Is Protein Phosphatase Inhibition Responsible for the Toxic Effects of Okadaic Acid in Animals?

Abstract

Okadaic acid (OA) and its derivatives, which are produced by dinoflagellates of the genera Prorocentrum and Dinophysis, are responsible for diarrhetic shellfish poisoning in humans. In laboratory animals, these toxins cause epithelial damage and fluid accumulation in the gastrointestinal tract, and at high doses, they cause death. These substances have also been shown to be tumour promoters, and when injected into the brains of rodents, OA induces neuronal damage reminiscent of that seen in Alzheimer’s disease. OA and certain of its derivatives are potent inhibitors of protein phosphatases, which play many roles in cellular metabolism. In 1990, it was suggested that inhibition of these enzymes was responsible for the diarrhetic effect of these toxins. It is now repeatedly stated in the literature that protein phosphatase inhibition is not only responsible for the intestinal effects of OA and derivatives, but also for their acute toxic effects, their tumour promoting activity and their neuronal toxicity. In the present review, the evidence for the involvement of protein phosphatase inhibition in the induction of the toxic effects of OA and its derivatives is examined, with the conclusion that the mechanism of toxicity of these substances requires re-evaluation.

Diarrhetic effect of okadaic acid could be related with its neuronal action: Changes in neuropeptide Y

“…The viability of the differentiated intestinal Caco-2 cells was not impaired by the concentrations of OA tested. OA was previously reported to induce several cytoskeleton alterations in different cell systems that could be due to different mechanisms that involve disruption of F-actin and that stimulate tight junction disassembly leading to diarrhea in vivo (Munday, 2013;Vale and Botana, 2008;Vilarino et al, 2008). We found a dose and time dependent reduction of TEER values on these Caco-2 monolayers exposed to OA indicating tight-junctions alterations.…”

“…There is some controversy about this phosphatase inhibition being the only responsible for the toxic effects of OA and its analogs and recent papers have suggested that it should be re-evaluated (Espina et al, 2009;Louzao et al, 2005Louzao et al, , 2003Munday, 2013;Vilarino et al, 2008;Wang et al, 2012), especially when focusing on the exact triggering mechanism of the diarrheic effects (Munday, 2013). In this sense, methyl okadaate and OA disrupt the F-actin cytoskeleton in hepatocytes and in neuroblastoma cells even though this OA analog has little or no effect on the activities of PP2A and PP1 (Espina et al, 2009;Louzao et al, 2005Louzao et al, , 2003Vilarino et al, 2008).…”

“…The symptoms appear in a time frame of about thirty minutes to a few hours after ingestion of contaminated seafood and include episodes of nausea, vomiting, strong abdominal pain and diarrhea. Intoxicated individuals usually recover in 2 or 3 days (Dominguez et al, 2010;Munday, 2013).…”

Toxic Action Reevaluation of Okadaic Acid, Dinophysistoxin-1 and Dinophysistoxin-2: Toxicity Equivalency Factors Based on the Oral Toxicity Study

“…TEM analysis revealed that neither OA nor DTX1 changed tight junctions, therefore fluid accumulation in the intestine and diarrhea could not be related to increase in paracellular permeability along with tight junctions disruption as was previously suggested [11]. Intestine of mice administered with the highest dose of each toxin presented decreased enterocytes microvilli that were not seen after oral DTX2 administration [29].…”

“…It was previously suggested that PPs inhibition was responsible for the diarrheic effect of OA and derivatives [8]. However, other actions not related to PP inhibition [9,10], have been reported suggesting that the mechanism of toxicity of these compounds must be re-evaluated [11].…”