Ciguatoxin 1 or CTX-1 is a toxic chemical compound, the most common and potent type in the group of ciguatoxins. It is a large molecule consisting of polycyclic polyethers that can be found in certain types of fish in the Pacific Ocean. The compound is produced by Dinoflagellates Gambierdiscus toxicus and is passed on through the food chain by fish. The compound has no effect in fish but is toxic to humans.
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| Formula | C60H86O19 |
| Molar mass | 1111.329 g·mol−1 |
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History
editBefore ciguatoxin was discovered and identified, its presence in the food chain was hypothesised by Randall et al,[1] who assumed that the toxin enters the food chain via herbivorous fish that feed on toxic microalgae and then gets passed on to humans directly or by passing through other carnivorous fish. This hypothesis was proven by Helfrich and Banner,[2] who also showed that the toxin has no effect on fish, both herbivorous and carnivorous.
Ciguatoxin-1 was first discovered in 1967 by Scheuer et al[3] when studying ciguatera fish responsible for food poisoning. Later on, in 1977 Yasumoto et al isolated the compound from Dinoflagellates and named it ciguatoxin, after which it was classified as a polyether compound. In the 1980s and early 1990s the full structure of ciguatoxin-1 was elucidated using NMR- spectroscopy, mass-spectrometry and X-ray crystallography.[4] Due to the high complexity of its structure, ciguatoxin-1 has not been assigned an official IUPAC name and is denoted simply as ciguatoxin-1 or CTX-1.
As such the compound hasn't been found of any practical use in daily life.[5] However, it has been shown useful for the studies of voltage gated sodium channels, where it can be used as a tool to alter the channel permeability and polarisability.[6]
Ecosystem distribution
editCTX-1 is produced by dinoflagellates called Gambierdiscus toxicus.[7] These dinoflagellates are either free flowing in the water or associated to different types of microalgae.[8] The toxin from the Gambierdiscus Toxicus accumulates in the fish that consume these organisms, and through the food chain the toxin eventually enters the human body.[9] CTX-1 cannot fully be removed from the fish by cooking it.[10] The toxin is found in tropical and subtropical coral reef fishes. Typically, these fishes are large predator fishes like moray eels, barracudas, snappers, Spanish Mackerels and groupers.[11]
There have been studies suggesting the transmission of the toxin from a pregnant mother to the foetus,[12] and from a nursing mother to her child.[13] There have also been some reports about sexual partners of ciguatoxin poisoning patients also experiencing symptoms.[14]
Food poisoning symptoms
editEating fish containing a high enough dose of CTX-1 causes Ciguatera Food Poisoning (CFP). It is suspected that concentration of 0.08 ug/kg fish is high enough to cause clinical symptoms and concentrations over 0.1 ug/kg fish are considered a health risk.[15] There are different types of symptoms for CFP: gastrointestinal, cardiac, neurological and neuropsychological symptoms. Gastrointestinal symptoms include nausea, vomiting, abdominal pain and diarrhoea. These symptoms usually start to show within 6-12h of fish consumption and resolve spontaneously within 1-4 days.[7][8][16] Cardiac symptoms include hypotension and bradycardia. These signs can lead to necessity of emergency medical care.[7][8][16] The neurological and neuropsychological symptoms usually become prominent after the gastrointestinal symptoms appear and they usually become present within two days of the illness. The signs and symptoms include weakness, toothache, the sensation of loose teeth, paraesthesia, dysesthesia, itching, confusion, reduced memory, difficulty concentrating, sweating and blurred vision. A characteristic symptom is cold allodynia, sometime referred to as ‘hot-cold reversal’, which is characterised by an abnormal sensation when touching cold water or objects.[7][8][16]
Mechanism of action
editIn neuronal neural tissue
editOne 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.[17] 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.[18] 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:[19] 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,[20][21] 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.[22]
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.[18] These findings could further explain the origin of various symptoms of ciguatera such as paraesthesia or dysesthesia.
It was also found that CTX-1 releases noradrenaline and ATP by asynchronous discharge of preganglionic perivascular axons.[23] CTX-1 prolongs the action potential and afterhyperpolarisation duration. In a subpopulation of neurons, tonic action potential firing can be produced.[24]
In the gastrointestinal tract
editEven 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.[25] 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.[25]
Toxicokinetics
editAs of today, only several studies were carried out on the biodistribution and toxicokinetics of ciguatoxins, most of which were carried out in rats or in vitro.
