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PubMed1992

Methods for detecting brevetoxins in seawater, in biological matrices, and on excitable membranes.

Although the toxins differ in each of the principal polyether marine seafood intoxication syndromes, developing technology is of general applicability. The brevetoxins can be readily detected in seawater, in dinoflagellate cells, and in shellfish using standardized mouse bioassay, isocratic high performance liquid chromatography, radioimmunoassay and enzyme-linked immunoassay...each possessing distinct advantages and disadvantages. Clinical diagnosis, pharmacokinetics, and membrane-receptor studies on the contrary require specialized radioligand technology and immunofluorescent and immunodense imaging. The applicability of brevetoxins assays towards predictive, detection, and molecular mechanism of action of ciguatoxin is presented.

Animals↗
PubMed1993

Spongistatin 1, a highly cytotoxic, sponge-derived, marine natural product that inhibits mitosis, microtubule assembly, and the binding of vinblastine to tubulin.

A highly cytotoxic macrocyclic lactone polyether has been isolated from a Spongia species and named spongistatin 1. With L1210 murine leukemia cells an IC50 value for cell proliferation of 20 pM was obtained, and an increase in the mitotic index concordant with the decrease in cell number was observed. Kangaroo rat kidney PtK1 cells were examined by indirect immunofluorescence with a spongistatin 1 concentration that caused 50% reduction in cellular protein (0.3 nM) and with a 10-fold higher concentration. These cells displayed mitotic and nuclear aberrations at both concentrations, and intracellular microtubules were reduced in number at the lower concentration and disappeared at the higher. Similar changes in PtK1 cells were observed after treatment with equivalent toxic concentrations of the antimitotic agents colchicine, vinblastine, halichondrin B, and dolastatin 10. Spongistatin 1 inhibited the glutamate-induced polymerization of purified tubulin (IC50 value of 3.6 microM versus 2.1 microM for dolastatin 10 and vinblastine and 5.2 microM for halichondrin B). Spongistatin 1 had no effect on the binding of colchicine to tubulin, but it was a potent inhibitor of the binding of vinblastine and GTP to tubulin. In initial experiments with 5 microM tubulin and 5 microM vinblastine, spongistatin 1 and dolastatin 10 both had IC50 values of 2 microM, whereas halichondrin B had an IC50 value of 5 microM. Spongistatin 1 thus represents a new member of the group of complex natural products that inhibit mitosis by binding in the Vinca alkaloid domain of tubulin.

Animals↗
PubMed1990

Simplified solid-phase immunobead assay for detection of ciguatoxin and related polyethers.

This study examined the development of a highly simplified solid-phase colored latex immunobead assay for the detection of ciguatoxin and related polyethers. This procedure was compared with the stick enzyme immunoassay previously reported. Chi-square analysis of two separate experiments on 153 and 283 fish of various species gave chi 2 values of p less than 0.001 and p less than 0.005, respectively. Agreement between the two procedures with 26 fish implicated in ciguatera poisoning was 100%. A preliminary assessment in the field showed encouraging results. The procedure appears to be simple and applicable to field use. Furthermore, this procedure should be applicable to other antibody-antigen detections, especially low dalton determinations.

Animals↗
PubMed1998

Maitotoxin, a cationic channel activator.

Maitotoxin (MTX), a water soluble polyether obtained from the marine dinoflagellate Gambierdiscus toxicus is one of the entities responsible for Ciguatera, a form of seafood poisoning. This toxin is a potent activator of changes in the intracellular Ca2+ concentrations of cells from a wide variety of organisms. Evidence published in the last few years strongly suggests that this toxin has no ionophoretic activity. Molecular mechanics studies, shown for the first time in this review, models MTX as a molecular 'wire'. The present work compiles the few studies developed with electrophysiological techniques. All these reports indicate that MTX is activating a voltage independent, nonselective cationic channel, which in some preparations requires the presence of extracellular Ca2+ for channel activation. The conductance estimated from a variety of tissues is in the order of 12-40 pS. Thus far, no specific blocker has been identified for this channel. The nature of the MTX receptor remains a mistery.

