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PubMed1983

Contraction and increase in tissue calcium content induced by maitotoxin, the most potent known marine toxin, in intestinal smooth muscle.

Maitotoxin (MTX), the most potent known marine toxin, isolated from toxic dinoflagellates and poisonous fish, caused a dose-dependent contraction of the guinea-pig isolated ileum and taenia caeci at concentrations of 100 pg to 30 ng/ml. These contractile responses to MTX (3 ng/ml) in both tissues were abolished by incubation in Ca2+-free solution and were markedly inhibited by treatment with methoxyverapamil (D600), but were not affected by tetrodotoxin and atropine. Furthermore, MTX markedly elevated tissue Ca2+ content of the taenia caeci. These results suggest that MTX activates Ca2+ channels in the smooth muscle membrane of both tissues to increase Ca2+ influx and thus induces contractions.

Animals↗
PubMed2004

Maitotoxin-induced cell death cascade in bovine aortic endothelial cells: divalent cation specificity and selectivity.

The maitotoxin (MTX)-induced cell death cascade in bovine aortic endothelial cells (BAECs), a model for Ca(2+) overload-induced toxicity, reflects three sequential changes in plasmalemmal permeability. MTX initially activates Ca(2+)-permeable, nonselective cation channels (CaNSC) and causes a massive increase in cytosolic free Ca(2+) concentration ([Ca(2+)](i)). This is followed by the opening of large endogenous cytolytic/oncotic pores (COP) that allow molecules <800 Da to enter the cell. The cells then lyse not by rupture of the plasmalemma but through the activation of a "death" channel that lets large proteins (e.g., 140-160 kDa) leave the cell. These changes in permeability are accompanied by the formation of membrane blebs. In this study, we took advantage of the well-known differences in affinity of various Ca(2+)-binding proteins for Ca(2+) and Sr(2+) vs. Ba(2+) to probe their involvement in each phase of the cell death cascade. Using fluorescence techniques at the cell population level (cuvette-based) and at the single-cell level (time-lapse videomicroscopy), we found that the replacement of Ca(2+) with either Sr(2+) or Ba(2+) delayed both MTX-induced activation of COP, as indicated by the uptake of ethidium bromide, and subsequent cell lysis, as indicated by the uptake of propidium iodide or the release of cell-associated green fluorescent protein. MTX-induced responses were mimicked by ionomycin and were significantly delayed in BAPTA-loaded cells. Experiments at the single-cell level revealed that Ba(2+) not only delayed the time to cell lysis but also caused desynchronization of the lytic phase. Last, membrane blebs, which were numerous and spherical in Ca(2+)-containing solutions, were poorly defined and greatly reduced in number in the presence of Ba(2+). Taken together, these results suggest that intracellular high-affinity Ca(2+)-binding proteins are involved in the MTX-induced changes in plasmalemmal permeability that are responsible for cell demise.

Animals↗
PubMed2004

Airway responses to aerosolized brevetoxins in an animal model of asthma.

Florida red tide brevetoxins are sodium channel neurotoxins produced by the dinoflagellate Karenia brevis. When aerosolized, the toxin causes airway symptoms in normal individuals and patients with airway disease, but systematic exposures to define the pulmonary consequences and putative mechanisms are lacking. Here we report the effects of airway challenges with lysed cultures of Karenia brevis (crude brevetoxin), pure brevetoxin-2, brevetoxin-3, and brevetoxin-tbm (brevetoxin-2 minus the side chain) on pulmonary resistance and tracheal mucus velocity, a marker of mucociliary clearance, in allergic and nonallergic sheep. Picogram concentrations of toxin caused bronchoconstriction in both groups of sheep. Brevetoxin-tbm was the least potent, indicating the importance of the side chain for maximum effect. Both histamine H(1)- and cholinergic-mediated pathways contributed to the bronchoconstriction. A synthetic antagonist, beta-naphthoyl-brevetoxin-3, and brevenal, a natural antagonist, inhibited the bronchoconstriction. Only crude brevetoxin and brevetoxin-3 decreased tracheal mucus velocity; both antagonists prevented this. More importantly, picomolar concentrations of the antagonists alone improved tracheal mucus velocity to the degree seen with mM concentrations of the sodium channel blocker amiloride. Thus, Karenia brevis, in addition to producing toxins that adversely affect the airways, may be a source of agents for treating mucociliary dysfunction.