In a study by Bottein et al in 2011 it was shown that in rats, detectable levels of P-CTX-1 were observed in liver, muscle and brain up to 96 hours after intraperitoneal and oral administration.[26] The terminal half-lives were reported at 112 h and 82 h respectively. The main excretion route was shown to be faecal, with P-CTX-1 or its other polar metabolites being present in faeces for up to 4 days after administration.[26]
Another article speculated that ciguatoxins might be biotransformed in vitro by the means of glucuronidation.[27] However, it was shown that glucuronidation was not observed for any of the ciguatoxins used in the study (including P-CTX-1) by both rat and human, which could suggest the prevalence of other conjugation pathways in mammals[27]
References
edit- ^ Friedman MA, Fleming LE, Fernandez M, Bienfang P, Schrank K, Dickey R, et al. (September 2008). "Ciguatera fish poisoning: treatment, prevention and management". Marine Drugs. 6 (3): 456–479. doi:10.3390/md20080022. PMC 2579736. PMID 19005579.
- ^ Helfrich P, Banner AH (March 1963). "Experimental Induction of Ciguatera Toxicity in Fish through Diet". Nature. 197 (4871): 1025–1026. Bibcode:1963Natur.197Q1025H. doi:10.1038/1971025a0. ISSN 0028-0836.
- ^ Scheuer PJ, Takahashi W, Tsutsumi J, Yoshida T (March 1967). "Ciguatoxin: isolation and chemical nature". Science. 155 (3767): 1267–1268. Bibcode:1967Sci...155.1267S. doi:10.1126/science.155.3767.1267. PMID 6018649.
- ^ Murata M, Legrand AM, Ishibashi Y, Yasumoto T (November 1989). "Structures of ciguatoxin and its congener". Journal of the American Chemical Society. 111 (24): 8929–8931. doi:10.1021/ja00206a032. ISSN 0002-7863.
- ^ Aydın Ö, Karaarslan E (2022). "OpenAI ChatGPT Generated Literature Review: Digital Twin in Healthcare". SSRN Electronic Journal. doi:10.2139/ssrn.4308687. ISSN 1556-5068.
- ^ Molgo J, Benoit E, Cornella JX, Legrand AM (1992). "Ciguatoxin: A Tool for Research on Sodium-Dependent Mechanisms". Methods in Neurosciences. Vol. 8. Elsevier. pp. 149–164. doi:10.1016/b978-0-12-185266-5.50016-6. ISBN 978-0-12-185266-5.
- ^ a b c d Hungerford JM, Wekell MM (2019-04-04), "Analytical Methods for Marine Toxins", Food Poisoning, Routledge, pp. 415–473, doi:10.1201/9780203752708-16, ISBN 978-0-203-75270-8
- ^ a b c d Parsons ML, Settlemier CJ, Ballauer JM (September 2011). "An examination of the epiphytic nature of Gambierdiscus toxicus, a dinoflagellate involved in ciguatera fish poisoning". Harmful Algae. 10 (6): 598–605. Bibcode:2011HAlga..10..598P. doi:10.1016/j.hal.2011.04.011. PMC 3182139. PMID 21966283.
- ^ Lehane L, Lewis RJ (November 2000). "Ciguatera: recent advances but the risk remains". International Journal of Food Microbiology. 61 (2–3): 91–125. doi:10.1016/S0168-1605(00)00382-2. PMID 11078162.
- ^ Abraham A, Jester EL, Granade HR, Plakas SM, Dickey RW (March 2012). "Caribbean ciguatoxin profile in raw and cooked fish implicated in ciguatera". Food Chemistry. 131 (1): 192–198. doi:10.1016/j.foodchem.2011.08.059.
- ^ Friedman MA, Fernandez M, Backer LC, Dickey RW, Bernstein J, Schrank K, et al. (March 2017). "An Updated Review of Ciguatera Fish Poisoning: Clinical, Epidemiological, Environmental, and Public Health Management". Marine Drugs. 15 (3): 72. doi:10.3390/md15030072. PMC 5367029. PMID 28335428.
- ^ Beadle A (May 1997). "Ciguatera fish poisoning". Military Medicine. 162 (5): 319–322. doi:10.1093/milmed/162.5.319. PMID 9155099.
