Okadaic acid

805

805.00

616-589-8

Crystals from dichloromethane/hexane; crystals from benzene-CHCl3|White crystals or powder

182.83000

5.21360

white crystals or powder

1.0795

164-166 °C

672.95°C (rough estimate)

269.4ºC

1.5940 (estimate)

It is soluble in ethanol (25 mg/ml), DMSO (25 mg/ml), methanol (<1 mg/ml), chloroform, acetone, ethyl acetate, DMF, and dimethylsulfoxide. Insoluble in water, unless first dissolved in organic solvents, such as DMSO or ethanol.

-20ºC

LD50 i.p. in mice: 192 mg/kg (Shibata)

3.87±0.16

Ionophoric polyether identified in marine organisms

II

6.1(a)

UN 3462 6.1/PG 1

3

23/24/25-38

26-36/37-45

AA8227800

T

Stable. Light and heat-sensitive. Combustible. Incompatible with strong oxidizing agents.

P261; P280; P301 + P310; P311

H301; H311; H315; H331

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product.

Incompatible materials: Strong oxidizing agents

FAO; Marine Biotoxins (2004). FAO is publishing this Food and Nutrition Paper on Marine Biotoxins in an effort to support the exchange of scientific information on an important subject of concern for food safety worldwide. Marine biotoxins represent a significant and expanding threat to human health in many parts of the world. The impact is visible in terms of human poisoning or even death ollowing the consumption of contaminated shellfish or fish, as well as mass killings of fish and shellfish, and the death of marine animals and birds. This paper provides an extensive review of different aspects of five shellfish poisoning syndromes (paralytic shellfish poisoning, diarrheic shellfish poisoning, amnesic shellfish poisoning, neurologic shellfish poisoning, azaspiracid shellfish poisoning), as well as one fish poisoning syndrome (ciguatera fish poisoning). Various aspects of these poisoning syndromes are discussed in detail including the causative toxins produced by marine organisms, chemical structures and analytical methods of the toxins, habitat and occurrence of the toxin producing organisms, case studies and existing regulations. Based on this analysis, risk assessments are carried out for each of these different toxins, and recommendations elaborated to better manage these risks in order to reduce the harmful effect of these toxins on public health.[Available from, as of October 9, 2018: http://www.fao.org/docrep/007/y5486e/y5486e00.htm]

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P310, P302+P352, P304+P340, P311, P312, P321, P322, P330, P332+P313, P361, P362, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 41 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H301: Toxic if swallowed [Danger Acute toxicity, oral]

Eye/face protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

ACCIDENTAL RELEASE MEASURES; Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed.|ACCIDENTAL RELEASE MEASURES; Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.|Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

In recent years, our group and several others have been describing the presence of new, not previously reported, toxins of high toxicity in vectors that may reach the human food chain. These include tetrodotoxin in gastropods in the South of Europe, ciguatoxin in fish in the South of Spain, palytoxin in mussels in the Mediterranean Sea, pinnatoxin all over Europe, and okadaic acid in the south of the U.S. There seem to be new marine toxins appearing in areas that are heavy producers of seafood, and this is a cause of concern as most of these new toxins are not included in current legislation and monitoring programs. Along with the new toxins, new chemical analogues are being reported. The same phenomenom is being recorded in freshwater toxins, such as the wide appearance of cylindrospermopsin and the large worldwide increase of microcystin. The problem that this phenomenon, which may be linked to climate warming, poses for toxicologists is very important not only because there is a lack of chronic studies and an incomplete comprehension of the mechanism driving the production of these toxins but also because the lack of a legal framework for them allows many of these toxins to reach the market. In some cases, it is very difficult to control these toxins because there are not enough standards available, they are not always certified, and there is an insufficient understanding of the toxic equivalency factors of the different analogues in each group. All of these factors have been revealed and grouped through the massive increase in the use of LC-MS as a monitoring tool, legally demanded, creating more toxicological problems.

