" />


==Mechanism== ==Mechanism==
The toxicity of palytoxin is due to its binding to external part of ] (the ]–] pump),<ref name="vasconcelos" /> where it interacts with the natural binding site of ] with very high affinity. Na<sup>+</sup>/K<sup>+</sup>-ATPase is a ], which is found on the surface of every ] cell. The sodium–potassium pump is necessary for viability of all ], and this explains the fact that palytoxin affects all cells.<ref name="wu"/> Through this channel, which it forms within the sodium–potassium pump, ] positive ]s such as sodium and potassium can ] freely, thereby destroying the ] of the cell.<ref name="habermann">{{cite journal | vauthors = Habermann E | title = Palytoxin acts through Na+,K+-ATPase | journal = Toxicon | volume = 27 | issue = 11 | pages = 1171–87 | year = 1989 | pmid = 2575806 | doi = 10.1016/0041-0101(89)90026-3 }}</ref><ref name="redondo">{{cite journal | vauthors = Redondo J, Fiedler B, Scheiner-Bobis G | title = Palytoxin-induced Na+ influx into yeast cells expressing the mammalian sodium pump is due to the formation of a channel within the enzyme | journal = Molecular Pharmacology | volume = 49 | issue = 1 | pages = 49–57 | date = January 1996 | pmid = 8569711 | url = http://molpharm.aspetjournals.org/content/49/1/49.long }}</ref> Once palytoxin is bound to the pump, it flips constantly between open and normal ]. 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.<ref name="gadsby">{{cite journal | vauthors = Gadsby DC, Takeuchi A, Artigas P, Reyes N | title = Review. Peering into an ATPase ion pump with single-channel recordings | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 364 | issue = 1514 | pages = 229–38 | date = January 2009 | pmid = 18986966 | pmc = 2674102 | doi = 10.1098/rstb.2008.0243 }}</ref>
<!-- Deleted image removed: ] -->


Loss of ion gradient leads to death and ] of ]s, for example, and also to violent contractions of ] and other ].<ref name="vasconcelos" />
The toxicity of palytoxin is due to its binding to Na<sup>+</sup>,K<sup>+</sup>-ATPase (sodium pump), where it interacts with the natural binding site of ouabain with very high affinity. Na<sup>+</sup>,K<sup>+</sup>-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.<ref name="wu">{{cite journal |author=Wu CH |year=2009 |title=Palytoxin: Membrane mechanisms of action |journal=Toxicon |volume=54 |issue=8 |pages=1183–1189 |doi=10.1016/j.toxicon.2009.02.030 |pmid=19269304}}</ref>
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.<ref name="habermann">{{cite journal |author=Habermann E |year=1989 |title=Palytoxin Acts through Na+,K+-Atpase |journal=Toxicon |volume=27 |issue=11 |pages=1171–1187 |doi=10.1016/0041-0101(89)90026-3 |pmid=2575806}}</ref><ref name="redondo">{{cite journal |author=Redondo J, Fiedler B, ''et al.'' |year=1996 |title=Palytoxin-induced Na+ influx into yeast cells expressing the mammalian sodium pump is due to the formation of a channel within the enzyme |journal=Molecular Pharmacology |volume=49 |issue=1 |pages=49–57 |pmid=8569711}}</ref> 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.<ref name="gadsby">{{cite journal |author=Gadsby DC, Takeuchi A, ''et al.'' |year=2009 |title=Peering into an ATPase ion pump with single-channel recordings |journal=Philosophical Transactions of the Royal Society B-Biological Sciences |volume=364 |issue=1514 |pages=229–238 |doi=10.1098/rstb.2008.0243}}</ref> 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.<ref name="gadsby" />


