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Not to be confused with Cicutoxin.
Chemical structure of the ciguatoxins C-CTX-1 (top) and P-CTX-1 (bottom)

Ciguatoxins are a class of toxic polycyclic polyethers found in fish that cause ciguatera.

There are several different chemicals in this class. "CTX" is often used as an abbreviation.

Symptoms

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Ciguatoxins do not seem to harm the fish that carry them, but they are poisonous to humans. They cannot be smelled or tasted and cannot be destroyed by cooking.[1] While it is possible to test for ciguatoxins in fish, rapid and affordable tests for commercial use are not available.[2]

Ciguatoxins are lipophilic, able to cross the blood–brain barrier, and can cause both central and peripheral neurologic symptoms.[3]

Gastrointestinal symptoms usually develop within 1–6 hours of toxin ingestion, while neurological symptoms can take as long as 96 hours to appear and may persist for weeks to years.[4] Major symptoms include vomiting, diarrhea, numbness of extremities, mouth, and lips, reversal of hot and cold sensation, muscle and joint aches.[5][6] There is no known antidote, though several therapeutic targets have been identified.[5][7] The LD50 of ciguatoxin in mice is around 200 to 300 ng/kg.[8]

Types of ciguatoxins

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There are over 30 reported ciguatoxin molecules.[9] Pacific ciguatoxin 1 (P CTX-1) and Caribbean ciguatoxin 1 (C-CTX-1) are primarily responsible for ciguatera poisonings.[10] As their names suggest, the two are found in different locations. P-CTX-1 is 10 times more toxic than C-CTX-1.[10] Ciguatoxin CTX3C, though less prevalent in nature, is also of note because of its synthetic history.

History

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As of 1967, ciguatera and ciguatoxins were known, but their origin was still a matter of speculation. At that time, isolation of a ciguatoxin from the flesh of fish had been achieved, but chemical characterization of the molecule was incomplete, in large part due to the difficulty of obtaining substantial quantities of pure ciguatoxins.[11] In 1977, a link was proven between ciguatoxins in fish and some microorganism source, and by 1987 dinoflagellate algae had been identified as that source.[12] Also in 1987, chemical analysis was used to correctly find the molecular weight and polycyclic polyether shape of P-CTX-1, though the exact formula and structure were still unknown.[13] Beginning in the late 1980s, the exact formulas and structures of several ciguatoxins have been elucidated.[14][15][16]

Of all ciguatoxins, CTX3C has the most noteworthy synthetic history. Its total synthesis was first reported in 2001, and multiple synthetic pathways to CTX3C have been discovered since.[17] Since this synthesis, four other ciguatoxins have been synthesized.[18][19] Synthesis of some component rings of C-CTX-1 has also been reported.[20]

Bioaccumulation

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Ciguatoxin is produced by Gambierdiscus toxicus, a type of dinoflagellate. The phenomenon occurs in the Caribbean Sea, Hawaii, and coastal Central America. The toxin usually accumulates in the skin, head, viscera, and roe of big reef fish like grouper, wrasse, triggerfish, lionfish, and amberjack. It also affects barracuda, snapper, hogfish, king mackerel, and sea bass.[21]

Mechanism of action

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In neuronal neural tissue

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One of the most prominent studies on the effects of P-CTX-1 on the neural tissue by Benoit et al in 1994 revealed that ciguatoxin-1 can induce spontaneous action potentials in frog myelinated neural fibres, that were eliminated by the addition of TTX.[22] This allowed researchers to conclude that P-CTX-1 mechanism of action must involve voltage-dependent (Nav) sodium channels. Later in 2005, a similar study by Birinyi-Strachan et al confirmed this hypothesis by analysing the effects of P-CTX-1 on the excitability of rat dorsal root ganglion.[23] This study has shown that ciguatoxin-1 can prolong the action potential and increase the afterhyperpolarisation of the cells.

It has also been shown that P-CTX-1 acts differently on TTX-sensitive and TTX-resistant cells:[24] in the former, it causes leakage current and reduction in peak signal amplitude, while in the latter it causes the reduction of peak amplitude and increased recovery rate from inactivation. These findings show that different action mechanisms of P-CTX-1may contribute to the big variety neurological symptoms as each type of neural tissue reacts to ciguatoxin in a different manner.

