Okadaic acid

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Okadaic acid
Okadaic acid.svg
Identifiers
CAS number 78111-17-8 YesY
PubChem 446512
ChemSpider 393845 YesY
KEGG C01945 N
MeSH Acid Okadaic Acid
ChEBI CHEBI:CHEBI:7733 N
ChEMBL CHEMBL280487 N
Jmol-3D images Image 1
Properties
Molecular formula C44H68O13
Molar mass 805.00 g mol−1
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

Okadaic acid is a toxin that accumulates in bivalves and causes diarrheal shellfish poisoning. The molecular formula of okadaic acid, which is a derivative of a C38 fatty acid, is C44H68O13.

History[edit]

Okadaic acid was named from the marine sponge Halichondria okadai, from which okadaic acid was isolated for the first time.[1] It has also been isolated from another marine sponge, H. malanodocia, as a cytotoxin. The real producers of okadaic acid belong to the algae group of the dinoflagellates, namely the benthic dinoflagellate Prorocentrum and the planktonic forms of Dinophysis,[2] for example Dinophysis acuminata and D. acuta.[3] Administration of okadaic acid has been shown to profoundly increase the secretion of nerve growth factor, and to also promote nerve growth factor gene transcription and the stability of mRNA in primary cultures of cortical astrocytes.[4]

Derivatives[edit]

Structural analogs of okadaic acid are the isomeric compound, dinophysistoxin-2 (DTX2), the methylated derivative, dinophysistoxin-1 (DTX1), and the toxins acylated at the C-7 hydroxyl group with long-chain fatty acids, collectively known as dinophysistoxin-3 (DTX3).[5][6][7]

Biochemistry[edit]

The cytotoxicities of okadaic acid as EC50 against the P388 and L1210 cell lines are 1.7 nanomolar and 17 nanomolar, respectively. Additionally, okadaic acid strongly inhibits protein serine / threonine phosphatase 1, 2A, and 2B.[8] The different inhibitory potencies of DSP toxins on protein phosphatases have been determined allowing the establishment of inhibition equivalency factors (IEFs). The IEFs were calculated as the ratio of the IC50 for OA to the IC50 for DTX1 or DTX2. The IEF of DTX1 for PP1 is in the 0.4–0.9 range, whereas for PP2A, it is between 0.9 and 2.4,[9][10][11][12] indicating more inhibition of this phosphatase than that exerted by OA. Regarding DTX2, the IEF for PP2A is lower, with reported values ranging from 0.4 to 0.6.[12][13] According to the current studies, the rest of the derivatives have even less inhibition effect over both phosphatases [9][14][15][16][17]

The Toxic Equivalency Factor (TEFs) of these compounds are a matter of vital importance for the analytical detection of marine and freshwater toxins. The control methods require an estimation of the toxic potential of a mixture of toxins with different potency to protect consumers' health.[12][18] To propose the TEFs for this group of toxins, the European Food Safety Authority (EFSA) assumed that all this compounds share the same biochemical mechanism of action and, therefore, were established based only on mice i.p. toxicity. TEFs are defined as the ratio of the toxic potency (usually LD50) for each compound compared to the potency of the reference compound (in this case, Okadaic Acid). The actual values are the following: Okadaic Acid = 1; DTX1 = 1; and DTX2 = 0.6.[19] The lower inhibitory potency of DTX2 with respect to Okadaic Acid is comparable to its reduced acute intraperitoneal toxicity observed in mice, which allowed for the establishment of a TEF of 0.6.[20] Nevertheless, Smienk et al.[21] have recently reported equal toxicity for DTX2 and Okadaic Acid. However, a recent study by Fernandez et al.[22] has demonstrated that DTX1 is able to disrupt the Caco-2 cells monolayer integrity (one of the main cell models to perform In vitro intestinal permeability assays) and to modify occludin distribution between adjacent cells revealing a greater intestinal absorption of DTX1 when compared to Okadaic Acid or DTX2. These data suggest new evidence that the oral toxicity of DTX1 is higher than Okadaic Acid or DTX2 and it constitutes a strong argument for a future revision of the actual TEF values for the toxins of this group.

