Scaritoxin

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Scaritoxin
Scaritoxin.svg
Names
Other names
Ciguatoxin 4A; CTX4A; (52S)-1,2,54-Trideoxy-1,2-didehydrociguatoxin
Identifiers
3D model (JSmol)
ChemSpider
KEGG
PubChem CID
UNII
  • InChI=1S/C60H84O16/c1-7-8-13-34-14-11-17-41-56(65-34)53(63)57-49(69-41)26-43-40(72-57)21-20-38-39(67-43)19-18-37-35(66-38)15-9-10-16-36-45(68-37)28-50(61)59(6)51(71-36)29-46-47(75-59)25-30(2)24-42-44(70-46)27-48-54(73-42)32(4)52(62)58-55(74-48)31(3)33(5)60(76-58)22-12-23-64-60/h7-11,13-14,18-21,30-58,61-63H,1,12,15-17,22-29H2,2-6H3/b10-9+,13-8+/t30-,31+,32+,33+,34+,35-,36+,37+,38+,39-,40-,41+,42+,43+,44-,45-,46+,47-,48+,49-,50-,51-,52+,53-,54-,55-,56+,57-,58+,59+,60+/m1/s1
    Key: QFYRPKKCVYDHFZ-FKFYNGSCSA-N
  • C[C@@H]1C[C@H]2[C@@H](C[C@H]3[C@H](O2)[C@H]([C@@H]([C@H]4[C@H](O3)[C@H]([C@@H]([C@@]5(O4)CCCO5)C)C)O)C)O[C@H]6C[C@@H]7[C@]([C@@H](C[C@@H]8[C@@H](O7)C/C=C/C[C@@H]9[C@@H](O8)C=C[C@@H]2[C@@H](O9)C=C[C@@H]3[C@@H](O2)C[C@@H]2[C@@H](O3)[C@@H]([C@@H]3[C@@H](O2)CC=C[C@@H](O3)/C=C/C=C)O)O)(O[C@@H]6C1)C
Properties
C60H84O16
Molar mass 1061.316 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Scaritoxin, a potent toxic substance, is a ciguatoxin with molecular formula C60H84O16. [1] Scaritoxin is also referred to as ciguaotoxin 4A, CTX4A. [1] Like other ciguatoxins, CTX4A is produced by dinoflagellate Gambierdiscus toxicus and isolated from poisonous fish. [2] [3] [4]

Contents

The name of scaritoxin is derived from the poisonous fish Scarus gibus, which is now known as the Chlorurus gibbus family of the Scaridae. [5] Namely, ciguatoxins accumulate in various fish species via the food chain as a result of biotransformation of the precursor gambiertoxins produced by Gambierdiscus toxicus. [3] Since CTX4A was identified in Gambierdiscus toxicus and in parrotfish, the first link in the food chain, it was concluded that Gambierdiscus toxicus is the biogenetic origin of ciguatera toxins found in fish. [6] Ciguatoxins, CTX-group toxins, generally accumulate in the skin, head, viscera, and roe of big reef fish [7]

Ingestion of these fish with accumulated CTX-group toxins, marine biotoxins, results in ciguatera fish poisoning (CFP). [2] Poisoning with scaritoxin, however, is not well described. [8]

Ciguatera poisoning

Ciguatera fish poisoning (CFP) is a clinical syndrome caused by eating fish containing accumulated ciguatoxins (CTXs), marine biotoxins, due to feeding on toxic microalgae. Traditional endemic regions for ciguatoxic fish include areas in the Caribbean sea and the Pacific and Indians oceans, but autochthonous outbreaks have also been reported in Europe. [5] The accumulated ciguatoxins remain stable at various temperatures, meaning they are not eliminated through cooking or freezing fish. [9] Additionally, these toxins lack color, odor, and flavor, making it impossible to detect them by taste or smell. [9]

Fatality risks from CFP arise from cardio-respiratory failure. CFP stands as the most prevalent marine biotoxin food poisoning globally, affecting an estimated 10.000 to 50.000 individuals annually. [2] [3] Associated to ciguatera fish poisoning is primarily the consumption of large predator fish, which accumulate CTX-group toxins by preying on smaller contaminated coral reef fish. [3] However, ciguatoxins rarely accumulate in fish at levels that are lethal to humans, so CFP comes along with a low mortality rate, but a significant high morbidity rate. [2] [4]