Administration, Inhalation↗
PubMedDate not supplied

Brevetoxicosis in manatees (Trichechus manatus latirostris) from the 1996 epizootic: gross, histologic, and immunohistochemical features.

In 1996, at least 149 manatees (Trichechus manatus latirostris) died in an unprecedented epizootic along the southwest coast of Florida. At about the same time, a bloom of the brevetoxin-producing dinoflagellates, Gymnodinium breve, was present in the same area. Grossly, severe nasopharyngeal, pulmonary, hepatic, renal, and cerebral congestion was present in all cases. Nasopharyngeal and pulmonary edema and hemorrhage were also seen. Consistent microscopic lesions consisted of catarrhal rhinitis, pulmonary hemorrhage and edema, multiorgan hemosiderosis, and nonsuppurative leptomeningitis. Immunohistochemical staining using a polyclonal primary antibody to brevetoxin (GAB) showed intense positive staining of lymphocytes and macrophages in the lung, liver, and secondary lymphoid tissues. Additionally, lymphocytes and macrophages associated with the inflammatory lesions of the nasal mucosa and meninges were also positive for brevetoxin. These findings implicate brevetoxicosis as a component of and the likely primary etiology for the epizootic. The data suggest that mortality resulting from brevetoxicosis may not necessarily be acute but may occur after chronic inhalation and/or ingestion. Immunohistochemical staining with interleukin-1-beta-converting enzyme showed positive staining with a cellular tropism similar to GAB. This suggests that brevetoxicosis may initiate apoptosis and/or the release of inflammatory mediators that culminate in fatal toxic shock.

Adrenal Glands↗
PubMed2005

Actin cytoskeleton of rabbit intestinal cells is a target for potent marine phycotoxins.

Biotoxins produced by harmful marine microalgae (phycotoxins) can be accumulated into seafood, representing a great risk for public health. Some of these phycotoxins are responsible for a variety of gastrointestinal disturbances; however, the relationship between their mechanism of action and toxicity in intestinal cells is still unknown. The actin cytoskeleton is an important and highly complicated structure in intestinal cells, and on that basis our aim has been to investigate the effect of representative phycotoxins on the enterocyte cytoskeleton. We have quantified for the first time the loss of enterocyte microfilament network induced by each toxin and recorded fluorescence images using a laser-scanning cytometer and confocal microscopy. Our data show that pectenotoxin-6, maitotoxin, palytoxin and ostreocin-D cause a significant reduction in the actin cytoskeleton. In addition, we found that the potency of maitotoxin, palytoxin and ostreocin-D to damage filamentous actin is related to Ca(2+) influx in enterocytes. Those results identify the cytoskeleton as an early target for the toxic effect of those toxins.

Acrylamides↗
PubMed1999

Maitotoxin-induced phosphoinositide hydrolysis is dependent on extracellular but not intracellular Ca2+ in human astrocytoma cells.

Since maitotoxin, a potent marine toxin, is known to cause not only Ca2+ influx but also phosphoinositide hydrolysis, we investigated the Ca2+ dependency of maitotoxin-induced phosphoinositide hydrolysis in 1321N1 human astrocytoma cells. Maitotoxin elicited inositol 1,4,5-trisphosphate accumulation in a time-dependent manner. In [3H]inositol-labeled cells, maitotoxin stimulated phosphoinositide hydrolysis in an extracellular Ca2+-dependent manner. Maitotoxin also caused an intracellular Ca2+ elevation, which was abolished by an intracellular Ca2+ chelater BAPTA-AM. Interestingly, maitotoxin still caused phosphoinositide hydrolysis in the BAPTA-AM-treated cells. These results indicate that maitotoxin-induced phosphoinositide hydrolysis is dependent on extracellular but not intracellular Ca2+ in 1321N1 human astrocytoma cells.

Astrocytoma↗
PubMed2005

Inhalation toxicity of brevetoxin 3 in rats exposed for twenty-two days.