IDENTIFICATION AND USE: Okadaic acid (OA) is a solid. OA is one of the most frequent and worldwide distributed marine toxins. It is easily accumulated by shellfish, mainly bivalve mollusks and fish, and, subsequently, can be consumed by humans causing alimentary intoxications. OA is used as a biochemical tool as tumor promoter and probe of cellular regulation. HUMAN STUDIES: OA is the main representative diarrheic shellfish poisoning (DSP) toxin and its ingestion induces gastrointestinal symptoms, although it is not considered lethal. At the molecular level, OA is a specific inhibitor of several types of serine/threonine protein phosphatases. Induction of DNA adducts by OA was shown in human keratinocytes and human bronchial epithelial cells. ANIMAL STUDIES: In mice after 7 days of oral administration of 1 mg/kg/day OA induced diarrhea, body weight loss, reduced food consumption, and death. OA was a tumor promoter in two-stage experiments on mouse skin. OA can induce disorganization in cytoskeletal architecture and cell-cell contact, cause chromosome loss, apoptosis, DNA damage and inhibit phosphatases, suggesting its potential embryotoxicity. OA is used as a pharmacologically induced model of Alzheimer's disease in different species. In rats intrahippocampal bilateral microinjection of OA led to a spatial memory impairment. A significantly higher frequency of micronuclei was observed in hemocytes from the OA-exposed group of the mussel Perna perna compared to control. Induction of DNA adducts by OA was shown in Baby Hamster Kidney (BHK) cells, also the induction of DNA adducts in zebra fish embryos was demonstrated. ECOTOXICITY STUDIES: The blue mussel, Mytilus edulis and the pacific oyster, Crassostrea gigas were exposed in vivo to OA and impacts on DNA fragmentation were measured. A significant increase in DNA fragmentation was observed in the two cell types from both species relative to the controls. This increase was greater in the pacific oyster at the higher toxin concentration. In mussel Mytilus galloprovincialis mussel gill cells display higher sensitivity to early OA-mediated genotoxicity than hemocytes. In maize cells, OA caused the cell cycle arrest at preprophase, leading to seedling growth inhibition.

/The authors/ generated a neuroblastoma (SH-SY5Y) cell system in which cytoskeletal proteins are abnormally phosphorylated resulting in microtubule disruption due to the marked inhibition of protein phosphatase activities by okadaic acid (OA). OA-induced declines in cell viability and mitochondrial metabolic activity were remarkably prevented by melatonin. In addition, the hyperphosphorylation/accumulation of neurofilament-(NF-) H/M subunits and the disruption of microtubules, induced by OA, were significantly inhibited by melatonin.|In awake rats the microinjection into the hippocampus of okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A, induces in about 20 min intense electroencephalographic and behavioral limbic-type seizures, which are suppressed by the systemic administration of the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine hydrogen maleate and by the intrahippocampal administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, an inhibitor of protein kinases.|Okadaic acid (OA) is a marine toxin, a tumor promoter and an inducer of apoptosis. It mainly inhibits protein-phosphatases, protein synthesis and enhances lipid peroxidation. Caco-2 cells were treated exclusively by OA (15 ng/mL) or cadmium (Cd) (0.625 and 5 ug/mL) for 24 hr, protein synthesis was inhibited (by 42 +/- 5%, 18 +/- 13%, and 90 +/- 4% respectively) while /malondialdehyde/ (MDA) production was 2,235 +/- 129, 1710 +/- 20, and 11,496 +/-1,624 pmol/mg protein respectively. In addition, each toxicant induced modified bases in DNA; increases in oxidised bases and methylated dC. The combination of OA and cadmium was more cytotoxic and caused more DNA base modifications; the ratio m(5)dC/(m(5)dC + dC) was increased from 3 +/- 0.15 to 9 +/- 0.15 and the ratio 8-(OH)-dG/10(5) dG also (from 36 +/- 2 to 76 +/- 6). The combination of OA and Cd also increased the level of MDA (1,6874 +/- 2,189 pmole/mg protein). The present results strongly suggest that DNA damage resulting from the oxidative stress induced by these two toxicants may significantly contribute to increasing their carcinogenicity via epigenetic processes.|25 nM okadaic acid promotes DNA fragmentation in B16 melanoma, increasing cell detachment as well as pigmentation, a characteristic of melanocytic cell differentiation. At lower levels, okadaic acid synergizes with UV exposure to increase DNA fragmentation.|For more Interactions (Complete) data for Okadaic acid (20 total), please visit the HSDB record page.

