Maitotoxin

Ciguatera poisoning is treated with supportive care. Some medications such as the use of Amitriptyline may reduce some symptoms of ciguatera, such as fatigue and paresthesia, although benefit does not occur in every case. Also used are steroids and vitamin supplements, but these merely support the body's recovery rather than directly reducing the toxic effects. (L995)

Of the marine polyethers, maitotoxin is not only the most complex and most toxic of the class, but is also the largest nonpolymeric natural product known to date.

Maitotoxin activates calcium permeable, non-selective cation channels, leading to an increase in levels of cytosolic calcium ions. It is thought that maitotoxin leads to the formation of pores on these ion channels. Ultimately, a cell death cascade is activated, resulting in membrane blebbing and eventually cell lysis. Maitotoxin is also known to activate cytosolic calcium-activated proteases calpain-1 and calpain-2, contributing to necrosis. (L1114)

/AQUATIC SPECIES/ Maitotoxin (MTX) ... inhibited sea urchin egg fertilization in a dose-dependent manner with an IC50 of 7.5 x 10-3 MU (mouse-unit)/mL. It did not affect male gametes fertilizing capabilities but provoked exocytosis in female gametes. It induced a K+ loss simultaneously with a Na+ entry into unfertilized eggs and increased the Ca2+ influx at higher concentrations. On isolated cortex preparations, high concentrations of MTX reduced the rate of ATP-dependent Ca2+ accumulation into reticulum compartments and caused a leakage of Ca2+ from a preparation pre-loaded with 45Ca2+. ...

Toxin from Gambierdiscus toxicus can cause a type of food poisoning called ciguatera. Hallmark symptoms of ciguatera include gastrointestinal and neurological effects. Gastrointestinal symptoms include nausea, vomiting, and diarrhea usually followed by neurological symptoms such as headaches, muscle aches, paresthesia, numbness, ataxia, and hallucinations. Severe cases of ciguatera can also result in cold allodynia. (L995)

Maitotoxin is the largest nonpolymeric, nonproteogenic natural product known. It has extremely potent hemolytic and ichthyotoxic activity and was first isolated from the viscera of coral reef fish Ctentochaetus straiatus. Later it was found to be produced by the dinoflagellete Gambierdiscus toxicus(1).

Maitotoxin /has/ been isolated from the biodetritus layer of coral reefs, from dinoflagellate Gambierdiscus toxicus collected from seawater, and from anexic cultures of G. toxicus(1).

/SIGNS AND SYMPTOMS/ The ciguatoxins are a family of heat-stable, lipid-soluble, highly oxygenated, cyclic polyether molecules with a structural framework reminiscent of the brevetoxins, and more than 20 toxins may be involved in ciguatera fish poisoning (CFP). ... Ciguatoxins ... are regarded as the most potent activators of sodium and/or calcium fluxes in the cytoplasm in various cells. They produce more than 175 ciguateric symptoms, classified into four categories: gastrointestinal, neurological, cardiovascular and general symptoms. It should be emphasized that the symptoms of ciguatera vary in different oceans: in the Pacific Ocean neurological symptoms predominate, while in the Caribbean Sea the gastrointestinal symptoms dominate due to the difference in toxin composition. Ciguatoxin and maitotoxin are the two most common toxins associated with CFP ...

/SIGNS AND SYMPTOMS/ Ciguatera fish poisoning (CFP) produces gastrointestinal, neurological, and cardiovascular symptoms which usually begin developing within 12 to 24 hours of eating contaminated fish. Initially, gastrointestinal symptoms of diarrhea, abdominal pain, nausea, and vomiting occur, followed by neurological symptoms of numbness and tingling of hands and feet, dizziness, altered hot/ cold perception , muscle aches, and low heart rates and blood pressure. In extreme cases, death occurs through respiratory failure. /Ciguatera/