Metabolism

Generally, ciguatoxins produced by the causative Gambierdiscus toxicus exist in multiple forms as a result of biotransformation by passage through the food web. [5] Through the biotransformation and the acid catalyzed Spiro isomerization of gambiertoxin, they arise in the fish. [5] It is said that the toxins undergo varying extents of biotransformation, but very little is known about the specifics. The different digestive strategies among the herbivores and carnivores are possibly influencing the nature of the toxin biotransformation via the marine food chain. [10]

Symptoms and side effects

Symptoms of ciguatera fish poisoning in humans include several effects which are mainly gastrointestinal, cardiovascular, and neurological. [3] The symptoms of acute ciguatera fish poisoning can already start 30 minutes after eating contaminated fish. [3] [11] However, in milder cases the first symptoms arise 24 to 48 hours later. [3] The initial symptoms may include itching, tingling, and numbness of the lips, tongue, hands, throat and/or feet. [11] During the first 6 to 17 hours gastrointestinal symptoms like abdominal cramps, nausea, vomiting, diarrhea, and/or a red skin rash (pruritus), can occur. [11] Accompanying these gastrointestinal symptoms, neurological symptoms become prominent 3 to 48 hours after eating of the contaminated fish. [9] Moreover, chills, hot and cold temperature reversal, generalized weakness, restlessness, dizziness, wheezing, blurred vision, abnormal sensitivity to light (photophobia), muscle aches (myalgias), and joint pain (arthralgias) can also occur. [11]

The severe symptoms of ciguatera fish poisoning disappear generally disappear after a few days, but the neurological symptoms can remain present for months. [11] Abnormally low blood pressure upon standing from a seated position (orthostatic hypotension) is a symptom of CFP that can be experienced. [11] Severe instances may proceed quickly to muscle paralysis and dyspnoea, which are breathing difficulties. [9] Acute cases that progress to life-threatening consequences (irregularly slow heartbeat, respiratory arrest, convulsions, or coma) happen within 24 hours. [9]

Poisoning with scaritoxin actually emerges in two stages. The first set of symptoms resemble typical ciguatera poisoning as described. The second stage, developing five to ten days after the initial symptoms, start with failure of equilibration and marked locomotor ataxia. [5] There is no known antidote, medication or treatment for scaritoxin poisoning. [4] [5] [9] Medical care towards CFP-patients consists of supportive care, varying with the symptoms a patient shows.

Structure

Scaritoxin is a rather large lipid soluble polycyclic polyether toxin with molecular formula C60H84O16. [3] The compound contains 31 defined stereo-centres, one E/Z centre and its optical activity is unspecified. [12] The structure contains 13 rings fused by ether linkages, which make the structure of scaritoxin into a rigid ladder like-structure. [8] Because of its rigidity the structure is known not to be affected by heat and acidic or basic conditions. [8]

Mechanism of action

Scaritoxin, recognized as a potent toxin, induces diverse effects across various biological systems through its interaction with specific cellular receptors or ion channels, thereby initiating notable physiological alterations. [13] A guinea-pig vas deferens investigation characterizes a pronounced excitatory impact of scaritoxin, indicative of its engagement with receptors or ion channels within smooth muscle cells, precipitating muscle contraction and heightened excitability. [13] Additionally, investigations into the autonomic effects of scaritoxin on animals suggest potential interactions with receptors or ion channels within the autonomic nervous system, utilizing influence over parameters such as heart rate, cardiac function, and other autonomic-controlled processes. [14] Alternative mechanisms, including a hypothesized digitalis-like effect due to the cyclopentanone ring present in the scaritoxin molecule, validates consideration. [14]

Notably, a separate inquiry observed that a medication employed for arrhythmia prevention could diminish scaritoxin-induced cardiac detriment, implying a tendency of scaritoxin to induce arrhythmias or other harmful cardiac manifestations, possibly through modulation of specific components within the cardiac electrical conduction system. [15]

The mechanism of action for scaritoxin is not clearly defined, but knowing it is a ciguatoxin it is likely to follow the same mechanism. It is said that the toxin bind and modulate the activity of cell membrane voltage-gated sodium channels. [16] Ciguatoxins bind on the alpha subunit at site 5, this induces the opening of the channels at resting membrane potential. [16] This activation of voltage-gated sodium channels in cell membranes thus increases the sodium ion permeability, which causes membrane depolarization and thereby spontaneous action potentials. [9] [16] As a result the neuronal tissue has decreased conduction velocity and neurotransmission. [16]

Toxicity

Since the feeding history of fish and the population of alga causing ciguatera fish poisoning, the toxicity of individual fish is very unpredictable. [2] The fish that carry scaritoxin in their flesh do not seem to be harmed by it. [8] Testing for scaritoxin in these fish is not a standard practice and it is really difficult to prevent scaritoxin poisoning since toxin is not harmed by heat, acid or basic conditions and cannot be detected  with taste or smell.