Brevetoxins are potent neurotoxins produced by the marine dinoflagellate Karenia brevis. Exposure to brevetoxins may occur during a K. brevis red tide when the compounds become aerosolized by wind and surf. This study assessed possible adverse health effects associated with inhalation exposure to brevetoxin 3, one of the major brevetoxins produced by K. brevis and present in aerosols collected along beaches affected by red tide. Male F344 rats were exposed to brevetoxin 3 at 0, 37, and 237 microg/m3 by nose-only inhalation 2 hr/day, 5 days/week for up to 22 exposure days. Estimated deposited brevetoxin 3 doses were 0.9 and 5.8 microg/kg/day for the low- and high-dose groups, respectively. Body weights of the high-dose group were significantly below control values. There were no clinical signs of toxicity. Terminal body weights of both low- and high-dose-group rats were significantly below control values. Minimal alveolar macrophage hyperplasia was observed in three of six and six of six of the low- and high-dose groups, respectively. No histopathologic lesions were observed in the nose, brain, liver, or bone marrow of any group. Reticulocyte numbers in whole blood were significantly increased in the high-dose group, and mean corpuscular volume showed a significant decreasing trend with increasing exposure concentration. Humoral-mediated immunity was suppressed in brevetoxin-exposed rats as indicated by significant reduction in splenic plaque-forming cells in both low- and high-dose-group rats compared with controls. Results indicate that the immune system is the primary target for toxicity in rats after repeated inhalation exposure to relatively high concentrations of brevetoxins.

Aerosols↗
PubMed2002

Clinicopathologic features of suspected brevetoxicosis in double-crested cormorants (Phalacrocorax auritus) along the Florida Gulf Coast.

Outbreaks of morbidity and mortality in double-crested cormorants (Phalacrocorax auritus) along Florida's Gulf Coast have occurred sporadically for at least 30 yr. During these outbreaks, the Clinic for the Rehabilitation of Wildlife, located on Sanibel Island in Florida, has admitted a substantial number of cormorants with consistent presentation of primarily neurologic clinical signs. In order to investigate the association of these outbreaks in cormorants with exposure to brevetoxin, we compared the timing of admittance of cormorants with outbreak-specific clinical signs to blooms of the brevetoxin-producing marine algae, Karenia brevis (formerly Gymnodinium breve), around Sanibel Island from 1995 through 1999. The clinic admitted 360 out of 613 cormorants with the common clinical sign of severe cerebellar ataxia in six outbreaks occurring during this period. The ataxia was characterized by a broad-based stance, truncal incoordination, hypermetric gait, and intention tremors of the head. The histopathologic findings in 10 cormorants euthanized in 1997 were mild and nonspecific. An immunohistochemical staining technique for the detection of brevetoxin in cormorants documented the uptake of brevetoxin in tissues from four cormorants admitted during an outbreak in 1997, but a modified technique used on samples from 11 cormorants admitted during a K. brevis bloom in 2000 produced indeterminate results. Admittance of cormorants with outbreak-specific clinical signs was positively correlated (P < 0.05) with concurrent concentrations of K. brevis in local water. The cross-correlation coefficient was also significant when increased K. brevis levels preceded cormorant admittances by 2, 4, 6, and 8 wk. This delay in time between K. brevis blooms and cormorant admittance and our clinical finding of neurologic abnormalities in cormorants without overt histopathologic features suggest an association between K. brevis blooms and local cormorant morbidity.

Animals↗
PubMed2001

Synthetic studies toward the C5-C20 domain of the azaspiracids.

[structure: see text]. An approach toward the C5-C20 THF-fused trioxadispiroketal portion of the azaspiracids is reported. The highly substituted azaspiracid D ring (C16-C19) was prepared by the one-pot conversion of a tetraol into a tetrahydrofuran. Efforts to establish the C10 and C13 spiroketal centers via an oxonium-initiated bis-spiroketalization under both kinetic and thermodynamic conditions have yielded the (10R,13S)-trioxadispiroketal 19 as the major product, which is diastereomeric with the (10R,13R) relative configuration assigned to the azaspiracids.