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.<ref name="wu"/> Therefore, there were some alternative hypotheses, which were reviewed by Frelin and van Renterghem in 1995.<ref name="frelin">{{cite journal |author=Frelin C and Vanrenterghem C |year=1995 |title=Palytoxin - Recent Electrophysiological and Pharmacological Evidence for Several Mechanisms of Action |journal=General Pharmacology |volume=26 |issue=1 |pages=33–37 |pmid=7713364}}</ref> 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<sup>+</sup>,K<sup>+</sup>-ATPase, they were killed by palytoxin.<ref name="scheiner">{{cite journal |author=Scheinerbobis G, Heringdorf DMZ, ''et al.'' |year=1994 |title=Palytoxin Induces K+ Efflux from Yeast-Cells Expressing the Mammalian Sodium-Pump |journal=Molecular Pharmacology |volume=45 |issue=6 |pages=1132–1136 |pmid=7912814}}</ref> First evidence of the mechanism described above was obtained in 1981 and the proposed mechanism was published in 1982.<ref>{{Cite journal| vauthors = Habermann E, Chhatwal GS | date=1982-05-01|title=Ouabain inhibits the increase due to palytoxin of cation permeability of erythrocytes|journal=Naunyn-Schmiedeberg's Archives of Pharmacology|volume=319|issue=2|pages=101–107|doi=10.1007/BF00503920 | pmid=6125898| s2cid=12069168}}</ref> 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 provides ], could become an ] by binding of a compound such as palytoxin.<ref name="wu" /> Therefore, there were some alternative hypotheses, which were reviewed by Frelin and van Renterghem in 1995.<ref name="frelin">{{cite journal | vauthors = Frelin C, Van Renterghem C | title = Palytoxin. Recent electrophysiological and pharmacological evidence for several mechanisms of action | journal = General Pharmacology | volume = 26 | issue = 1 | pages = 33–7 | date = January 1995 | pmid = 7713364 | doi = 10.1016/0306-3623(94)00133-8 }}</ref> The breakthrough research which is seen as proof for the sodium–potassium pump mechanism was performed in yeast cells ('']''). These cells do not have the sodium–potassium pump, and hence palytoxin does not affect them. But once they were given the ] to encode for complete sheep Na<sup>+</sup>/K<sup>+</sup>-ATPase, they were killed by palytoxin.<ref name="scheiner">{{cite journal | vauthors = Scheiner-Bobis G, Meyer zu Heringdorf D, Christ M, Habermann E | title = Palytoxin induces K+ efflux from yeast cells expressing the mammalian sodium pump | journal = Molecular Pharmacology | volume = 45 | issue = 6 | pages = 1132–6 | date = June 1994 | pmid = 7912814 | url = http://molpharm.aspetjournals.org/content/45/6/1132 }}</ref>


==Toxicity== ==Toxicity==
From ] (IV) animal studies the toxic dose (]) of palytoxin via IV for humans has been estimated by ] to be between 2.3 and 31.5 ]s (μg) of palytoxin.<ref name="vasconcelos" /><ref>{{Cite journal|last1=Riobó|first1=P|last2=Paz|first2=B|last3=Franco|first3=JM|date=2006|title=Analysis of palytoxin-like in Ostreopsis cultures by liquid chromatography with precolumn derivatization and fluorescence detection|journal=Analytica Chimica Acta|volume=566|issue=2|pages=217–223|doi=10.1016/j.aca.2006.03.013|bibcode=2006AcAC..566..217R|issn=0003-2670}}</ref> An acute oral ] has been suggested to be 64&nbsp;μg for a person with weight of 60&nbsp;kg.<ref name="vasconcelos" /> Acute reference dose means a dose that can be safely ingested over a short period of time, usually during one meal or one day.<ref>{{Cite journal|date=2001-07-05|title=Guidance for the Setting of an Acute Reference Dose (ARfD)|url=https://ec.europa.eu/food/sites/food/files/plant/docs/pesticides_ppp_app-proc_guide_tox_acute-ref-dose.pdf|url-status=live|journal=European Commission|archive-url=https://web.archive.org/web/20180430125347/https://ec.europa.eu/food/sites/food/files/plant/docs/pesticides_ppp_app-proc_guide_tox_acute-ref-dose.pdf|archive-date=2018-04-30}}</ref>
An early toxicological characterization classified palytoxin as "relatively non-toxic" after intragastric administration to rats. The lethal dose (LD<sub>50</sub>) was greater than 40µg/kg. The LD<sub>50</sub> after parenteral administration was lower than 1µg/kg.<ref name="wiles">{{cite journal |author=Wiles JS, Vick JA, Christensen MK |year=1974 |title=Toxicological evaluation of palytoxin in several animal species |journal=Toxicon |volume=12 |pages=427–433 |doi=10.1016/0041-0101(74)90011-7 |pmid=4155146 |issue=4}}</ref> 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{{When|date=April 2011}} a study discovered an LD<sub>50</sub> 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.<ref name="ito09">{{cite journal |author=Ito E, Yasumoto T |year=2009 |title=Toxicological studies on palytoxin and ostreocin-d administered to mice by three different routes |journal=Toxicon |volume=54 |pages=244–251 |doi=10.1016/j.toxicon.2009.04.009 |pmid=19376151 |issue=3}}</ref> It was also found that palytoxin is very toxic after intraperitoneal injection. The LD<sub>50</sub> in mice was less than 1µg/kg.<ref name="rhodes">{{cite journal |author=Rhodes LL, Towers N, Briggs L, Munday R, Adamson JE |year=2002 |title=Uptake of palytoxin like compounds by shellfish fed Ostreopsis siamensis (Dinophyceae) |journal=New Zealand J. Med. Freshwater Res. |volume=36 |pages=631–636 |doi=10.1080/00288330.2002.9517118 |issue=3}}</ref>