- ^ Blythe DG, de Sylva DP (1990-10-24). "Mother's milk turns toxic following fish feast". JAMA. 264 (16): 2074b–2074. doi:10.1001/jama.264.16.2074b. PMID 2214071.
- ^ Lange WR, Lipkin KM, Yang GC (1989). "Can ciguatera be a sexually transmitted disease?". Journal of Toxicology. Clinical Toxicology. 27 (3): 193–197. doi:10.3109/15563658909038583. PMID 2810444.
- ^ Lehane L, Lewis RJ (November 2000). "Ciguatera: recent advances but the risk remains". International Journal of Food Microbiology. 61 (2–3): 91–125. doi:10.1016/S0168-1605(00)00382-2. PMID 11078162.
- ^ a b c Nicholson G, Lewis R (2006-04-06). "Ciguatoxins: Cyclic Polyether Modulators of Voltage-gated Iion Channel Function". Marine Drugs. 4 (3): 82–118. doi:10.3390/md403082. hdl:10453/6103. ISSN 1660-3397.
- ^ Benoit E, Legrand AM, Dubois JM (January 1986). "Effects of ciguatoxin on current and voltage clamped frog myelinated nerve fibre". Toxicon. 24 (4): 357–364. Bibcode:1986Txcn...24..357B. doi:10.1016/0041-0101(86)90195-9. PMID 2424144.
- ^ a b Birinyi-Strachan LC, Gunning SJ, Lewis RJ, Nicholson GM (April 2005). "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. Bibcode:2005ToxAP.204..175B. doi:10.1016/j.taap.2004.08.020. hdl:10453/4825. PMID 15808523.
- ^ Birinyi-Strachan LC, Gunning SJ, Lewis RJ, Nicholson GM (April 2005). "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. Bibcode:2005ToxAP.204..175B. doi:10.1016/j.taap.2004.08.020. hdl:10453/4825. PMID 15808523.
- ^ Lewis RJ, Hoy AW, McGiffin DC (August 1992). "Action of ciguatoxin on human atrial trabeculae". Toxicon. 30 (8): 907–914. Bibcode:1992Txcn...30..907L. doi:10.1016/0041-0101(92)90389-M. PMID 1523682.
- ^ Lewis RJ, Endean R (November 1986). "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. PMID 2433605.
- ^ Lewis RJ (January 1988). "Negative inotropic and arrhythmic effects of high doses of ciguatoxin on guinea-pig atria and papillary muscles". Toxicon. 26 (7): 639–649. Bibcode:1988Txcn...26..639L. doi:10.1016/0041-0101(88)90246-2. PMID 2459809.
- ^ Brock JA, McLachlan EM, Jobling P, Lewis RJ (October 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. PMC 1908980. PMID 8564251.
- ^ Birinyi-Strachan LC, Gunning SJ, Lewis RJ, Nicholson GM (April 2005). "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. Bibcode:2005ToxAP.204..175B. doi:10.1016/j.taap.2004.08.020. hdl:10453/4825. PMID 15808523.
- ^ a b Terao K, Ito E, Oarada M, Ishibashi Y, Legrand AM, Yasumoto T (January 1991). "Light and electron microscopic studies of pathologic changes induced in mice by ciguatoxin poisoning". Toxicon. 29 (6): 633–643. Bibcode:1991Txcn...29..633T. doi:10.1016/0041-0101(91)90056-W. PMID 1926165.
- ^ a b Bottein MY, Wang Z, Ramsdell JS (June 2011). "Toxicokinetics of the ciguatoxin P-CTX-1 in rats after intraperitoneal or oral administration". Toxicology. 284 (1–3): 1–6. Bibcode:2011Toxgy.284....1D. doi:10.1016/j.tox.2011.02.005. PMID 21349314.
- ^ a b Gwinn JK, Uhlig S, Ivanova L, Fæste CK, Kryuchkov F, Robertson A (August 2021). "In Vitro Glucuronidation of Caribbean Ciguatoxins in Fish: First Report of Conjugative Ciguatoxin Metabolites". Chemical Research in Toxicology. 34 (8): 1910–1925. doi:10.1021/acs.chemrestox.1c00181. PMC 9215509. PMID 34319092.