See also[edit]

References[edit]

  1. ^ Tachibana, K.; Scheuer, P. J.; Tsukitani, Y.; Kikuchi, H.; van Engen, D.; Clardy, J.; Gopichand, Y.; Schmitz, F. J. (1981). "Okadaic acid, a cytotoxic polyether from two marine sponges of the genus Halichondria". Journal of the American Chemical Society 103 (9): 2469–2471. doi:10.1021/ja00399a082. 
  2. ^ Lee, R. E. (2008). Phycology (4th ed.). Cambridge University Press. ISBN 978-0-521-68277-0. 
  3. ^ "Dinophysis acuminata". www.algaebase.org. Retrieved 2010-05-04. 
  4. ^ Pshenichkin, S. P.; Wise, B. C. (1995). "Okadaic Acid Increases Nerve Growth Factor Secretion, mRNA Stability, and Gene Transcription in Primary Cultures of Cortical Astrocytes" (pdf). Journal of Biological Chemistry 270 (11): 5994–5999. doi:10.1074/jbc.270.11.5994. PMID 7890729. 
  5. ^ Dominguez, H.J.; Paz, B.; Daranas, A.H.; Norte, M.; Franco, J.M.; Fernandez, J.J. (2010). "Dinoflagellate polyether within the yessotoxin, pectenotoxin and okadaic acid toxin groups: Characterization, analysis and human health implications". Toxicon 56 (2): 191–217. doi:10.1016/j.toxicon.2009.11.005. PMID 19925818. 
  6. ^ Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.; Matsumoto, G.K.; Clardy, J. (1985). "Diarrhetic shellfish toxins". Tetrahedron 41 (6): 1019–1025. doi:10.1016/S0040-4020(01)96469-5. 
  7. ^ Munday, R. (2013). "Is protein phosphatase inhibition responsible for the toxic effects of okadaic acid in animals?". Toxins 5 (2): 267–285. doi:10.3390/toxins5020267. PMC 3640535. PMID 23381142. 
  8. ^ Garcia, A.; Cayla, X.; Guergnon, J.; Dessauge, F.; Hospital, V.; Rebollo, M. P.; Fleischer, A.; Rebollo, A. (2003). "Serine / threonine protein phosphatases PP1 and PP2A are key players in apoptosis". Biochimie 85 (8): 721–726. doi:10.1016/j.biochi.2003.09.004. PMID 14585537. 
  9. ^ a b Takai, A.; Murata, M.; Torigoe, K.; Isobe, M.; Mieskes, G.; Yasumoto, T. (1992). "Inhibitory effect of okadaic acid derivatives on protein phosphatases. A study on structure-affinity relationship.". Biochem. J. 284: 539–544. PMC 1132671. PMID 1318034. 
  10. ^ Holmes, C.F.; Luu, H.A.; Carrier, F.; Schmitz, F.J. (1990). "Inhibition of protein phosphatases-1 and -2a with acanthifolicin. Comparison with diarrhetic shellfish toxins and identification of a region on okadaic acid important for phosphatase inhibition". FEBS Lett 270 (1-2): 216–218. doi:10.1016/0014-5793(90)81271-o. PMID 2171991. 
  11. ^ Rivas, M.; Garcia, C.; Liberona, J.L.; Lagos, N. (2000). "Biochemical characterization and inhibitory effects of dinophysistoxin-1, okadaic acid and microcystine 1-r on protein phosphatase 2a purified from the mussel Mytilus chilensis". Biol. Res 33 (3-4): 197–206. doi:10.4067/s0716-97602000000300005. PMID 15696679. 
  12. ^ a b c Garibo, D.; De la Iglesia Gonzalez, P.; Diogene, J.; Campas, M. (2013). "Inhibition equivalency factors for dinophysistoxin-1 and dinophysistoxin-2 in protein phosphatase assays, applicability to the analysis of shellfish samples and comparison with LC-MS/MS". J. Agric. Food Chem 61 (10): 2572–2579. doi:10.1021/jf305334n. PMID 23406170. 
