Dinophysistoxin
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Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). | |
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History
Dinophysistoxins (DTXs) are a group of lipophilic marine biotoxins produced by certain species of marine dinoflagellates, such as Dinophysis and Prorocentrum [1]. These species are classified under the superclass of Dinoflagellata which are unicellular marine plankton that can also be found in freshwater habitats. The population of these species is recorded to be higher during higher water temperatures [2].
At times of rapid accumulation of dinoflagellates, the water can appear to have a red-ish color, known as red tide. This harmful algal bloom contaminates shellfish that eat them and can cause diarrhetic shellfish poisoning (DSP) once the contaminated shellfish are eaten by humans. DSP cases have been documented in Japan, Europe, North and South America, Thailand, Australia, and New Zealand [3].
It wasn’t until the late 1970s that Dinophysis species were considered to be a cause for DSP. In the summer of 1981, more than 5000 people were affected from DSP after eating Mediterranean mussels and the cause was attributed to a D. acuminata bloom. After incidents such as this one, researchers concluded that the poisoning is a result of DTXs [1].
Structure
Dinophysistoxins are lipophilic thermo-stable molecules analogous to okadaic acid. They are polyketide compounds with furane and pyrane-type ether rings with α-hydroxycarboxyl as a functional group [4]. Dinophysistoxins include dinophysistoxin 1 (DTX1), dinophysistoxin 2 (DTX2) and dinophysistoxin 3 (DTX3). DTX 1 has the same carbon skeleton as okadaic acid, the only difference being an additional, equatorially oriented methyl group at the C35 position. Compared to DTX1, DTX 2 does not have the methyl substituent at C31 and its C35 methyl group is axially oriented. This axially oriented C35 methyl group plays an important role in its reactivity [5]. DTX3 comprises toxins acetylated at the C-7 hydroxyl group with long-chain fatty acids [6].
Synthesis
The biosynthesis of DTXs is facilitated by polyketide synthases (PKSs), which are multi-enzyme complexes that construct these compounds from basic acetate units.The process includes several unique modifications, such as carbon deletions and additions, leading to the formation of the characteristic polyether structures found in DTXs and OA [7].
The whole chemical synthesis of DTXs, including okadaic acid, has proven to be a difficult undertaking because of their complex structures. To date, only a limited number of complete syntheses, each comprising multiple steps and yielding low overall results. For instance, Isobe et al. carried out the first comprehensive synthesis of okadaic acid in 1986, requiring 106 stages total, with the longest linear sequence consisting of 54 steps [8].
Available forms
The most thoroughly documented forms are:
- Dinophysistoxin-1 (DTX-1): A potent toxin with structural similarities to okadaic acid, is predominantly produced by Dinophysis fortii. It inhibits protein phosphatases, resulting in gastrointestinal symptoms linked with DSP [9]
- Dinophysistoxin-2 (DTX-2): A closely related analog of DTX-1, this variant has been found in Dinophysis acuminata and is often detected in contaminated shellfish. Studies suggest that DTX-2 may have slightly lower toxicity compared to DTX-1. [10]
- Dinophysistoxin-3 (DTX-3): Unlike DTX-1 and DTX-2, DTX-3 is not a different toxin but rather an acylated derivative of DTX-1 and DTX-2. It forms when these toxins bind to fatty acids in the tissues of shellfish, changing their bioavailability and toxicity when consumed.[11]
Mechanism of action
Molecular targets of dinophysistoxins are serine/threonine protein phosphatases. Specifically, they are potent inhibitors of protein phosphatase 2A (PP2A) and as secondary targets protein phosphatase 1 (PP1) and protein phosphatase 2B (PP2B) [12]. They have a significantly higher affinity for PP2A, although not all the toxins have the same affinity. Affinity of PP2A for DTX 1 is 1.6-fold higher, and for DTX 2 is 2-fold lower than for okadaic acid as a reference. DTX 3, on the other hand, is inactive against PP2A if not hydrolyzed [13]. Protein phosphatases play an important role in the regulation of essential cellular processes like division, growth, death, and maintenance of cytoskeleton. Their inhibition by DTXs results in severe alterations on phosphorylation of many proteins that results in the collapse of regulatory processes and in significant cellular disruptions [13]. Specifically, PP2A, their primary target, is a regulatory enzyme, which is essential in multiple signaling pathways, such as survival, apoptosis and differentiation. Moreover, it functions as a tumor suppressor and a regulator of intrinsic and extrinsic apoptotic pathways. Thus, its inhibition results in important cellular alterations [4].