Because toxin-producing organisms spread to temperate climates and palytoxin-contaminated shellfish were discovered in the Mediterranean Sea<ref name"aligizaki">{{cite journal |author=Aligizaki K, Panagiota K, Nikolaidis G, Panou A |year=2008 |title=First episode of shellfish contamination by palytoxin-like compounds from Ostreopsis species (Aegean Sea, Greece) |journal=Toxicon |volume=51 |pages=418–427 |doi=10.1016/j.toxicon.2007.10.016 |pmid=18067938 |issue=3}}</ref> 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 LD<sub>50</sub> calculated to be 767µg/kg. This is comparable to the LD<sub>50</sub> 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.<ref name="ito96">{{cite journal |author=Ito E, Ohkusu M, Yasumoto T |year=1996 |title=Intestinal injuries caused by experimental palytoxicosis in mice |journal=Toxicon |volume=34 |pages=643–652 |doi=10.1016/0041-0101(96)00005-0 |pmid=8817810 |issue=6}}</ref>
In comparison to IV injection, the toxicity of palytoxin in various animals via ] and ]s are 2.5 and 4–30 times higher, respectively. Upon ingestion the toxicity in animals has been 200 times less than via IV.<ref name="deeds" /> In the table below, there are listed some ] values for partially pure palytoxin obtained from different '']''. These values represent the amount of palytoxin required to kill half of the test animals. Values are in ]s (μg) per ] of the animal's weight and have been measured 24 hours after the initial exposure.<ref name="vasconcelos" />
Palytoxin is most toxic after intravenous injection. The LD<sub>50</sub> in mice is 0.045µg/kg and in rats 0.089µg/kg. In other mammals (rabbits, dogs, monkeys and guinea pigs) the LD<sub>50</sub> is ranged between 0.025 and 0.45µg/kg. They all died in several minutes to heart failure.<ref name="deeds">{{cite journal |author=Deeds JR, Schwartz MD |title=Human risk associated with palytoxin exposure |journal=Toxicon |year=2009 |doi=10.1016/j.toxicon.2009.05.035 |volume=56 |issue=2 |pages=150–162 |pmid=19505494}}</ref>