LD50 Mouse ip 185.6 ug/kg|LD50 Mouse ip 192 ug/kg

/AQUATIC SPECIES/ Two bivalve species of global economic importance: the blue mussel, Mytilus edulis and the pacific oyster, Crassostrea gigas were exposed in vivo, to the diarrhoetic shellfish toxin okadaic acid (OA), and impacts on DNA fragmentation were measured. Shellfish were exposed using two different regimes, the first was a single (24 hr) exposure of 2.5 nM OA (~0.1 ug/shellfish) and algal feed at the beginning of the trial (T0), after which shellfish were only fed algae. The second was daily exposure of shellfish to two different concentrations of OA mixed with the algal feed over 7 days; 1.2 nM OA (~0.05 ug OA/shellfish/day) and 50 nM OA (~2 ug OA/shellfish/day). Hemolymph and hepatopancreas cells were extracted following 1, 3 and 7 days exposure. Cell viability was measured using the trypan blue exclusion assay and remained above 85% for both cell types. DNA fragmentation was examined using the single-cell gel electrophoresis (comet) assay. A significant increase in DNA fragmentation was observed in the two cell types from both species relative to the controls. This increase was greater in the pacific oyster at the higher toxin concentration. However, there was no difference in the proportion of damage measured between the two cell types, and a classic dose response was not observed, increasing toxin concentration did not correspond to increased DNA fragmentation.|/AQUATIC SPECIES/ Okadaic acid (OA) is the predominant biotoxin responsible for diarrhetic shellfish poisoning (DSP) syndrome in humans. While its harmful effects have been extensively studied in mammalian cell lines, the impact on marine organisms routinely exposed to OA is still not fully known. Few investigations available on bivalve molluscs suggest less genotoxic and cytotoxic effects of OA at high concentrations during long exposure times. In contrast, no apparent information is available on how sublethal concentrations of OA affect these organisms over short exposure times. In order to fill this gap, this study addressed for the first time in vitro analysis of early genotoxic and cytotoxic effects attributed to OA in two cell types of the mussel Mytilus galloprovincialis. Accordingly, hemocytes and gill cells were exposed to low OA concentrations (10, 50, 100, 200, or 500 nM) for short periods of time (1 or 2 hr). The resulting DNA damage, as apoptosis and necrosis, was subsequently quantified using the comet assay and flow cytometry, respectively. Data demonstrated that (1) mussel hemocytes seem to display a resistance mechanism against early genotoxic and cytotoxic OA-induced effects, (2) mussel gill cells display higher sensitivity to early OA-mediated genotoxicity than hemocytes, and (3) mussel gill cells constitute more suitable systems to evaluate the genotoxic effect of low OA concentrations in short exposure studies. Taken together, this investigation provides evidence supporting the more reliable suitability of mussel gill cells compared to hemocytes to evaluate the genotoxic effect of low short-duration exposure to OA.|/AQUATIC SPECIES/ Harmful Algal Blooms (HABs) responsible for Diarrhetic Shellfish Poisoning (DSP) represent a major threat for human consumers of shellfish. The biotoxin Okadaic Acid (OA), a well-known phosphatase inhibitor and tumor promoter, is the primary cause of acute DSP intoxications. Although several studies have described the molecular effects of high OA concentrations on sentinel organisms (e.g., bivalve molluscs), the effect of prolonged exposures to low (sublethal) OA concentrations is still unknown. In order to fill this gap, this work combines Next-Generation sequencing and custom-made microarray technologies to develop an unbiased characterization of the transcriptomic response of mussels during early stages of a DSP bloom. Mussel specimens were exposed to a HAB episode simulating an early stage DSP bloom (200 cells/L of the dinoflagellate Prorocentrum lima for 24 hr). The unbiased characterization of