The lethal dose fifty (LD50) of scaritoxin administered intraperitoneally in mice was determined to be 50 micrograms per kilogram. [17] This denotes a pronounced toxicity of scaritoxin towards mice, presumably due to its disruptive effects on vital physiological mechanisms or harmful impacts on organ systems. [17] This translates for an average human of around 70 kilograms to 3.5 milligrams, hence this shows that a small amount can potentially cause significant harm to humans. However, directly translation of the results from mice to humans is not a reliable source to draw specific conclusions from about the toxicity for humans.  

Related Research Articles

<span class="mw-page-title-main">Toxin</span> Naturally occurring organic poison

A toxin is a naturally occurring poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919) and is derived from the word "toxic".

Bioaccumulation is the gradual accumulation of substances, such as pesticides or other chemicals, in an organism. Bioaccumulation occurs when an organism absorbs a substance faster than it can be lost or eliminated by catabolism and excretion. Thus, the longer the biological half-life of a toxic substance, the greater the risk of chronic poisoning, even if environmental levels of the toxin are not very high. Bioaccumulation, for example in fish, can be predicted by models. Hypothesis for molecular size cutoff criteria for use as bioaccumulation potential indicators are not supported by data. Biotransformation can strongly modify bioaccumulation of chemicals in an organism.

<span class="mw-page-title-main">Mahi-mahi</span> Species of fish

The mahi-mahi or common dolphinfish is a surface-dwelling ray-finned fish found in off-shore temperate, tropical, and subtropical waters worldwide. Also widely called dorado and dolphin, it is one of two members of the family Coryphaenidae, the other being the pompano dolphinfish. These fish are most commonly found in the waters around the Gulf of Mexico, Costa Rica, Hawaii and the Indian Ocean.

<span class="mw-page-title-main">Tetrodotoxin</span> Neurotoxin

Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an order that includes pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Although tetrodotoxin was discovered in these fish, it is found in several other animals. It is also produced by certain infectious or symbiotic bacteria like Pseudoalteromonas, Pseudomonas, and Vibrio as well as other species found in symbiotic relationships with animals and plants.

Ciguatera fish poisoning (CFP), also known as ciguatera, is a foodborne illness caused by eating reef fish contaminated with ciguatoxins. Such individual fish are said to be ciguatoxic. Symptoms may include diarrhea, vomiting, numbness, itchiness, sensitivity to hot and cold, dizziness, and weakness. The onset of symptoms varies with the amount of toxin eaten. If a lot of toxins are consumed symptoms may appear within half an hour. If a low amount of toxins are consumed symptoms make take a few days to appear. Diarrhea may last up to four days. Symptoms may last a few weeks to a few months. Heart problems such as slow heart rate and low blood pressure may occur.

<span class="mw-page-title-main">Saxitoxin</span> Paralytic shellfish toxin

Saxitoxin (STX) is a potent neurotoxin and the best-known paralytic shellfish toxin. Ingestion of saxitoxin by humans, usually by consumption of shellfish contaminated by toxic algal blooms, is responsible for the illness known as paralytic shellfish poisoning (PSP).

<span class="mw-page-title-main">Palytoxin</span> Chemical compound

Palytoxin, PTX or PLTX is an intense vasoconstrictor, and is considered to be one of the most poisonous non-protein substances known, second only to maitotoxin in terms of toxicity in mice.

<span class="mw-page-title-main">Paralytic shellfish poisoning</span> Syndrome of shellfish poisoning

Paralytic shellfish poisoning (PSP) is one of the four recognized syndromes of shellfish poisoning, which share some common features and are primarily associated with bivalve mollusks. These shellfish are filter feeders and accumulate neurotoxins, chiefly saxitoxin, produced by microscopic algae, such as dinoflagellates, diatoms, and cyanobacteria. Dinoflagellates of the genus Alexandrium are the most numerous and widespread saxitoxin producers and are responsible for PSP blooms in subarctic, temperate, and tropical locations. The majority of toxic blooms have been caused by the morphospecies Alexandrium catenella, Alexandrium tamarense, Gonyaulax catenella and Alexandrium fundyense, which together comprise the A. tamarense species complex. In Asia, PSP is mostly associated with the occurrence of the species Pyrodinium bahamense.