Animals↗
PubMed1992

Maitotoxin, a novel activator of mediator release from human basophils, induces large increases in cytosolic calcium resulting in histamine, but not leukotriene C4, release.

Maitotoxin (MTX) is a potent marine toxin which stimulates several Ca(++)-dependent processes presumably through an increase in Ca++ permeability. We have examined the effect of MTX on the release of chemical mediators from human basophils and its mechanism of action. 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 degrees 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 microM) inhibited the release of histamine induced by MTX, whereas the dihydropyridine nifedipine (0.1-10 microM) 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.

Basophils↗
PubMed1992

Toxicity of French Polynesian strains of Gambierdiscus toxicus in cultures.

Seven clonal strains of Gambierdiscus toxicus isolated from three ciguateric areas around Tahiti island were mass cultured and extracted for ciguatoxins and maitotoxin. CTX analogs were detected only in one clone (GTP1), suggesting that CTX production may be strain-dependent. However, this in vitro production of CTXs, which remains fairly poor with regards to the toxicity levels encountered in wild G. toxicus, is not a stable temporal characteristic. On the other hand, maitotoxic compounds were detected in all 7 strains in copious amount, especially in clone GTH2.

Animals↗
PubMed1983

Nakahara memorial lecture. New classes of tumor promoters: teleocidin, aplysiatoxin, and palytoxin.

Teleocidin and aplysiatoxin, which are structurally different from 12-O-tetradecanoylphorbol-13-acetate (TPA), were found to be potent tumor promoters in two-step mouse skin carcinogenesis. The class of teleocidin includes dihydroteleocidin B, teleocidin, and lyngbyatoxin A. Teleocidin, which is a mixture of 93% teleocidin A and 7% teleocidin B, was isolated from Streptomyces mediocidicus as a strong skin irritant. Teleocidin A consists of C-14S-teleocidin A and C-14R-teleocidin A. One teleocidin A-isomer corresponds to lyngbyatoxin A, which was isolated from the blue-green alga, Lyngbya majuscula. Teleocidin B has four isomers, C-14, C-17-diastereomers. The two teleocidin A-isomers and three of the teleocidin B-isomers (all but one, which was obtained in too low yield) were shown to be biologically active and also potent tumor promoters. Synthetic analogues (indolactams) of teleocidin were obtained and their structure-activity relations were examined by several biological tests. The finding that only (-)-indolactam-V was active showed that the S, S configuration of native teleocidin was necessary for expression of the activity. The class of aplysiatoxin, which was isolated from the blue-green alga, L. majuscula, includes debromoaplysiatoxin, aplysiatoxin, bromoaplysiatoxin, and oscillatoxin A (nordebromoaplysiatoxin). The former three were potent tumor promoters, while oscillatoxin A was a moderate one. Dibromoaplysiatoxin, which is a chemically brominated derivative of debromoaplysiatoxin, in addition to aplysiatoxin and bromoaplysiatoxin, possessed the same promoting activity as that of oscillatoxin A.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylamides↗
PubMed1983

Ca2+ channel activating function of maitotoxin, the most potent marine toxin known, in clonal rat pheochromocytoma cells.

Actions of maitotoxin, the most potent marine toxin known obtained from toxic dinoflagellate, Gambier-discus toxicus, were studied using clonal rat pheochromocytoma cells (PC12), rat liver mitochondria and liposomes. Maitotoxin induced a profound release of norepinephrine and dopamine from PC12 cells and the molar ratio of norepinephrine to dopamine was almost the same as that stored in the cells. This releasing action was apparent at a concentration of 5 X 10(-10) g/ml or more, the releasing rate increased with an increase in the concentration of applied maitotoxin and attained maximum at about 10(-6) g/ml. The [3H]norepinephrine release induced by maitotoxin was abolished in the absence of external Ca2+ and increased with increasing concentration of external Ca2+ up to 10 mM. The release gradually decreased as the external Na+ concentrations were reduced from 130 to 20 mM, but maitotoxin is still able to induce a profound release in the absence of external Na+. The releasing action of maitotoxin was markedly suppressed by various Ca2+ channel blockers, such as Mn2+, verapamil, and nicardipine, and by a local anesthetic, tetracaine. The inhibitory actions of Ca2+ channel blockers were antagonized by external Ca2+ and became less obvious in the higher Ca2+ concentration range. Maitotoxin did not exhibit any ionophoretic activities on rat mitochondrial and liposomal membranes. These results suggest that maitotoxin has the ability to activate voltage-dependent Ca2+ channels of PC12 cells.

