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Azaspiracids Increase Mitochondrial Dehydrogenases Activity in Hepatocytes: Involvement of Potassium and Chloride Ions

1
Department of Life Sciences, University of Trieste, Via A. Valerio 6, 34127 Trieste, Italy
2
Marine Institute, Rinville, Oranmore, Co. H91 R673 Galway, Ireland
3
IFREMER, Laboratoire Phycotoxines, Rue de l’Ile d’Yeu, 44311 Nantes, France
*
Author to whom correspondence should be addressed.
Mar. Drugs 2019, 17(5), 276; https://doi.org/10.3390/md17050276
Received: 10 April 2019 / Revised: 29 April 2019 / Accepted: 6 May 2019 / Published: 8 May 2019
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Abstract

Background: Azaspiracids (AZAs) are marine toxins that are produced by Azadinium and Amphidoma dinoflagellates that can contaminate edible shellfish inducing a foodborne poisoning in humans, which is characterized by gastrointestinal symptoms. Among these, AZA1, -2, and -3 are regulated in the European Union, being the most important in terms of occurrence and toxicity. In vivo studies in mice showed that, in addition to gastrointestinal effects, AZA1 induces liver alterations that are visible as a swollen organ, with the presence of hepatocellular fat droplets and vacuoles. Hence, an in vitro study was carried out to investigate the effects of AZA1, -2, and -3 on liver cells, using human non-tumor IHH hepatocytes. Results: The exposure of IHH cells to AZA1, -2, or -3 (5 × 10−12–1 × 10−7 M) for 24 h did not affect the cell viability and proliferation (Sulforhodamine B assay and 3H-Thymidine incorporation assay), but they induced a significant concentration-dependent increase of mitochondrial dehydrogenases activity (MTT reduction assay). This effect depends on the activity of mitochondrial electron transport chain complex I and II, being counteracted by rotenone and tenoyl trifluoroacetone, respectively. Furthermore, AZAs-increased mitochondrial dehydrogenase activity was almost totally suppressed in the K+-, Cl-, and Na+-free media and sensitive to the specific inhibitors of KATP and hERG potassium channels, Na+/K+, ATPase, and cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels. Conclusions: These results suggest that AZA mitochondrial effects in hepatocytes derive from an imbalance of intracellular levels of K+ and, in particular, Cl ions, as demonstrated by the selective reduction of toxin effects by CFTR chloride channel inhibition. View Full-Text
Keywords: azaspiracids; hepatocytes; mitochondrial activity; mechanism of toxicity azaspiracids; hepatocytes; mitochondrial activity; mechanism of toxicity
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Pelin, M.; Kilcoyne, J.; Florio, C.; Hess, P.; Tubaro, A.; Sosa, S. Azaspiracids Increase Mitochondrial Dehydrogenases Activity in Hepatocytes: Involvement of Potassium and Chloride Ions. Mar. Drugs 2019, 17, 276.

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