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.<ref name="ito09"/>
There are cases where humans died after consumption of palytoxin. In the Philippines people died after eating ''Demania reynaudii'', a crab species.<ref name="alcala">{{cite journal |author=Alcala AC, Alcala LC, Garth JS, Yasumura D, Yasumoto T |title=Human fatality due to ingestion of the crab Demania reynaudii that contained a palytoxin-like toxin |journal=Toxicon |year=1988 |volume=26 |pages=105–107 |doi=10.1016/0041-0101(88)90142-0 |pmid=2894726 |issue=1}}</ref> After eating the sardine species Herklotsichthys quadrimaculatus some people died in Madagascar.<ref name="onuma">{{cite journal |author=Onuma Y, Satake M, Ukena T, Roux J, Chanteau S, Rasolofonirina N, Ratsimaloto M, Naoki H, Yasumoto T |title=Identification of putative palytoxin as the cause of clupeotoxism |journal=Toxicon |year=1999 |volume=37 |pages=55–65 |doi=10.1016/S0041-0101(98)00133-0 |pmid=9920480 |issue=1}}</ref> Near fatal cases took place in Hawaii<ref name="kodama">{{cite journal |author=Kodama AM, Hokama Y, Yasumoto T, Fukui M, Manea SJ, Sutherland N |title=Clinical and laboratory findings implicating palytoxin as cause of ciguatera poisoning due to Decapterus macrosoma (mackerel) |journal=Toxicon |year=1989 |volume=27 |pages=1051–1053 |doi=10.1016/0041-0101(89)90156-6 |pmid=2572075 |issue=9}}</ref> and Japan.<ref name="okano">{{cite journal |author=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 |title=Rhabdomyolysis and myocardial damage induced by palytoxin, a toxin of blue humphead parrotfish |journal=Internal Med. |year=1998 |volume=37 |pages=330–333 |doi=10.2169/internalmedicine.37.330 |issue=3}}</ref>
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<ref name="hoffmann">{{cite journal |author=Hoffmann K, Hermanns-Clausen M, Buhl C, Buchler MW, Schemmer P, Mebs D, Kauferstein S |title=A case of palytoxin poisoning due to contact with zoanthid corals through a skin injury |journal=Toxicon |year=2008 |volume=51 |pages=1535–1537 |doi=10.1016/j.toxicon.2008.03.009 |pmid=18433818 |issue=8}}</ref> and the USA <ref name="deeds"/>, touched zoanthid corals in their aquariums at home. Another person was exposed to palytoxin via inhalation<ref name"majlesi">{{cite journal |author=Majlesi N, Su MK, Chan GM, Lee DC, Greller HA |title=A case of inhalational exposure to palytoxin |journal=Clin. Toxicol. |year=2008 |volume=46 |page=637}}</ref> 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.<ref name="riobo">{{cite journal |author=Riobó P, Paz B, Franco JM |title=Analysis of palytoxin-like in Ostreopsis cultures by liquid chromatography with precolumn derivatization and fluorescence detection |journal=Anal. Chim. Acta |year=2006 |volume=566 |pages=217–223 |doi=10.1016/j.aca.2006.03.013 |issue=2}}</ref> An acute reference dose was suggested to be 64µg for a person with weight of 60 kg.<ref name="rhodes08">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</ref>
{| class="wikitable" {| class="wikitable"
|+LD<sub>50</sub> values for palytoxin<ref name="vasconcelos" />
|- |-
! Exposure !! LD<sub>50</sub> in animals ! Exposure
!Animal!! LD<sub>50</sub> (μg/kg)
|- |-
| rowspan="2" | ]
| Intravenous || Mice 0.054 μg/kg
|Mouse|| 0.045
|- |-
| || Rats 0.089 μg/kg |Rat|| 0.089
|- |-
| Intratracheal || Mice >2 μg/kg | ]
|Rat|| 0.36
|- |-
| rowspan="2" | ]
| Intraperitoneal || Mice <1 μg/kg
|Mouse|| 0.295
|- |-
|Rat
| Oral || Mice 767 μg/kg
|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 (LD<sub>50</sub>) was greater than 40&nbsp;μg/kg. The LD<sub>50</sub> after parenteral administration was lower than 1&nbsp;μg/kg.<ref name="wiles">{{cite journal | vauthors = Wiles JS, Vick JA, Christensen MK | title = Toxicological evaluation of palytoxin in several animal species | journal = Toxicon | volume = 12 | issue = 4 | pages = 427–33 | date = August 1974 | pmid = 4155146 | doi = 10.1016/0041-0101(74)90011-7 | bibcode = 1974Txcn...12..427W }}</ref> 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 LD<sub>50</sub> of 510&nbsp;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&nbsp;μg/kg.