Studies on mice show drastic morphological alterations in different organs, especially intestines and liver, after toxin administration. Morphological changes of cells include formation of blebs on the surface, changes in cellular shape, degeneration of absorptive epithelium and of endothelial lining [13]. Changes in metabolic profile are also one of the results of DTX 1 toxicity. Oral administration of this toxin triggers mitophagy that could be related with the reduction of glycogen observed in hepatocytes in the liver with the aim of favoring specific cellular processes [12]. DTXs show not only cellular, but also macroscopic changes in the gastrointestinal tract, ultimately resulting in inhibition of gastric emptying and the symptoms associated with their toxicity [12].
DTX toxins also play a role in carcinogenesis. Their toxicity is linked to the production of proinflammatory chemokines and cytokines, specifically upregulation of TNF-α, an endogenous tumor factor. Moreover, they also increase mitosis and activate AKT, ERK and the expression of c-May, all involved in the inflammatory response and carcinogenesis [4].
The toxic effects of dinophysistoxins are in general attributed to the inhibition of protein phosphatases, however, this process does not always explain the cellular and molecular results of these toxins. This suggests that other cellular targets might also be involved. Studies are reporting effects of dinophysistoxins in cytotoxicity, neurotoxicity, immunotoxicity, embryotoxicity, genotoxicity etc. For example, cytotoxicity is a result of oxidative stress and changes in catabolic and anabolic pathways in the cell, as a result of dinophysistoxins [13].
Metabolism
In shellfish, on the other hand, OA/DTX toxins are often transformed to their 7-O-acyl fatty acid ester derivatives (collectively known as Dinophysistoxin-3, DTX-3), and these frequently comprise more than half the total OA/DTX in mussels.
Ingestion of contaminated shellfish exposes humans to DTX-3. In the human body, DTX-3 can be metabolically transformed into Dinophysistoxin-1 (DTX-1). This transformation occurs in the stomach after consuming contaminated shellfish. DTX-1 is responsible for the diarrheic symptoms and intoxication syndrome observed in patients [2]. Analyses of fecal samples from intoxicated patients have revealed the presence of DTX-1, while DTX-3 was absent, indicating the in vivo transformation of DTX-3 to DTX-1. Likewise, mussels are known to transform PTX-2 to PTX-2 seco acid (PTX-2sa), but data on PTX in shellfish are scarce.
Efficacy and side effects
Dinophysistoxins, including DTX-1 and DTX-2, are potent inhibitors of protein phosphatases 1 and 2A. These are enzymes that regulate cell signalling, apoptosis and cytoskeletal integrity. The inhibition thus causes a disruption of cellular function and affects processes like cell division and signal transduction [6].
Along with this, the toxins can lead to hyperphosphorylation of proteins. This has several implications. The hyperphosphorylation can cause an increased intestinal permeability leading to symptoms such as diarrhea, nausea, vomiting, and abdominal pain. They additionally activate chloride channels in the gastrointestinal tracts, which causes water loss from intestinal cells. The hyperphosphorylation can also induce tumor formation. The oral toxicity of DTX-1 is higher compared to okadaic acid and DTX-2, making it a significant concern for human health [12]. Apart from these acute effects, chronic effects have also been reported, including carcinogenic effects and effects on the immune- and nervous systems and alterations in DNA and cellular components [13].
Toxicity
Dinophysistoxins (DTXs) are strong lipophilic marine toxins that are members of the okadaic acid (OA) toxin group, which are responsible for diarrhetic shellfish poisoning (DSP). These toxins exert their toxicity primarily by inhibiting protein phosphatases 1 (PP1) and 2A (PP2A), which causes disruptions in cellular signaling and increased phosphorylation of proteins. Humans experience significant gastrointestinal distress when phosphorylated proteins build up in intestinal cells [14].
Effects
Humans
DTXs are a major cause of diarrhetic shellfish poisoning (DSP), a gastrointestinal illness resulting from the consumption of contaminated shellfish. The symptoms typically appear within a few hours of ingestion and can last up to three days. Common effects include:
- Diarrhea
- Nausea and vomiting
- Abdominal cramps
- Dehydration
Although DSP is generally not fatal, severe cases can lead to extensive dehydration and require medical intervention. Chronic exposure to okadaic acid and dinophysistoxins has also been linked to tumor-promoting activity, suggesting a potential carcinogenic risk [11].