Adrenal Gland Neoplasms↗
PubMed2006

Biosynthesis of 13-desmethyl spirolide C by the dinoflagellate Alexandrium ostenfeldii.

Biosynthetic origins of the cyclic imine toxin 13-desmethyl spirolide C were determined by supplementing cultures of the toxigenic dinoflagellate Alexandrium ostenfeldii with stable isotope-labeled precursors [1,2-13C2]acetate, [1-13C]acetate, [2-13CD3]acetate, and [1,2-13C2,15N]glycine and measuring the incorporation patterns by 13C NMR spectroscopy. Despite partial scrambling of the acetate labels, the results show that most carbons of the macrocycle are polyketide-derived and that glycine is incorporated as an intact unit into the cyclic imine moiety. This work represents the first conclusive evidence that such cyclic imine toxins are polyketides and provides support for biosynthetic pathways previously defined for other polyether dinoflagellate toxins.

Animals↗
PubMed1994

Selection of cytotoxic responses to maitotoxin and okadaic acid and evaluation of toxicity of dinoflagellate extracts.

The cytotoxicity of maitotoxin (MTX) and okadaic acid (OA) was studied on three mammalian fibroblast cell lines. Neutral red uptake (NRU), which measures cell viability, and morphological alterations were selected as rapid suitable responses. NRU allowed a precise toxicity quantification while the observations of morphological damage revealed differences specific to MTX (cell blebbing) and OA (cell rounding). BHK21 C13 fibroblasts, although less sensitive to MTX than the other cell lines, were chosen since they gave stable information and a two-stage morphological response with OA ("square"-shaped cells, then round cells). When NRU and morphology alterations were studied with crude extracts of Gambierdiscus toxicus and Prorocentrum lima, responses were typical of the dominant toxins, MTX and OA or related toxins respectively. Applied to several dinoflagellate extracts, the two tests revealed no toxicity for Amphidinium carterae, Ostreopsis siamensis, O. ovata and Coolia monotis (from La Réunion) and toxicity for A. carterae and A. operculatum (from Saint Barthélémy). When toxic, A. carterae extracts showed blebbing similar to that caused by MTX. Morphology alterations caused by A. operculatum crude extracts, different from those corresponding to MTX or OA, were also observed.

3T3 Cells↗
PubMed1992

The sodium channel activator Brevetoxin-3 uncovers a multiplicity of different open states of the cardiac sodium channel.

The interaction of Brevetoxin 3 (Pbtx-3), a sodium channel activator, with the cardiac sodium channel was studied at the single channel level. It was found that Pbtx-3 (20 microM) shifted steady-state activation to negative potentials, without major effects on the time course of macroscopic activation or macroscopic currents decay, as calculated from averaged single-channel records. Single-channel open times were found to be prolonged. Under the influence of the toxin, sodium channel openings could be observed frequently even at maintained depolarisation. These openings occurred to at least nine different subconductance levels of the open state with smaller conductivities than the maximal one and differed in their open times. Current amplitudes of these open substates were found to cluster around certain amplitude values. Appearance of substates at maintained depolarisation was dependent on the transmembrane potential (Em): Substates with smaller conductivity appeared more frequently at lower Em values whereas at higher Em values substates with higher conductivity values dominated. Furthermore, it was demonstrated that appearance of substates did not result from incomplete recovery from inactivation. From these observations it was concluded that the open substates observed correspond to different conformational states of the channel's activation gates. Under physiological conditions, when the sodium channel opens directly from its closed state these 'incomplete'-open states of the cardiac sodium channel are obscured by fast gating transitions between the corresponding, electrically silent, preopen states. Thus, Pbtx-3 acts mainly via stabilisation of the channel's preopen and different open states. A classification of sodium channel modifiers, based on their interaction with different conformational states of the channel is suggested.

Animals↗