  13. ^ Aune, T.; Larsen, S.; Aasen, J.A.; Rehmann, N.; Satake, M.; Hess, P. (2007). "Relative toxicity of dinophysistoxin-2 (dtx-2) compared with okadaic acid, based on acute intraperitoneal toxicity in mice". Toxicon 49 (1): 1–7. doi:10.1016/j.toxicon.2006.07.033. PMID 17092529. 
  14. ^ Hu, T.; Curtis, J.M.; Walter, J.A.; Wright, J.L.C (1995). "Identification of dtx-4, a new water-soluble phosphatase inhibitor from the toxic dinoflagellate prorocentrum lima". J. Chem. Soc. Chem. Commun 49 (5): 597–599. doi:10.1039/C39950000597. 
  15. ^ Yanagi, T.; Murata, M.; Torigoe, K.; Yasumoto, T. (1989). "Biological activities of semisynthetic analogs of dinophysistoxin-3, the major diarrhetic shellfish toxin". Agric. Biol. Chem 53 (2): 525–529. doi:10.1271/bbb1961.53.525. 
  16. ^ Nishiwaki, S.; Fujiki, H.; Suganuma, M.; Furuya-Suguri, H.; Matsushima, R.; Iida, Y.; Ojika, M.; Yamada, K.; Uemura, D.; Yasumoto, T. (1990). "Structure-activity relationship within a series of okadaic acid derivatives". Carcinogenesis 11 (10): 1837–1841. doi:10.1093/carcin/11.10.1837. PMID 2170047. 
  17. ^ 23. Hu, T.; Curtis, J.M.; Walter, J.A.; McLachlan, J.L.; Wright, J.L.C. (1995). "Two new water-soluble dsp toxin derivatives from the dinoflagellate prorocentrum maculosum: Possible storage and excretion products". Tetrahedron Letters 36 (51): 9273–9276. doi:10.1016/0040-4039(95)02010-M. 
  18. ^ Botana, L.M.; Vilariño, N.; Alfonso, A.; Vale, C.; Louzao, C.; Elliott, C.T.; Campbell, K.; Botana, A.M. (2010). "The problem of toxicity equivalent factors in developing alternative methods to animal bioassays for marine-toxin detection". TrAC Trends Anal. Chem 29 (11): 1316–1325. doi:10.1016/j.trac.2010.09.004. 
  19. ^ The European Food Safety Authority (2008). "Opinion of the scientific panel on contaminants in the food chain on a request from the european commission on marine biotoxins in shellfish—Okadaic acid and analogues". EFSA J 510: 1–62. doi:10.2903/j.efsa.2008.589. 
  20. ^ Aune, T.; Larsen, S.; Aasen, J.A.; Rehmann, N.; Satake, M.; Hess, P. (2007). "Relative toxicity of dinophysistoxin-2 (dtx-2) compared with okadaic acid, based on acute intraperitoneal toxicity in mice". Toxicon 49 (1): 1–7. doi:10.1016/j.toxicon.2006.07.033. PMID 17092529. 
  21. ^ Smienk, H.G.; Calvo, D.; Razquin, P.; Dominguez, E.; Mata, L. (2012). "Single laboratory validation of a ready-to-use phosphatase inhibition assay for detection of okadaic acid toxins". Toxins 4 (1): 339–352. doi:10.3390/toxins4050339. PMC 3386634. PMID 22778904. 
  22. ^ Fernandez, D.A.; Louzao, M.C.; Fraga, M.; Vilarino, N.; Vieytes, M. R.; Botana, L. M. (2014). "Experimental Basis for the High Oral Toxicity of Dinophysistoxin 1: A Comparative Study of DSP". Toxins 6 (1): 211–228. doi:10.3390/toxins6010211. PMC 3920258. PMID 24394641. 

External links[edit]