Marine organisms
In marine ecosystems, DTXs can have significant impacts on bivalve mollusks, which accumulate these toxins without apparent harm. However, these toxins biomagnify through the food chain, affecting predators that consume contaminated shellfish. Potential effects on marine organisms include [11]:
- Reduced feeding and growth in fish and shellfish
- Changes in immune response
- Increased mortality in sensitive species
- Possible disruption of reproductive functions in marine life
Notes
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References
- ↑ 1.0 1.1 Reguera B, Riobó P, Rodríguez F, Díaz PA, Pizarro G, Paz B, Franco JM, Blanco J. Dinophysis toxins: causative organisms, distribution and fate in shellfish. Mar Drugs. 2014 Jan 20;12(1):394-461. doi: 10.3390/md12010394. PMID: 24447996; PMCID: PMC3917280.
- ↑ 2.0 2.1 Park, J.B., Cho, S., Lee, S.Y. et al. Occurrence and risk assessment of okadaic acid, dinophysistoxin-1, dinophysistoxin-2, and dinophysistoxin-3 in seafood from South Korea. Environ Sci Pollut Res 31, 6243–6257 (2024). https://doi.org/10.1007/s11356-023-31568-4
- ↑ Tubaro, Aurelia & Sosa, Silvio & Hungerford, James. (2012). Toxicology and diversity of marine toxins. 10.1016/B978-0-12-385926-6.00080-6
- ↑ 4.0 4.1 4.2 del Campo, M., Zhong, T. Y., Tampe, R., García, L., & Lagos, N. (2017). Sublethal doses of dinophysistoxin-1 and okadaic acid stimulate secretion of inflammatory factors on innate immune cells: Negative health consequences. Toxicon, 126, 23–31. https://doi.org/10.1016/j.toxicon.2016.12.005
- ↑ Forsyth, C. J., & Wang, C. (2008). Synthesis and stereochemistry of the terminal spiroketal domain of the phosphatase inhibitor dinophysistoxin-2. Bioorganic and Medicinal Chemistry Letters, 18(10), 3043–3046. https://doi.org/10.1016/j.bmcl.2008.01.002
- ↑ 6.0 6.1 Fernández, D. A., Louzao, M. C., Fraga, M., Vilariño, N., Vieytes, M. R., & Botana, L. M. (2013). Experimental basis for the high oral toxicity of dinophysistoxin 1: A comparative study of DSP. Toxins, 6(1), 211–228. https://doi.org/10.3390/toxins6010211
- ↑ Van Wagoner, R. M.; Satake, M.; Wright, J. L. C. (2014). "Polyketide biosynthesis in dinoftagellates: what makes it different?". Nat. Prod. Rep. 31 (9): 1101–1137. doi:10.1039/c4np00016a
- ↑ Dounay, A. B.; Forsyth, C. J. (2002). "Okadaic acid: The archetypal serine/threonine protein phosphatase inhibitor". Curr. Med. Chem. 9 (22): 1939–1980. doi:10.2174/0929867023368791
- ↑ "caymanchem product Dinophysistoxin-1".
- ↑ "Cifca Dinophysistoxin-2".
- ↑ 11.0 11.1 11.2 García, C., Truan, D., Lagos, M., Santelices, J. P., Díaz, J. C., & Lagos, N. (2005). METABOLIC TRANSFORMATION OF DINOPHYSISTOXIN-3 INTO DINOPHYSISTOXIN-1 CAUSES HUMAN INTOXICATION BY CONSUMPTION OF O-ACYL-DERIVATIVES DINOPHYSISTOXINS CONTAMINATED SHELLFISH. In The Journal of Toxicological Sciences (Vol. 30, Issue 4).
- ↑ 12.0 12.1 12.2 12.3 Abal, P., Carmen Louzao, M., Suzuki, T., Watanabe, R., Vilariño, N., Carrera, C., Botana, A. M., Vieytes, M. R., & Botana, L. M. (2018). Toxic Action Reevaluation of Okadaic Acid, Dinophysistoxin-1 and Dinophysistoxin-2: Toxicity Equivalency Factors Based on the Oral Toxicity Study. Cellular Physiology and Biochemistry, 49(2), 743–757. https://doi.org/10.1159/000493039
- ↑ 13.0 13.1 13.2 13.3 13.4 Valdiglesias, V., Prego-Faraldo, M. V., Paśaro, E., Meńdez, J., & Laffon, B. (2013). Okadaic Acid: More than a diarrheic toxin. In Marine Drugs (Vol. 11, Issue 11, pp. 4328–4349). MDPI AG. https://doi.org/10.3390/md11114328
- ↑ "Compound summary".
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