Animals↗
PubMed1993

Alteration of the voltage-dependence of the twitch tension in frog skeletal muscle fibres by a polyether, Bistramide A.

Bistramide A, a toxin isolated from Lissoclinum bistratum Sluiter, was applied to frog skeletal muscle fibres. Micromolar concentrations of toxin decreased the amplitude of the twitch tension. Bistramide A shifted the activation and the steady-state inactivation characteristics of the tension on the voltage axis towards more positive and negative membrane potentials respectively. The data suggest that Bistramide A binds to the activated and inactivated state of the dihydropyridine-receptor which senses the T-tubule membrane potential.

Acetamides↗
PubMed1998

Environmental poisoning: presentation and management.

Environmental poisoning is most commonly associated with chronic long-term exposure to toxins rather than to acute exposure. Such repeated exposure to sublethal doses of compounds and elements presents problems in risk assessment. This is primarily because the data are unavailable to describe relationships between dose and effect at lower levels of exposure to toxins. Bioavailability of toxins also presents a problem because the data on bioavailability are sparse and seldom as high as the default of 100% bioavailability commonly used in risk assessment. Examples are presented of two toxins: arsenic as an elemental anthropogenic and geologic poison and ciguatoxin, a polyether ladder compound, as a toxin produced naturally by dinoflagellates. Bioavailability drives the toxicity of arsenic from contaminated sites, whereas tissue accumulation drives the toxicity of ciguatoxin. Considerable benefit is derived from the harmonization of regulatory processes where there is linkage of health and environmental factors in the derivation of credible risk assessment.

Arsenic↗
PubMed1994

Maitotoxin activates a nonselective cation channel and stimulates Ca2+ entry in MDCK renal epithelial cells.

We examined the mechanisms of maitotoxin (MTX), a water-soluble polyether from the marine dinoflagellate Gambierdiscus toxicus, in stimulation of Ca2+ entry into Mardin-Darby canine kidney cells. In the presence of bath Ca2+, MTX (3 nM) caused an elevation of the intracellular calcium concentration ([Ca2+]i), which was partially inhibited by SK&F 96365 (25 microM) or La3+ (100 microM). A stimulation of Ca(2+)-dependent K+ channels in cell-attached membrane patches coincided with this rise in [Ca2+]i and was also partially inhibited by SK&F 96365. Before the rise in [Ca2+]i, a nonselective cation current (Ins), studied by the whole-cell patch-clamp technique, was irreversibly activated. Ins poorly discriminated between Na+, K+, and Cs+, was unaffected by replacement of Cl- with gluconate-, and was not voltage gated. MTX-induced Ins was partially blocked by La3+ ions (100 microM) but not by SK&F 96365 (25 microM) or nifedipine (10 microM). SK&F 96365 by itself induced a small but significant stimulation of Ins and a rise in [Ca2+]i. The activation of Ins by MTX was instantaneous and depended on the presence of extracellular Ca2+ ions. In the absence of other cations, the inward current of Ins was dependent on the bath Ca2+ concentration. Cell-attached and excised single-channel measurements revealed that MTX activated a SK&F 96365-insensitive, approximately 40-pS, nonselective cation channel from the outside. We conclude that the initial action of MTX is the stimulation of a nonselective cation channel, which requires the presence of extracellular Ca2+ ions. The subsequent rise in [Ca2+]i is at least in part caused by another, SK&F 96365-sensitive, Ca2+ entry pathway, which may be activated as a result of or independently of Ins.

Animals↗
PubMed1997

Characterization of the maitotoxin-induced calcium influx pathway from human skin fibroblasts.

Maitotoxin (MTX), a water-soluble polyether obtained from the marine dinoflagellate Gambierdiscus toxicus increased intracellular calcium in a concentration-dependent manner in fibroblasts obtained from human skin. The effect of this toxin was both saturable and of high affinity, showing an apparent half activation constant of 450 fM. The toxin did not release intracellular calcium storage compartments nor did the release of these compartments with thapsigargin or ionomycin affect the toxin response. The toxin effect was reduced significantly by pre-incubating the cells with 0.1% trypsin for 30 min, strongly suggesting that the toxin receptor is a plasmalemmal protein. The effect of MTX was partially inhibited by diphenoxylate.