<ref name="ito09">{{cite journal | vauthors = Ito E, Yasumoto T | title = Toxicological studies on palytoxin and ostreocin-D administered to mice by three different routes | journal = Toxicon | volume = 54 | issue = 3 | pages = 244–51 | date = September 2009 | pmid = 19376151 | doi = 10.1016/j.toxicon.2009.04.009 | bibcode = 2009Txcn...54..244I }}</ref> It was also found that palytoxin is very toxic after intraperitoneal injection. The LD<sub>50</sub> in mice was less than 1&nbsp;μg/kg.<ref name="rhodes">{{cite journal |vauthors=Rhodes LL, Towers N, Briggs L, Munday R, Adamson JE |year=2002 |title=Uptake of palytoxin like compounds by shellfish fed Ostreopsis siamensis (Dinophyceae) |journal=New Zealand J. Med. Freshwater Res. |volume=36 |pages=631–636 |doi=10.1080/00288330.2002.9517118 |issue=3|s2cid=84191389 |doi-access=free |bibcode=2002NZJMF..36..631R }}</ref> As toxin-producing organisms spread to temperate climates and palytoxin-contaminated shellfish were discovered in the Mediterranean Sea<ref name="aligizaki">{{cite journal | vauthors = Aligizaki K, Katikou P, Nikolaidis G, Panou A | title = First episode of shellfish contamination by palytoxin-like compounds from Ostreopsis species (Aegean Sea, Greece) | journal = Toxicon | volume = 51 | issue = 3 | pages = 418–27 | date = March 2008 | pmid = 18067938 | doi = 10.1016/j.toxicon.2007.10.016 | bibcode = 2008Txcn...51..418A }}</ref> a study was done to better define the toxic effects of palytoxin after oral exposure in mice. Palytoxin was lethal from 600&nbsp;μg/kg doses. The number of deaths were dose-dependent and the LD<sub>50</sub> calculated to be 767&nbsp;μg/kg. This is comparable to the LD<sub>50</sub> of 510&nbsp;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.<ref name="ito96">{{cite journal | vauthors = Ito E, Ohkusu M, Yasumoto T | title = Intestinal injuries caused by experimental palytoxicosis in mice | journal = Toxicon | volume = 34 | issue = 6 | pages = 643–52 | date = June 1996 | pmid = 8817810 | doi = 10.1016/0041-0101(96)00005-0 | bibcode = 1996Txcn...34..643I }}</ref> A recent study by Fernandez et al.<ref name="Fernandez2013">{{cite journal | vauthors = Fernández DA, Louzao MC, Vilariño N, Espiña B, Fraga M, Vieytes MR, Román A, Poli M, Botana LM | title = The kinetic, mechanistic and cytomorphological effects of palytoxin in human intestinal cells (Caco-2) explain its lower-than-parenteral oral toxicity | journal = The FEBS Journal | volume = 280 | issue = 16 | pages = 3906–19 | date = August 2013 | pmid = 23773601 | doi = 10.1111/febs.12390 | s2cid = 30378906 }}</ref> 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 LD<sub>50</sub> in mice is 0.045&nbsp;μg/kg and in rats 0.089&nbsp;μg/kg. In other mammals (rabbits, dogs, monkeys and guinea pigs) the LD<sub>50</sub> is ranged between 0.025 and 0.45&nbsp;μg/kg. They all died in several minutes from heart failure.<ref name="deeds">{{cite journal | vauthors = Deeds JR, Schwartz MD | title = Human risk associated with palytoxin exposure | journal = Toxicon | volume = 56 | issue = 2 | pages = 150–62 | date = August 2010 | pmid = 19505494 | doi = 10.1016/j.toxicon.2009.05.035 | bibcode = 2010Txcn...56..150D | url = https://zenodo.org/record/1259397 }}</ref> The lethal dose for mice by the intratracheal route is above 2&nbsp;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.<ref name="ito09" /> 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<ref>{{cite journal | vauthors = Ciminiello P, Dell'Aversano C, Dello Iacovo E, Fattorusso E, Forino M, Tartaglione L | title = LC-MS of palytoxin and its analogues: State of the art and future perspectives | journal = Toxicon | volume = 57 | issue = 3 | pages = 376–89 | date = March 2011 | pmid = 21070802 | doi = 10.1016/j.toxicon.2010.11.002 | bibcode = 2011Txcn...57..376C }}</ref> or immunoassay<ref>{{cite journal | vauthors = Zamolo VA, 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 | title = Highly sensitive electrochemiluminescent nanobiosensor for the detection of palytoxin | journal = ACS Nano | volume = 6 | issue = 9 | pages = 7989–97 | date = September 2012 | pmid = 22913785 | doi = 10.1021/nn302573c | s2cid = 46427496 | url = https://zenodo.org/record/3443880 }}</ref>).