Further studies were carried out to identify the mechanism of action of P-CTX-1 on Nav channels,[25][26] which assumed a direct interaction between the toxin and the sodium channels. However, in 1992 Lewis disproved the original hypothesis and showed that the interaction is indirect, by the means of beta1-adrenoceptor stimulation.[27]

In their study Birinyi-Strachan et al have also shown that P-CTX-1 can also block delayed rectifier voltage gated potassium channels in rat neurons, which could generally contribute to the overall membrane depolarisation, prolonged action potentials, increased afterhyperpolarisation, and lowered threshold for action potential firing.[23] These findings could further explain the origin of various symptoms of ciguatera such as paraesthesia or dysesthesia.[28]

It was also found that CTX-1 releases noradrenaline and ATP by asynchronous discharge of preganglionic perivascular axons.[29] CTX-1 prolongs the action potential and afterhyperpolarisation duration. In a subpopulation of neurons, tonic action potential firing can be produced.

In the gastrointestinal tract

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Even though ciguatera causes major gastrointestinal issues, so far P-CTX-1 hasn't been proven to have a direct effect on digestive systems. Terao et al showed that no morphological alterations were observed in the mucosa or muscle layers of the small intestine, despite the severe diarrhoea commonly observed upon P-CTX-1 administration.[30] Other studies (Lewis et al 1984, Lewis, Hoy 1983) have shown that P-CTX-1 causes acetyl choline release from parasympathetic cholinergic nerve terminals, which suggests that nerve stimulation by P-CTX-1 is followed by nerve blockade, likely due to further nerve depolarisation.[30]