Calcium↗
PubMed2003

Toxicogenomic effects of marine brevetoxins in liver and brain of mouse.

Although the polyether brevetoxins (PbTx's) produced by Karenia brevis (the organism responsible for blooms of the Florida red tide) are known to exert their acute toxic effects through ion-channel mediated pathways in neural tissue, prior studies have also demonstrated that at least one form of the toxin (PbTx-6) is bound avidly by the aryl hydrocarbon receptor (AhR). Since AhR binding of a prototypical ligand such as dioxin is the first step in a cascade pathway producing major changes in gene expression, we reasoned that PbTx-6 might produce similar genomic-wide changes in expression. Mice were injected i.p. with sub-lethal doses of PbTx's (either 1.5 or 3 mg/g body weight of PbTx-6; or 0.15 mg/g body weight of PbTx-2, a toxin not avidly bound by the AhR), and liver and brain tissues were sampled at 8, 24 and 72 h and RNA was isolated. Changes in gene-specific RNA levels were assessed using commercially available mouse cDNA arrays (Incyte) containing >9600 array elements, including many elements from AhR-mediated genes. Histopathology of the two organs was also assessed. We observed minor histopathological effects and a total of only 29 significant (>2.0-fold) changes in gene expression, most of which occurred in the liver, and most of which could be attributable to an 'acute phase' inflammatory response. These results argue against the hypothesis that PbTx-6 acts via a classic AhR-mediated mechanism to evoke gene expression changes. However, given the avidity with which PbTx-6 binds to the AhR, these findings have important implications for how PbTx's may act in concert with other toxicants that are sensed by the AhR.

Animals↗
PubMed2000

Electrospray ionization tandem mass spectrometry for structural elucidation of protonated brevetoxins in red tide algae.

Brevetoxins, the toxic components of "red tide" algae, all share one of two robust polycyclic ether backbone structures, but they are distinguished by differing side-chain substituents. Electrospray ionization mass spectrometry analyses of brevetoxins have shown that the polyether structure invariably has a very high affinity for sodium cations that results in the production of abundant (M + Na)+ ions even when sodium cations are only present as impurities. Because the ionic charge tends to remain localized on the sodium atom and because at least two bonds must be broken in order to produce polycyclic backbone fragmentation, it is extremely difficult to obtain abundant product ions (other than Na+) from (M + Na)+ brevetoxin precursor ions in low-energy collision-induced dissociation (CID) MS/MS experiments. This report establishes that acid additives (oxalic acid, trifluoroacetic acid, and particularly hydrochloric acid) in aqueous methanol solutions can promote high yields of protonated brevetoxin molecules (MH+ ions) for Btx-1, -2, and -9 brevetoxins. Most importantly, unlike their (M + Na)+ counterparts, MH+ precursor ions offer readily detectable product ions in CID MS/MS experiments, even under low-energy collisions. This direct structural characterization approach has provided decomposition information from brevetoxins that was previously inaccessible, including the identification of diagnostic product ions for "type A" brevetoxins (m/z 611) and "type B" brevetoxins (m/z 779, 473, 179) and characteristic ions for Btx-1 (m/z 221, 139), Btx-2 (m/z 153), and Btx-9 (m/z 157, 85). Precursor ion scans and constant neutral loss scans are proposed to enable screening of individual type A or type B brevetoxins present in naturally occurring mixtures.

Animals↗
PubMed1999

[Ciguatoxins and brevetoxins: dissection of the neurobiological actions].