the transcriptomic responses triggered by OA was carried out using two complementary methods of cDNA library preparation: normalized and Suppression Subtractive Hybridization (SSH). Libraries were sequenced and read datasets were mapped to Gene Ontology and KEGG databases. A custom-made oligonucleotide microarray was developed based on these data, completing the expression analysis of digestive gland and gill tissues. Findings show that exposure to sublethal concentrations of OA is enough to induce gene expression modifications in the mussel Mytilus. Transcriptomic analyses revealed an increase in proteasomal activity, molecular transport, cell cycle regulation, energy production and immune activity in mussels. Oppositely, a number of transcripts hypothesized to be responsive to OA (notably the Serine/Threonine phosphatases PP1 and PP2A) failed to show substantial modifications. Both digestive gland and gill tissues responded similarly to OA, although expression modifications were more dramatic in the former, supporting the choice of this tissue for future biomonitoring studies. Exposure to OA concentrations within legal limits for safe consumption of shellfish is enough to disrupt important cellular processes in mussels, eliciting sharp transcriptional changes as a result. By combining the study of cDNA libraries and a custom-made OA-specific microarray, /this/ work provides a comprehensive characterization of the OA-specific transcriptome, improving the accuracy of the analysis of expresion profiles compared to single-replicated RNA-seq methods. The combination of /this/ data with related studies helps understanding the molecular mechanisms underlying molecular responses to DSP episodes in marine organisms, providing useful information to develop a new generation of tools for the monitoring of OA pollution.|/AQUATIC SPECIES/ Okadaic Acid (OA) is a marine toxin responsible for DSP (Diarrheic Shellfish Poisoning) in humans produced by dinoflagellate. The genotoxic and cytotoxic effects of OA have been well reported in mammalian experimental animals and in vitro cultured cells. However, there are no available investigations regarding the involvement of the oxidative stress pathways in OA toxicity, especially on aquatic animals such as fish. In this context, ...the present work /aims/ to demonstrate whether OA (7.5 ug/mL) induces oxidative stress and histopathological damages in the fish species Sparus aurata under short term exposure (2 hr, 4 hr and 24 hr). To this end, we have assessed lipid peroxidation and anti-oxidative stress response in liver tissue, and finally ultrastructural changes were investigated in hepatic and gills tissues. Results clearly showed that OA induced significant enhancement in all tested parameters in a time dependent manner and seems to be a strong inducer of oxidative stress in aquatic animals. The data of the present study indicate also that histology is a successful tool to reveal OA impact on liver and gill tissues of Sparus aurata since the animal showed vascular dilation and hepatocellular membrane disintegration in liver and hypertrophy in secondary lamellae and necrotic aspect in the primary lamellae in gill tissue.|For more Ecotoxicity Excerpts (Complete) data for Okadaic acid (11 total), please visit the HSDB record page.

Very recently, several toxic components have been isolated from shellfish .... Five of the toxic components have been structurally elucidated as okadaic acid and derivatives, and polyether lactones. ... Several species of dinoflagellates have been identified as organisms that produce okadaic acid and are also associated with disease outbreaks. ... okadaic acid, has been confirmed in a benthic dinoflagellate, Prorocentrum lima, though involvement of this species in /Diarrhoeic Shellfish Poisoning/ has never been known(1). /Diarrhoeic Shellfish Poisons/|Okadaic acid is isolated from marine sponges Halichondria okadai or H. melanodocia. It is a tumor-associated cytotoxin associated with diarrhetic seafood poisoning(1).