See also

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References

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  1. ^ Swift AE, Swift TR (2008). "Ciguatera". Journal of Toxicology. Clinical Toxicology. 31 (1): 1–29. doi:10.3109/15563659309000371. PMID 8433404. S2CID 222017205.
  2. ^ Friedman, Melissa; Fernandez, Mercedes; Backer, Lorraine; Dickey, Robert; Bernstein, Jeffrey; Schrank, Kathleen; Kibler, Steven; Stephan, Wendy; Gribble, Matthew; Bienfang, Paul; Bowen, Robert; Degrasse, Stacey; Flores Quintana, Harold; Loeffler, Christopher; Weisman, Richard (2017-03-14). "An Updated Review of Ciguatera Fish Poisoning: Clinical, Epidemiological, Environmental, and Public Health Management". Marine Drugs. 15 (3): 72. doi:10.3390/md15030072. ISSN 1660-3397. PMC 5367029. PMID 28335428.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ Beasley, Val Richard (2020-01-01), "Harmful Algal Blooms (Phycotoxins)", Reference Module in Earth Systems and Environmental Sciences, Elsevier, doi:10.1016/b978-0-12-409548-9.11275-8, ISBN 978-0-12-409548-9, retrieved 2025-05-07
  4. ^ Vetter, Irina; Touska, Filip; Hess, Andreas; Hinsbey, Rachel; Sattler, Simon; Lampert, Angelika; Sergejeva, Marina; Sharov, Anastasia; Collins, Lindon S; Eberhardt, Mirjam; Engel, Matthias; Cabot, Peter J; Wood, John N; Vlachová, Viktorie; Reeh, Peter W (2012-10-03). "Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling". The EMBO Journal. 31 (19): 3795–3808. doi:10.1038/emboj.2012.207. ISSN 0261-4189. PMC 3463840. PMID 22850668.
  5. ^ a b Patel, Ryan; Brice, Nicola L.; Lewis, Richard J.; Dickenson, Anthony H. (2015). "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera". European Journal of Neuroscience. 42 (11): 3004–3011. doi:10.1111/ejn.13098. ISSN 1460-9568. PMC 4744673. PMID 26454262.
  6. ^ Vetter, Irina; Touska, Filip; Hess, Andreas; Hinsbey, Rachel; Sattler, Simon; Lampert, Angelika; Sergejeva, Marina; Sharov, Anastasia; Collins, Lindon S; Eberhardt, Mirjam; Engel, Matthias; Cabot, Peter J; Wood, John N; Vlachová, Viktorie; Reeh, Peter W (2012-10-03). "Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling". The EMBO Journal. 31 (19): 3795–3808. doi:10.1038/emboj.2012.207. ISSN 0261-4189. PMC 3463840. PMID 22850668.
  7. ^ Vetter I, Touska F, Hess A, Hinsbey R, Sattler S, Lampert A, Sergejeva M, Sharov A, Collins LS, Eberhardt M, Engel M, Cabot PJ, Wood JN, Vlachová V, Reeh PW, Lewis RJ, Zimmermann K (October 2012). "Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling". The EMBO Journal. 31 (19): 3795–808. doi:10.1038/emboj.2012.207. PMC 3463840. PMID 22850668.
  8. ^ Fusetani, Nobuhiro; Kem, William (2009-01-31). Marine Toxins as Research Tools. Springer Science & Business Media. ISBN 978-3-540-87895-7.
  9. ^ Darracq, M. A. (2014-01-01), Wexler, Philip (ed.), "Ciguatoxin", Encyclopedia of Toxicology (Third Edition), Oxford: Academic Press, pp. 963–965, doi:10.1016/b978-0-12-386454-3.00712-0, ISBN 978-0-12-386455-0, retrieved 2025-05-07
  10. ^ a b Hambright, K. D.; Zamor, R. M.; Easton, J. D.; Allison, B. (2014-01-01), Wexler, Philip (ed.), "Algae", Encyclopedia of Toxicology (Third Edition), Oxford: Academic Press, pp. 130–141, doi:10.1016/b978-0-12-386454-3.00983-0, ISBN 978-0-12-386455-0, retrieved 2025-05-07
  11. ^ Scheuer, Paul J.; Takahashi, Wataru; Tsutsumi, Junzo; Yoshida, Tamao (1967). "Ciguatoxin: Isolation and Chemical Nature". Science. 155 (3767): 1267–1268. ISSN 0036-8075.
  12. ^ Anderson, Donald M.; Lobel, Phillip S. (1987-02). "The continuing enigma of ciguatera". The Biological Bulletin. 172 (1): 89–107. doi:10.2307/1541609. ISSN 0006-3185. {{cite journal}}: Check date values in: |date= (help)
  13. ^ Tachibana, Kazuo; Nukina, Manabu; Joh, Yong-Goe; Scheuer, Paul J. (1987-02). "Recent developments in the molecular structure of ciguatoxin". The Biological Bulletin. 172 (1): 122–127. doi:10.2307/1541611. ISSN 0006-3185. {{cite journal}}: Check date values in: |date= (help)
  14. ^ Murata, Michio; Legrand, Anne M.; Ishibashi, Yoshihiko; Yasumoto, Takeshi (1989-11-01). "Structures of ciguatoxin and its congener". Journal of the American Chemical Society. 111 (24): 8929–8931. doi:10.1021/ja00206a032. ISSN 0002-7863.
  15. ^ Lewis, Richard J.; Vernoux, Jean-Paul; Brereton, Ian M. (1998-06-01). "Structure of Caribbean Ciguatoxin Isolated from Caranx latus". Journal of the American Chemical Society. 120 (24): 5914–5920. doi:10.1021/ja980389e. ISSN 0002-7863.