This review focuses on the neurobiological actions of ciguatoxins and brevetoxins which are phycotoxins produced respectively by the dinoflagellates Gambierdiscus toxicus and Ptychodiscus brevis. These actions are illustrated in particular by the effects of the toxins on myelinated nerve fibres and on skeletal neuromuscular junctions of vertebrates. Ciguatoxins and brevetoxins, through different vectors, are responsible for human intoxications characterized mainly by neurological disturbances. The molecular target of these families of lipid-soluble cyclic polyethers is the voltage-gated sodium channel, a fundamental transmembrane protein involved in cellular excitability. The different toxins share a common binding site (the receptor-site 5) located on the alpha sub-unit of this neuronal transmembrane protein. Electrophysiological studies of the mode of action of ciguatoxins and brevetoxins identify these toxins as specific sodium channel activators. Indeed, during the action of these phycotoxins, sodium channels remain permanently opened, at the resting membrane potential, which produces a continuous entry of sodium ions in most excitable cells. Such a sodium entry has various consequences on sodium-dependent physiological mechanisms, consisting in a membrane depolarization which, in turn, causes spontaneous and/or repetitive action potential discharges and thereby increases membrane excitability. These neuronal discharges may be transient or continuous according to the preparation and the toxin tested. The increase in membrane excitability during the action of ciguatoxins and brevetoxins is responsible for the different effects exerted by these toxins on various chemical synapses and secretory cells. Another consequence of the continuous entry of sodium ions into cells was revealed using confocal laser scanning microscopy and vital staining of plasma membranes with the fluorescent dye FM1-43. These techniques made feasible the dynamic study of morphological alterations produced by ciguatoxins and brevetoxins on various cellular preparations in situ. Thus, it has been possible to bring to the fore that these phycotoxins cause a marked increase in the volume of nodes of Ranvier of myelinated nerve fibres, motor nerve terminals innervating skeletal muscle and perisynaptic non-myelinating Schwann cell somata. This increase could be reversed by hyperosmotic external solutions and completely prevented by the blockade of voltage-gated sodium channels. The mechanisms involved in the increase in cellular volume, during the action of ciguatoxins and brevetoxins, are discussed.

Animals↗
PubMed1996

First report of pectenotoxin-2 (PTX-2) in algae (Dinophysis fortii) related to seafood poisoning in Europe.

Pectenotoxin-2 (PTX-2), a polyether-lactone included in the neutral class of diarrhoetic shellfish poisoning (DSP) toxins, has been unambiguously detected in Dinophysis fortii collected in the northern Adriatic Sea (Emilia Romagna coasts). This is the first report of such a toxin in Europe. This lipid soluble toxin was identified both in crude methanolic phytoplankton extract and in the neutral fraction obtained by extract chromatography on a basic alumina column. The techniques used were reversed phase high-performance liquid chromatography followed either by UV diode-array detection (LC-UV-DAD) or by mass spectrometry (LC-MS) and tandem mass spectrometry (LC-MS-MS) using an atmospheric-pressure ionization source and an ionspray interface. Okadaic acid (OA) was also found in the D. fortii specimens and quantified as 15 pg/cell. Although quantitation of PTX-2 was not possible due to the lack of pure toxin, the high PTX-2:OA ratio suggested PTX-2 was significant in the D. fortii specimens. The presence of PTX-2 in a region with no previous report of DSP neutral toxic compounds may indicate a risk of human poisoning. Serious efforts should therefore be made to develop suitable routine methods capable of detecting the presence of PTXs in biological materials of marine origin, in order to assure the wholesomeness of seafood products.

Chromatography, Liquid↗
PubMed1995

On-line high-performance liquid chromatography-electrospray ionization mass spectrometry for the determination of brevetoxins in "red tide" algae.

On-line high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESMS) has been successfully applied to the separation and identification of brevetoxins associated with "red tide" algae. Brevetoxins are toxic polyethers produced by the marine dinoflagellate Gymnodinium breve. They are responsible for fish kills, and they pose certain health risks to humans. The LC-MS method employs reversed-phase microbore HPLC on a C18 column with a mobile phase consisting of 85:15 methanol/water, a flow rate of 8 microL/min, and a postcolumn split ratio of 3:1 (UV absorbance detector/mass spectrometer). A brevetoxin culture sample was found to contain at least six components, including two well-separated peaks corresponding to the brevetoxins PbTx-2 and PbTx-1, as well as several unknown compounds, including one with a molecular mass of 899 Da (possibly an isomer of PbTx-9). The brevetoxin molecules exhibited a high tendency to bind to alkali cations in positive ion ESMS. For standard PbTx-9, PbTx-2, and PbTx-1 brevetoxins analyzed on our LC-MS system, the detection limits (employing mass spectrometer scans of 100 m/z units) were determined to be less than 600 fmol, 1 pmol, and 50 fmol, respectively (S/N = 3); the total analysis time was about 35 min.