Okadaic acid's limited use as a biochemical tool as tumor promotor and probe of cullular regulation(1) may result in its release to the environment through various waste streams(SRC).

SEAWATER: For the first time, the composition, concentration and distribution characteristics of typical lipophilic marine algal toxins (LMATs) are investigated in surface seawater, suspended particulate matter (SPM) and sediments from the Yellow Sea and the Bohai Sea, China. Pectenotoxin-2 (PTX2) and okadaic acid (OA) were detected in offshore surface seawater samples (n = 67) of the Yellow and Bohai Seas, and PTX2 was found in higher concentrations than OA. The concentrations of PTX2 were between 0.49 and 14.14 ng/L. OA, dinophysistoxin-1(DTX1), PTX2 and gymnodimine (GYM) were detected in the nearshore surface seawater samples (n = 20) of the Haizhou Bay of the Yellow Sea. OA concentrations were between 11.47 and 55.85ng/L. There was a large degree of variation in the concentrations of DTX1, from

Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. (See all compounds classified as Carcinogens.)|Chemical agents that increase the permeability of biological or artificial lipid membranes to specific ions. Most ionophores are relatively small organic molecules that act as mobile carriers within membranes or coalesce to form ion permeable channels across membranes. Many are antibiotics, and many act as uncoupling agents by short-circuiting the proton gradient across mitochondrial membranes. (See all compounds classified as Ionophores.)|Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

The results in this study show... that this marine toxin is able to cross the transplacental barrier. Fetal tissue contains more okadaic acid than the liver or kidney: 5.60% compared to 1.90 and 2.55% respectively as measured by HPLC and fluorescent detection after derivatization with 9-Anthryldiazomethane (ADAM).|This study concerns the distribution of 3H-okadaic acid (OA) in organs and biological fluids of Swiss mice having received a single dose per os of OA (50 ug/kg). The determination of the intestinal tissues and contents 24 hr after administration demonstrates a slow elimination of OA. When the dose of OA was increased from 50-90 ug/kg, the concentrations of the toxin in the intestinal content and feces increased proportionally. A good correlation was found between an increase of OA in the intestinal tissue and the diarrhea in animals given 90 ug/kg orally. Moreover OA was present in liver and bile and in all organs including skin and also fluids. Altogether these results confirmed an enterohepatic circulation of OA as previously shown.|The influence of nutritional regime and water temperature on depuration rates of OA-group toxins in the wedge shell Donax trunculus was examined by exposing naturally contaminated specimens to three nutritional regimes (microalgae, commercial paste of microalgae, and starvation) for 14 days at 16 °C and 20 °C. Total OA was quantified in the whole soft tissues of the individuals collected in days 2, 4, 6, 8, 10, 12 and 14. Mortality, dry weight, condition index, gross biochemical composition and gametogenic stages were surveyed. Low variation of glycogen and carbohydrates during the experiments suggest that wedge shells were under non-dramatic stress conditions. Wedge shells fed with non-toxic diets showed similar depuration rates being 15 and 38% higher than in starvation, at 16 and 20 °C, respectively. Depuration rates under non-toxic diets at 20 °C were 71% higher than at 16 °C. These results highlight the influence of water temperature on the depuration rate of total OA accumulated by D. trunculus, even when the increase is of only 4 °C, as commonly observed in week time scales in the southern Portuguese coastal waters. These results open the possibility of a faster release of OA in harvested wedge shells translocated to depuration systems when under a slight increase of water temperature.|... acidic toxins, include okadaic acid (OA) and its derivatives named dinophysistoxins (DTXs). OA and its derivatives (DTX1, DTX2 and DTX3) are lipophilic and accumulate in the fatty tissue of shellfish. These compounds are potent phosphatase inhibitors and this property is linked to inflammation of the intestinal tract and diarrhea in humans.|Okadaic acid is known as a diarrheal shellfish poison. It is thought that there is no specific target organ for okadaic acid after it has been absorbed into the body. However, the details of its pharmacokinetics are still unknown. In this study, we demonstrated that okadaic acid was more toxic to the hepatocyte-specific uptake transporter OATP1B1- or OATP1B3-expressing cells than control vector-transfected cells. In addition, PP2A activity, which is a target molecule of okadaic acid, was more potently inhibited by okadaic acid in OATP1B1- or OATP1B3-expressing cells compared with control vector-transfected cells. The cytotoxicity of okadaic acid in OATP1B1- or OATP1B3-expressing cells was attenuated by known substrates of OATP1B1- and OATP1B3, but not in control vector-transfected cells. Furthermore, after uptake inhibition study using OATP1B3-expressing cells, Dixon plot showed that okadaic acid inhibited the uptake of hepatotoxin microcystin-LR, which is a substrate for OATP1B1 and OATP1B3, in a competitive manner. These results strongly suggested that okadaic acid is a substrate for OATP1B3 and probably for OATP1B1, and could be involved in unknown caused liver failure and liver cancer. Since okadaic acid possesses cytotoxicity and cell proliferative activity by virtue of its known phosphatase inhibition activity.