==Symptoms== ==Symptoms==
The ]s 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.<ref name="deeds" />
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.<ref name="louzao">{{cite journal |author=Louzao MC, Ares IR, ''et al.'' |year=2008 |title=Marine toxins and the cytoskeleton: a new view of palytoxin toxicity |journal=FEBS Journal |volume=275 |issue=24 |pages=6067–6074 |doi=10.1111/j.1742-4658.2008.06712.x |pmid=19016862}}</ref> The most common complication of palytoxin poisoning is rhabdomyolysis. This involves skeletal muscle breakdown and the leakage of intracellular contents into the blood plasma.<ref name="vasconcelos">{{cite journal |author=Vasconcelos V, Ramos V |year=2010 |title=Palytoxin and Analogs: Biological and Ecological Effects |journal=Marine Drugs |volume=8 |issue=7 |pages=2021–2037 |doi=10.3390/md8072021 |pmid=20714422 |pmc=2920541}}</ref>
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.<ref name=":6" /> In different animals the symptoms have appeared in 30–60 minutes after intravenous injection and after 4 hours of eye-exposure.<ref name="deeds" />
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.<ref name="louzao" /><ref name="vasconcelos"/>

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.<ref name="louzao"/><ref name="vasconcelos"/> Palytoxin is also classified as a non-TPAtype tumor promoter.<ref name="fo"/>
The most common ] of severe palytoxin poisoning is ]. This involves ] breakdown and the leakage of ] contents into the blood. Other symptoms in humans are bitter/metallic taste, abdominal cramps, nausea, vomiting, diarrhea, mild to acute ], tingling, ], ], impairment of sensation, muscle spasms, tremor ], ], and respiratory distress. In lethal cases palytoxin usually causes death by ] via myocardial injury.<ref name="vasconcelos" /><ref name="louzao" />

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 ], mild dyspnea, and wheezes, while ] was observed in some cases.<ref name="louzao"/><ref name="vasconcelos"/>

], poisoning after consuming ], is also suggested to be caused by palytoxin. Neurological and gastrointestinal disturbances are associated with clupeotoxism.<ref name="louzao">{{cite journal | vauthors = Louzao MC, Ares IR, Cagide E | title = Marine toxins and the cytoskeleton: a new view of palytoxin toxicity | journal = The FEBS Journal | volume = 275 | issue = 24 | pages = 6067–74 | date = December 2008 | pmid = 19016862 | doi = 10.1111/j.1742-4658.2008.06712.x | doi-access = free }}</ref> ] might be related to palytoxin and is characterized by rhabdomyolysis and gastrointestinal problems.<ref name=":6" /> In addition to ], palytoxin could be related to ] seafood poisoning in some cases and thus give rise to a number of symptoms in this poisoning.<ref name="deeds" />


==Treatment== ==Treatment==
There is no ] for palytoxin. Only the symptoms can be alleviated.<ref>{{cite journal | vauthors = Thakur LK, Jha KK | title = Palytoxin-induced acute respiratory failure | journal = Respiratory Medicine Case Reports | volume = 20 | pages = 4–6 | date = 2016-10-21 | pmid = 27843763 | pmc = 5099280 | doi = 10.1016/j.rmcr.2016.10.014 }}</ref>
Animal studies have shown that ]s, such as ] and ], can be used as ]. The animal experiments only showed benefit if the antidotes were injected into the ] immediately following exposure.<ref name="wiles"/> Treatment in humans is symptomatic and supportive.


Animal studies have shown that ]s, such as ] and ], can be used as ]. The animal experiments only showed benefit if the antidotes were injected into the ] immediately following exposure.<ref name="wiles" />
==References==