Animals↗
PubMed2005

Characterization of marine aerosol for assessment of human exposure to brevetoxins.

Red tides in the Gulf of Mexico are commonly formed by the fish-killing dinoflagellate Karenia brevis, which produces nine potent polyether brevetoxins (PbTxs). Brevetoxins can be transferred from water to air in wind-powered white-capped waves. Inhalation exposure to marine aerosol containing brevetoxins causes respiratory symptoms. We describe detailed characterization of aerosols during an epidemiologic study of occupational exposure to Florida red tide aerosol in terms of its concentration, toxin profile, and particle size distribution. This information is essential in understanding its source, assessing exposure to people, and estimating dose of inhaled aerosols. Environmental sampling confirmed the presence of brevetoxins in water and air during a red tide exposure period (September 2001) and lack of significant toxin levels in the water and air during an unexposed period (May 2002). Water samples collected during a red tide bloom in 2001 showed moderate-to-high concentrations of K. brevis cells and PbTxs. The daily mean PbTx concentration in water samples ranged from 8 to 28 microg/L from 7 to 11 September 2001; the daily mean PbTx concentration in air samples ranged from 1.3 to 27 ng/m(3). The daily aerosol concentration on the beach can be related to PbTx concentration in water, wind speed, and wind direction. Personal samples confirmed human exposure to red tide aerosols. The particle size distribution showed a mean aerodynamic diameter in the size range of 6-12 microm, with deposits mainly in the upper airways. The deposition pattern correlated with the observed increase of upper airway symptoms in healthy lifeguards during the exposure periods.

Aerosols↗
PubMed2005

Effect of okadaic acid on glucose regulation.

Okadaic acid is the main toxin responsible for the natural phenomena known as diarrheic shellfish poisoning (DSP). This toxin is a tumor promoter C38 polyether fatty acid that contains acidic and hydrophobic moieties and is cyclic. Okadaic acid is a potent inhibitor of important classes of protein serine/threonine phosphatases such as protein phosphatase 1 and 2A. The toxin binds in a hydrophobic groove adjacent to the active site of the protein phosphatases and interacts with basic residues within the active site. Therefore okadaic acid causes increases in phosphorylation of proteins that affect a diverse array of cellular processes. For instance, this toxin modulates metabolic parameters in intact cells. In this sense it stimulates lipolysis, and inhibits fatty acid synthesis in adipocytes however increases glucose output and gluconeogenesis in hepatocytes. Additionally, okadaic acid reaches cytotoxic concentrations in the intestinal tissues in accordance with the diarrhea. Recent studies suggested that toxic effects of okadaic acid might be related to modification of nutrients, ionic and water absorption across the small intestine presumably by altering the transporter system. The subject of this review is limited to the effect of okadaic acid on glucose regulation and its cellular as well as clinical implications.

Animals↗
PubMed2006

Design and synthesis of an artificial ladder-shaped polyether that interacts with glycophorin A.

Ladder-shaped polyether (LSP) compounds, such as brevetoxins and ciguatoxins, are thought to interact with transmembrane (TM) proteins. As a model LSP compound, we designed and synthesized an artificial tetracyclic ether (1) and evaluated its interaction with glycophorin A (GpA), a membrane protein known to dimerize or oligomerize between membrane-integral alpha-helical domains. Model compound 1 was found to induce the dissociation of oligomeric GpA in a similar manner to natural LSPs when examined by SDS-PAGE. The results suggest that even an artificial tetracyclic ether possesses the ability to interact with TM proteins, presumably through the intermolecular hydrogen bonds (C(alpha)-Hcdots, three dots, centeredO) with the GXXXG motif.

Ciguatoxins↗