The ingestion of seafood contaminated with the marine biotoxin okadaic acid (OA) can lead to diarrhetic shellfish poisoning with symptoms like nausea, vomiting and abdominal cramps. Both rat and the human hepatic cytochrome P450 monooxygenases (CYP) metabolize OA. However, liver cell toxicity of metabolized OA is mainly unclear. The aim of our study was to detect the cellular effects in HepG2 cells exposed to OA in the presence of recombinant CYP enzymes of both rat and human for the investigation of species differences. The results should be set in correlation with a CYP-specific metabolite pattern. Comparative metabolite profiles of OA after incubation in rat and human recombinant CYP enzymes were established by using LC-MS/MS technique. Results demonstrated that metabolism of OA to oxygenated metabolites correlates with detoxification which was mainly catalyzed by human CYP3A4 and CYP3A5. Detoxification by rat Cyp3a1 was lower compared to human CYP3A enzymes and activation of OA by Cyp3a2 was observed, coincident with minor overall conversion capacity of OA. By contrast human and rat CYP1A2 seem to activate OA into cytotoxic intermediates. In conclusion, different mechanisms of OA metabolism may occur in the liver. At low OA doses, the human liver is likely well protected against cytotoxic OA, but for high shellfish consumers a potential risk cannot be excluded.|Four metabolites of okadaic acid were generated by incubation with human recombinant cytochrome P450 3A4. The structures of two of the four metabolites have been determined by MS/MS experiments and 1D and 2D NMR methods using 94 and 133 ug of each metabolite. The structure of a third metabolite was determined by oxidation to a metabolite of known structure. Like okadaic acid, the metabolites are inhibitors of protein phosphatase PP2A. Although one of the metabolites does have an alpha,beta unsaturated carbonyl with the potential to form adducts with an active site cysteine, all of the metabolites are reversible inhibitors of PP2A.

Microcystins, potent heptapeptide hepatotoxins produced by certain bloom-forming cyanobacteria, are strong protein phosphatase inhibitors. They covalently bind the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A), thereby influencing regulation of cellular protein phosphorylation. The paralytic shellfish poison, okadaic acid, is also a potent inhibitor of these PPs. Inhibition of PP1 and PP2A has a dualistic effect on cells exposed to okadaic acid or microcystin-LR, with both apoptosis and increased cellular proliferation being reported.

/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 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 TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) 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 (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Emergency and supportive measures; Most cases are mild and self-limited and require no specific treatment. However, because of the risk of respiratory arrest, all patients should be observed for several hours (except for patients with diarrhetic shellfish poisoning). 1. Maintain open airway and assist ventilation if necessary. 2. Replace fluid and electrolyte losses from gastroenteritis with intravenous crystalloids fluids /Food Poisoning: Fish and Shellfish/.|Decontamination procedures are not indicated in most cases. However, consider using activated charcoal if immediately available after ingestion of a highly toxic seafood (eg fugu fish). /Food Poisoning: Fish and Shellfish/.