  16. ^ Hamilton, Brett; Hurbungs, Mira; Vernoux, Jean-Paul; Jones, Alun; Lewis, Richard J. (2002-06-01). "Isolation and characterisation of Indian Ocean ciguatoxin". Toxicon. 40 (6): 685–693. doi:10.1016/S0041-0101(01)00259-8. ISSN 0041-0101.
  17. ^ Inoue, Masayuki; Miyazaki, Keisuke; Uehara, Hisatoshi; Maruyama, Megumi; Hirama, Masahiro (2004-08-17). "First- and second-generation total synthesis of ciguatoxin CTX3C". Proceedings of the National Academy of Sciences. 101 (33): 12013–12018. doi:10.1073/pnas.0401684101. PMC 514426. PMID 15199182.
  18. ^ Inoue, Masayuki; Miyazaki, Keisuke; Ishihara, Yuuki; Tatami, Atsushi; Ohnuma, Yuyu; Kawada, Yuuya; Komano, Kazuo; Yamashita, Shuji; Lee, Nayoung; Hirama, Masahiro (2006-07-01). "Total Synthesis of Ciguatoxin and 51-HydroxyCTX3C". Journal of the American Chemical Society. 128 (29): 9352–9354. doi:10.1021/ja063041p. ISSN 0002-7863.
  19. ^ Yamashita, Shuji; Takeuchi, Katsutoshi; Koyama, Takuya; Inoue, Masayuki; Hayashi, Yujiro; Hirama, Masahiro (2015). "Practical Route to the Left Wing of CTX1B and Total Syntheses of CTX1B and 54-deoxyCTX1B". Chemistry – A European Journal. 21 (6): 2621–2628. doi:10.1002/chem.201405629. ISSN 1521-3765.
  20. ^ Sasaki, Makoto; Iwasaki, Kotaro; Arai, Keisuke (2021-03-19). "Synthesis and Structural Implication of the JKLMN-Ring Fragment of Caribbean Ciguatoxin C-CTX-1". The Journal of Organic Chemistry. 86 (6): 4580–4597. doi:10.1021/acs.joc.0c03031. ISSN 0022-3263.
  21. ^ Yong, Shin Jie (2020-04-19). "Fishes Carrying This Incurable Poison Are on the Rise". Medium. Retrieved 2020-05-25.
  22. ^ Benoit, E.; Legrand, A. M.; Dubois, J. M. (1986-01-01). "Effects of ciguatoxin on current and voltage clamped frog myelinated nerve fibre". Toxicon. 24 (4): 357–364. doi:10.1016/0041-0101(86)90195-9. ISSN 0041-0101.
  23. ^ a b Birinyi-Strachan, Liesl C.; Gunning, Simon J.; Lewis, Richard J.; Nicholson, Graham M. (2005-04-15). "Block of voltage-gated potassium channels by Pacific ciguatoxin-1 contributes to increased neuronal excitability in rat sensory neurons". Toxicology and Applied Pharmacology. 204 (2): 175–186. doi:10.1016/j.taap.2004.08.020. ISSN 0041-008X.
  24. ^ Birinyi-Strachan, Liesl C.; Gunning, Simon J.; Lewis, Richard J.; Nicholson, Graham M. (2005-04-15). "Block of voltage-gated potassium channels by Pacific ciguatoxin-1 contributes to increased neuronal excitability in rat sensory neurons". Toxicology and Applied Pharmacology. 204 (2): 175–186. doi:10.1016/j.taap.2004.08.020. ISSN 0041-008X.
  25. ^ Lewis, Richard J.; Wong Hoy, Ashley W.; McGiffin, David C. (1992-08-01). "Action of ciguatoxin on human atrial trabeculae". Toxicon. 30 (8): 907–914. doi:10.1016/0041-0101(92)90389-M. ISSN 0041-0101.
  26. ^ Lewis, Richard J.; Endean, R. (1986-11-01). "Direct and indirect effects of ciguatoxin on guinea-pig atria and papillary muscles". Naunyn-Schmiedeberg's Archives of Pharmacology. 334 (3): 313–322. doi:10.1007/BF00508787. ISSN 1432-1912.
  27. ^ Lewis, Richard J. (1988-01-01). "Negative inotropic and arrhythmic effects of high doses of ciguatoxin on guinea-pig atria and papillary muscles". Toxicon. 26 (7): 639–649. doi:10.1016/0041-0101(88)90246-2. ISSN 0041-0101.
  28. ^ Birinyi-Strachan, Liesl C.; Gunning, Simon J.; Lewis, Richard J.; Nicholson, Graham M. (2005-04-15). "Block of voltage-gated potassium channels by Pacific ciguatoxin-1 contributes to increased neuronal excitability in rat sensory neurons". Toxicology and Applied Pharmacology. 204 (2): 175–186. doi:10.1016/j.taap.2004.08.020. ISSN 0041-008X.
  29. ^ Brock, James A.; McLachlan, Elspeth M.; Jobling, P.; Lewis, R.j. (1995). "Electrical activity in rat tail artery during asynchronous activation of postganglionic nerve terminals by ciguatoxin-1". British Journal of Pharmacology. 116 (4): 2213–2220. doi:10.1111/j.1476-5381.1995.tb15056.x. ISSN 1476-5381. PMC 1908980. PMID 8564251.
  30. ^ a b Terao, Kiyoshi; Ito, Emiko; Oarada, Motoko; Ishibashi, Yoshihiko; Legrand, Anne-Marie; Yasumoto, Takeshi (1991-01-01). "Light and electron microscopic studies of pathologic changes induced in mice by ciguatoxin poisoning". Toxicon. 29 (6): 633–643. doi:10.1016/0041-0101(91)90056-W. ISSN 0041-0101.
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