<span class="mw-page-title-main">Maitotoxin</span> Chemical compound

Maitotoxin (MTX) is an extremely potent biotoxin produced by Gambierdiscus toxicus, a dinoflagellate species. Maitotoxin has been shown to be more than one hundred thousand times as potent as VX nerve agent. Maitotoxin is so potent that it has been demonstrated that an intraperitoneal injection of 130 ng/kg was lethal in mice. Maitotoxin was named from the ciguateric fish Ctenochaetus striatus—called "maito" in Tahiti—from which maitotoxin was isolated for the first time. It was later shown that maitotoxin is actually produced by the dinoflagellate Gambierdiscus toxicus.

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

<span class="mw-page-title-main">Predatory dinoflagellate</span>

Predatory dinoflagellates are predatory heterotrophic or mixotrophic alveolates that derive some or most of their nutrients from digesting other organisms. About one half of dinoflagellates lack photosynthetic pigments and specialize in consuming other eukaryotic cells, and even photosynthetic forms are often predatory.

<span class="mw-page-title-main">Neurotoxic shellfish poisoning</span> Syndrome of shellfish poisoning

Neurotoxic shellfish poisoning (NSP) is caused by the consumption of brevetoxins, which are marine toxins produced by the dinoflagellate Karenia brevis. These toxins can produce a series of gastrointestinal and neurological effects. Outbreaks of NSP commonly take place following harmful algal bloom (HAB) events, commonly referred to as "Florida red tide". Algal blooms are a naturally-occurring phenomenon, however their frequency has been increasing in recent decades at least in-part due to human activities, climate changes, and the eutrophication of marine waters. HABs have been occurring for all of documented history, evidenced by the Native Americans' understanding of the dangers of shellfish consumption during periods of marine bioluminescence. Blooms have been noted to occur as far north as North Carolina and are commonly seen alongside the widespread death of fish and sea birds. In addition to the effects on human health, the economic impact of HAB-associated shellfish toxin outbreaks can have significant economic implications as well due to not only the associated healthcare costs, but the adverse impact on the commercial shellfish industry.

<i>Gambierdiscus toxicus</i> Species of protist

Gambierdiscus toxicus is a species of photosynthetic unicellular eukaryote belonging to the Alveolata, part of the SAR supergroup. It is a dinoflagellate which can cause the foodborne illness ciguatera, and is known to produce several natural polyethers including ciguatoxin, maitotoxin, gambieric acid, and gambierol. The species was discovered attached to the surface of brown macroalgae.

Dinotoxins are a group of toxins which are produced by flagellate, aquatic, unicellular protists called dinoflagellates. Dinotoxin was coined by Hardy and Wallace in 2012 as a general term for the variety of toxins produced by dinoflagellates. Dinoflagellates are an enormous group of marine life, with much diversity. With great diversity comes many different toxins, however, there are a few toxins that multiple species have in common.

Gambierdiscus australes is a species of toxic dinoflagellate. It is 76–93 μm long and 65–85 μm wide dorsoventrally and its surface is smooth. It is identified by a broad ellipsoid apical pore plate surrounded by 31 round pores. Its first plate occupies 30% of the width of the hypotheca.

Gambierdiscus polynesiensis is a species of toxic dinoflagellate. It is 68–85 μm long and 64–75 μm wide dorsoventrally and its surface is smooth. It is identified by a large triangular apical pore plate, a narrow fish-hook opening surrounded by 38 round pores, and a large, broad posterior intercalary plate. Its first plate occupies 60% of the width of the hypotheca.

<i>Gambierdiscus</i> Genus of protists

Gambierdiscus is a genus of marine dinoflagellates that produce ciguatoxins, a type of toxin that causes the foodborne illness known as ciguatera. They are usually epiphytic on macroalgae growing on coral reefs.

Gambierol is a marine polycyclic ether toxin which is produced by the dinoflagellate Gambierdiscus toxicus. Gambierol is collected from the sea at the Rangiroa Peninsula in French Polynesia. The toxins are accumulated in fish through the food chain and can therefore cause human intoxication. The symptoms of the toxicity resemble those of ciguatoxins, which are extremely potent neurotoxins that bind to voltage-sensitive sodium channels and alter their function. These ciguatoxins cause ciguatera fish poisoning. Because of the resemblance, there is a possibility that gambierol is also responsible for ciguatera fish poisoning. Because the natural source of gambierol is limited, biological studies are hampered. Therefore, chemical synthesis is required.