/SIGNS AND SYMPTOMS/ Diarrhetic Shellfish Poisoning; Symptoms: Exculusively gastrointestinal with nausea, vomiting, cramping abdominal pain, severe diarrhea (>20 stools/day), no CNS symptoms... Prognosis: Self-limited, symptoms resolve within 3 days, no fatalities.|/CASE REPORTS/ A new outbreak of human diarrheic poisonings (DSP) with esters of okadaic acid (OA) was confirmed after ingestion of razor clams (Solen marginatus) harvested at Aveiro lagoon (NW Portugal) in the summer of 2001. Accumulation of marine toxins in second order consumers was investigated in the edible parts of a shellfish predator abundant at Aveiro lagoon, the green crab Carcinus maenas. Okadaic acid was found, also in a predominant esterified form. Levels in edible parts (comprising mainly viscera) surpassed 16 ug/100 g. ... One patient may have developed profuse diarrhea after ingestion of a large number of green crabs contaminated with okadaic acid esters. At least 32 ug OA/100 g were found in a remaining sample of its meal. Domoic acid was also found but under the allowable level in force in USA of 30 ug/g crab viscera. In cooked crabs, significant losses of domoic acid were found and it is not suspected to have contributed to the poisoning event, although being a vector for this toxin. The low percentage of free okadaic acid found is in accordance with a predation predominantly on benthonic shellfish (razor clams, clams and common cockle) rather than on rock mussels.|/EPIDEMIOLOGY STUDIES/ OBJECTIVES: This investigation was undertaken in response to an outbreak of suspected shellfish poisoning in Zhejiang Province, China. The objectives of this project were to confirm the outbreak and to identify the etiology, source and mode of transmission. METHODS: A probable case was defined as an individual with diarrhea (=3 times/day) plus at least one of the following symptoms: fever (=37.5 °C), vomiting, or abdominal pain after consuming seafood between May 23(rd) and May 28(th), 2011. Using a case-control study design, we compared exposures to suspected seafood items and cooking methods between 61 probable cases and 61 controls. RESULTS: Over 220 suspected or probable cases of diarrhetic shellfish poisoning (DSP) were identified (incidence of 18 cases per 100,000). The case control study revealed that 100% of cases and 18% of controls had eaten mussels during the exposure period (OR=infinity, Chi(2)=84.72,P=0.000). The number of mussels consumed was related to DSP risk (P=0.004, Chi2 test for trend). Consumption of other seafood items was not associated with disease. The frequency of diarrhea and vomiting were positively correlated with the number of mussels consumed (r=0.424 and r=0.562, respectively). The frequency of vomiting and the incubation period were significantly correlated with the total time the mussels were boiled (r=0.594 and r=-0.336, respectively). Mussels from 3 food markets and one family contained Okadaic acid (OA) and Dinophysistoxin-1 (DTX-1). CONCLUSIONS: This outbreak was attributed to the consumption of mussels contaminated by DSP-toxins (OA and DTX-1) which are produced by different species of dinoflagellates (toxic microalgae) from the genus Dinophysis or Prorocentrum. Suspension of mussel sales and early public announcements were highly effective in controlling the outbreak, although oversight of seafood quality should be a priority to prevent future contamination and outbreaks.|/GENOTOXICITY-DNA ADDUCTS/ Induction of DNA adducts by okadaic acid was shown in Baby Hamster Kidney (BHK) cells, Human (HESV) keratinocytes and human bronchial epithelial cells. Also the induction of DNA adducts in zebra fish embryos was demonstrated. It was noted that the DNA adduct formation increased with the dose at lower and intermediate (non cytotoxic) concentrations whereas higher concentrations caused toxic stress.|For more Human Toxicity Excerpts (Complete) data for Okadaic acid (19 total), please visit the HSDB record page.