/ALTERNATIVE and IN VITRO TESTS/ Maitotoxin (MTX) is a potent marine toxin which stimulates several Ca(++)-dependent processes presumably through an increase in Ca++ permeability. ... The effect of MTX on the release of chemical mediators from human basophils /was examined/ ... . MTX (1-20 ng/mL) induced histamine release (37-100%) from both mixed leukocyte preparations and purified basophils. Histamine release activated by MTX was slow (t 1/2 approximately equal to 15 min), temperature and Ca++ dependent (optimal at 37 °C and 1-2.5 mM Ca++). Sr++ ion could substitute for Ca++ in the secretory process. Digital video microscopy analysis of purified (> 70%) basophils revealed that MTX (1-20 ng/mL) induced a slow and marked increase of cytosolic Ca++ levels that was temporally coincident with histamine release. MTX (1-20 ng/mL) stimulated the release of sulfidopeptide leukotriene C4 from mixed leukocyte preparations (approximately equal to 0.5% basophils). However, purified basophils (77 +/- 7%) showed no sulfidopeptide leukotriene C4 release even in the presence of large histamine secretion (84 +/- 14%). Two organic Ca(++)-channel entry blockers, verapamil and diltiazem (1-30 uM) inhibited the release of histamine induced by MTX, whereas the dihydropyridine nifedipine (0.1-10 uM) caused only minimal inhibition. These results suggest that MTX represents a novel stimulus useful to study the role of Ca++ in human basophil mediator release.

/ALTERNATIVE and IN VITRO TESTS/ Treatment of MCF-7 breast cancer cells with the marine toxin maitotoxin (MTX) induces cell death. The cytotoxic effects are clearly detectable within 2-4 hr after cell treatment with 10-10 to 10-9 M concentrations of MTX. The response was found to depend on extracellular Ca2+, inasmuch as cell death was prevented when culture dishes received MTX, following addition of EGTA. MTX caused transient phosphorylation of extracellular signal-regulated kinase isoforms 1 and 2 (ERK1 and ERK2) mitogen-activated protein kinase isoforms in MCF-7 cells, which was maximal 15 min after toxin addition to culture vessels. The effect was dependent on influx of extracellular Ca2+, as it was abolished by EGTA, and was induced by ionophores, such as A23187 and ionomycin. /The/ findings show that signaling pathways involving Ca2+ ions may cause activation of ERK1 and ERK2 in cell death responses.

/LABORATORY ANIMALS: Acute Exposure/ Maitotoxion, a putative Ca2+ channel agonist, was isolated from cultures of the marine dinoflagellate Gambierdiscus toxicus as a colorless amorphous solid. ... The mouse lethality of maitotoxin determined by intraperitoneal injection was 0.13 ug/kg. ...

/LABORATORY ANIMALS: Acute Exposure/ Maitotoxin ... induced severe pathomorphological changes in the stomach, heart and lymphoid tissues in mice and rats. Multiple erosions were observed in gastric mucosa accompanied by a marked increase in total calcium content 24 hr after ip injection of 200 or 400 ng/kg of maitotoxin. In contrast, there was no close temporal association between the accumulation of calcium and the morphological appearance of dead cells in the heart and thymus. Within 30 min of administration of 200 or 400 ng/kg of maitotoxin, a marked swelling was seen in the endothelial lining cells of blood capillaries between cardiac muscle fibers, followed by the cell death of the fibers. Injection of maitotoxin at a dose of 200 ng/kg or higher also resulted in necrosis of lymphocytes in the cortex of the thymus at 4 hr and in the medulla at 8 hr.

/LABORATORY ANIMALS: Acute Exposure/ Repeated injections of 45 ng/kg of maitotoxin into the peritoneal cavities of male ICR mice resulted in marked atrophy of lymphoid tissues, a reduction of lymphocytes in the circulating blood, reduced immunoglobulin M in serum, and an increase of calcium content in the adrenal glands. A single injection of 200 ng/kg of maitotoxin induced a marked increase in total calcium content of the adrenal glands as well as in plasma cortisol concentration (about seven times control) within 1 hr. In contrast, mice pretreated with CoCl2, a calcium channel inhibitor, and/or adrenalectomized mice, showed no discernible changes in the lymphoid tissues after repeated injections of maitotoxin. It is thus suggested that maitotoxin first stimulates calcium influx in the adrenal glands, which then causes the release of cortisol into the blood. The excess amount of cortisol in serum produces acute involution of the thymus and other lymphoid tissues.

/LABORATORY ANIMALS: Acute Exposure/ Maitotoxin ... is a water soluble, ladder-shaped polycyclic molecule with numerous hydroxyl groups and sulfate groups. Three forms of MTX, MTX-1, MTX-2 and MTX-3 have been identified from G. toxicus. MTX has been proved to be the most potent toxin identified on a weight basis: the LD50 of MTX in mice is less than 0.2 ug/kg (ip) and it is at least 5-fold more toxic than tetrodotoxin.

For more Non-Human Toxicity Excerpts (Complete) data for Maitotoxin (21 total), please visit the HSDB record page.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/