<span class="mw-page-title-main">Squaretail coral grouper</span> Species of fish

The squaretail coral grouper is a species of marine ray-finned fish. It is a grouper from the subfamily Epinephelinae, which is part of the family Serranidae. This family also includes anthias and sea basses. The squaretail coral grouper is also known as the spotted coral trout or the squaretail coral trout, and is fast-growing, short-lived, and early-maturing. However, due to the continued decrease in its population, it is now classified as vulnerable, as it continues to face threats from human activity.

<span class="mw-page-title-main">Ciguatoxin 1</span> Toxic compound found in some fish

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. 

References

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  3. 1 2 3 4 5 6 7 8 EFSA Panel on Contaminants in the Food Chain (June 2010). "Scientific Opinion on marine biotoxins in shellfish – Emerging toxins: Ciguatoxin group". EFSA Journal. 8 (6). doi:10.2903/j.efsa.2010.1627.
  4. 1 2 3 Friedman, Melissa A.; Fleming, Lora E.; Fernandez, Mercedes; Bienfang, Paul; Schrank, Kathleen; Dickey, Robert; Bottein, Marie-Yasmine; Backer, Lorraine; Ayyar, Ram; Weisman, Richard; Watkins, Sharon; Granade, Ray; Reich, Andrew (September 2008). "Ciguatera Fish Poisoning: Treatment, Prevention and Management". Marine Drugs. 6 (3): 456–479. doi: 10.3390/md6030456 . ISSN   1660-3397. PMC   2579736 . PMID   19005579.
  5. 1 2 3 4 5 6 de Fouw, JC; van Egmond, HP; Speijers, GJA (February 2001). "Ciguatera fish poisoning: a review" (PDF). RIVM Report 388802 021.
  6. ↑ Satake, Masayuki; Ishibashi, Yoshihiko; Legrand, Anne-Marie; Yasumoto, Takeshi (January 1996). "Isolation and Structure of Ciguatoxin-4A, a New Ciguatoxin Precursor, from Cultures of Dinoflagellate Gambierdiscus toxicus and Parrotfish Scarus gibbus". Bioscience, Biotechnology, and Biochemistry. 60 (12): 2103–2105. doi:10.1271/bbb.60.2103. ISSN   0916-8451. PMID   9026141.
  7. ↑ "Enjoy Coral Reef Fish but Mind Ciguatoxin Poisoning". www.cfs.gov.hk. Retrieved 2024-03-14.
  8. 1 2 3 4 "Marine biotoxins". www.fao.org. Retrieved 2024-03-14.
  9. 1 2 3 4 5 6 7 "Facts on ciguatera fish poisoning". www.ecdc.europa.eu. 2021-02-01. Retrieved 2024-03-14.
  10. ↑ Lewis, R. J. (January 2001). "The changing face of ciguatera". Toxicon. 39 (1): 97–106. Bibcode:2001Txcn...39...97L. doi:10.1016/s0041-0101(00)00161-6. ISSN   0041-0101. PMID   10936626.
  11. 1 2 3 4 5 6 "Ciguatera Fish Poisoning - Symptoms, Causes, Treatment | NORD". rarediseases.org. Retrieved 2024-03-14.
  12. ↑ "NCATS Inxight Drugs — SCARITOXIN". drugs.ncats.io. Retrieved 2024-03-14.
  13. 1 2 Tatsumi, M.; Kajiwara, A.; Yasumoto, T.; Ohizumi, Y. (December 1985). "Potent excitatory effect of scaritoxin on the guinea-pig vas deferens, taenia caeci and ileum". The Journal of Pharmacology and Experimental Therapeutics. 235 (3): 783–787. ISSN   0022-3565. PMID   4078732.
  14. 1 2 Boivin, R.; Bost, J.; Rentler, J. F. (1983). "[Autonomic effects of scaritoxin in the cat and guinea pig. Cardiac protection by an anti-arrhythmia agent]". Comptes Rendus des Séances de la Société de Biologie et de Ses Filiales. 177 (2): 203–210. ISSN   0037-9026. PMID   6224540.
  15. ↑ Legrand, A. M.; Galonnier, M.; Bagnis, R. (1982). "Studies on the mode of action of ciguateric toxins". Toxicon. 20 (1): 311–315. Bibcode:1982Txcn...20..311L. doi:10.1016/0041-0101(82)90233-1. ISSN   0041-0101. PMID   7080044.
  16. 1 2 3 4 Darracq, M. A. (2014-01-01), "Ciguatoxin", in Wexler, Philip (ed.), Encyclopedia of Toxicology (Third Edition), Oxford: Academic Press, pp. 963–965, ISBN   978-0-12-386455-0 , retrieved 2024-03-14
  17. 1 2 "Table of biological toxins" (PDF). University of North Texas.
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