{{Reflist|2}}
==Poisoning incidents==
{{Use dmy dates|date=April 2011}}

=== Ingestion ===
There have been cases where people died after eating foods containing palytoxin or poisons similar to it. In the ] people died after eating '']'' crabs.<ref name="alcala">{{cite journal | vauthors = Alcala AC, Alcala LC, Garth JS, Yasumura D, Yasumoto T | title = Human fatality due to ingestion of the crab Demania reynaudii that contained a palytoxin-like toxin | journal = Toxicon | volume = 26 | issue = 1 | pages = 105–7 | year = 1988 | pmid = 2894726 | doi = 10.1016/0041-0101(88)90142-0 | bibcode = 1988Txcn...26..105A }}</ref> After eating ] some people died in Madagascar.<ref name="onuma">{{cite journal | vauthors = Onuma Y, Satake M, Ukena T, Roux J, Chanteau S, Rasolofonirina N, Ratsimaloto M, Naoki H, Yasumoto T | title = Identification of putative palytoxin as the cause of clupeotoxism | journal = Toxicon | volume = 37 | issue = 1 | pages = 55–65 | date = January 1999 | pmid = 9920480 | doi = 10.1016/S0041-0101(98)00133-0 | bibcode = 1999Txcn...37...55O }}</ref> People who had eaten smoked ] and ] experienced near fatal poisoning in Hawaii<ref name="kodama">{{cite journal | vauthors = Kodama AM, Hokama Y, Yasumoto T, Fukui M, Manea SJ, Sutherland N | title = Clinical and laboratory findings implicating palytoxin as cause of ciguatera poisoning due to Decapterus macrosoma (mackerel) | journal = Toxicon | volume = 27 | issue = 9 | pages = 1051–3 | year = 1989 | pmid = 2572075 | doi = 10.1016/0041-0101(89)90156-6 | bibcode = 1989Txcn...27.1051K }}</ref> and Japan respectively.<ref name="okano">{{cite journal |vauthors=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|year=1998|title=Rhabdomyolysis and myocardial damage induced by palytoxin, a toxin of blue humphead parrotfish|journal=Intern. Med.|volume=37|issue=3|pages=330–333|doi=10.2169/internalmedicine.37.330 |pmid=9617874|doi-access=free}}</ref>

=== 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<ref name="hoffmann">{{cite journal | vauthors = Hoffmann K, Hermanns-Clausen M, Buhl C, Büchler MW, Schemmer P, Mebs D, Kauferstein S | title = A case of palytoxin poisoning due to contact with zoanthid corals through a skin injury | journal = Toxicon | volume = 51 | issue = 8 | pages = 1535–7 | date = June 2008 | pmid = 18433818 | doi = 10.1016/j.toxicon.2008.03.009 | bibcode = 2008Txcn...51.1535H }}</ref> and the USA.<ref name="deeds" />

=== Inhalation ===
Cases of inhalation are also known. A man inhaled palytoxin when he tried to kill a '']'' in his aquarium with boiling water.<ref name="majlesi">{{cite journal |vauthors=Majlesi N, Su MK, Chan GM, Lee DC, Greller HA |title=A case of inhalational exposure to palytoxin |journal=Clin. Toxicol. |year=2008 |volume=46 |page=637}}</ref> In 2018, six people from ], 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.<ref>{{Cite news|url=https://www.bbc.co.uk/news/uk-england-oxfordshire-43558736|title=Fish tank fumes leave 10 in hospital |date=2018-03-27|work=BBC News|access-date=2018-04-27|archive-url=https://web.archive.org/web/20180415171110/http://www.bbc.co.uk/news/uk-england-oxfordshire-43558736|archive-date=2018-04-15|url-status=live }}</ref> Also in 2018, a woman in ] 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.<ref>{{Cite news|url=http://www.kens5.com/article/news/health/cedar-park-mother-warning-others-after-aquarium-coral-nearly-kills-her-family/546756484|title=Cedar Park mother warning others after aquarium coral nearly kills her family|last=Perez|first=Pattrik | name-list-style = vanc |date=2018-04-27|work=KENS|access-date=2018-04-29|archive-url=https://web.archive.org/web/20180429221109/http://www.kens5.com/article/news/health/cedar-park-mother-warning-others-after-aquarium-coral-nearly-kills-her-family/546756484|archive-date=2018-04-29|url-status=live }}</ref> A similar event occurred in the UK in August 2019.<ref>{{Cite news|url=https://www.bbc.co.uk/news/uk-england-shropshire-49269013|title=Telford mum 'nearly died' after cleaning fish tank coral|work=BBC News|date=7 August 2019}}</ref>

=== Mass poisonings ===
A formerly unknown derivative of palytoxin, ovatoxin-a, produced as a marine aerosol by the tropical ] '']'' caused hundreds of people in ], 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.<ref name="fo" />

== See also ==
* ]
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== References ==
{{Reflist}}


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