Ocadaic Acid

Okadaic Acid (OA), a small seafood-borne toxin secreted by Dinophysis and Prorocentrum dinoflagellates, is generally distributed in various species of shellfish and has caused diarrhetic shellfish poisoning (DSP). In view of OA toxin threat to humans and animals, it is essential to develop a rapid, accurate and sensitive method for the detection and quantification of OA in real samples. In this study, a monoclonal antibody named 10E8 was screened by cells fusion of Sp2/0 with spleen cells isolated from immunized mouse, and the isotype of McAb 10E8 was belonged to IgG1. The resulted McAb 10E8 displayed higher specificity to OA antigen, with the highest affinity of 2.66x109 L/moL until now. Indirect competitive ELISA (ic-ELISA) indicated that the linear range to detect OA was 20-750 ng/mL. The limit of detection (LOD) was 12 pg/mL, and the recovery average was (84.04+/-5.08)%. The LOD of colloidal gold immunoassay by naked eye and strip reader was 1 ng/mL and 100 pg/mL, respectively, with an average recovery of (88.0275+/-4.4225)%. Therefore, the developed ELISA and colloidal gold immunoassay based on this McAb can be used for OA detection in real samples.|Rapid and cost-effective methods to monitor the presence of diarrhetic shellfish poisoning (DSP) toxins in seawater samples in an easy and reliable manner are required to protect human health and avoid economic losses to shellfish industry. Immunoassays for the detection of okadaic acid (OA) and dinophysistoxin-1 and dinophysistoxin-2 are developed by immobilising OA on self-assembled monothiols or dithiols in an ordered and oriented way, providing an effective limit of detection of ~1 ng OA equiv./mL seawater. The immunoassays are applied to the analysis of the particulate fraction of seawater samples from two Catalan harbours (NW Mediterranean) and samples collected periodically from the Galician Rias (E Atlantic), as well as a reference mussel sample. Results are in agreement with LC-MS/MS and the certified values. OA concentration in seawater correlates with Dinophysis cell abundance, with a 1-2 weeks lag. The immunoassays provide powerful high-throughput analytical methods potentially applicable as alternative monitoring tools.|ERETIC2 (Electronic Reference To access In vivo Concentrations 2) based on PULCON (Pulse Length-based Concentration determination) methodology is a quantitative NMR (qNMR) using an external standard. The performance of the PULCON method was assessed using maleic acid (MA). Quantification of the diarrhetic shellfish toxin and okadaic acid by PULCON was successfully consistent with that obtained by a conventional internal standard method, demonstrating that the PULCON method is useful for the quantification of invaluable marine toxins without any contaminations by an internal standard.|A single-step lateral flow immunoassay was developed and validated to detect okadaic acid (OA) and dinophysis toxins (DTXs), which cause diarrhetic shellfish poisoning. The performance characteristics of the test were investigated, in comparison to reference methods (liquid chromatography tandem mass spectrometry and/or bioassay), using both spiked and naturally contaminated shellfish. A portable reader was used to generate a qualitative result, indicating the absence or presence of OA-group toxins, at concentrations relevant to the maximum permitted level (MPL). Sample homogenates could be screened in 20 min (including extraction and assay time) for the presence of free toxins (OA, DTX1, DTX2). DTX3 detection could be included with the addition of a hydrolysis procedure. No matrix effects were observed from the species evaluated (mussels, scallops, oysters, and clams). Results from naturally contaminated samples (n = 72) indicated no false compliant results and no false noncompliant results at <50% MPL. Thus, the development of a new low-cost but highly effective tool for monitoring a range of important phycotoxins has been demonstrated.|For more Analytic Laboratory Methods (Complete) data for Okadaic acid (6 total), please visit the HSDB record page.