title: The kinetic, mechanistic and cytomorphological effects of palytoxin in human intestinal cells (Caco-2) explain its lower-than-parenteral oral toxicity.
abstract: Palytoxin is one of the most toxic marine toxins known. Distributed worldwide, it poses a potential human health risk linked to the consumption of contaminated seafood. Despite its high parenteral toxicity, the lethal oral dose of palytoxin is several times higher than the intraperitoneal lethal dose. In the present study, we investigated the passage of palytoxin through the human intestinal barrier by employing a well-characterized and accepted in vitro model of intestinal permeability that uses differentiated Caco-2 cell monolayers. Trans-epithelial electric resistance measurements showed that palytoxin disrupts the integrity of Caco-2 monolayers at concentrations > 0.135 nM. However, confocal microscopy imaging showed that the tight-junction protein occludin was not affected by palytoxin in the nanomolar range. This finding was supported by transmission electron microscopy imaging, where tight-junctions appeared to be unaffected by palytoxin treatment. In addition, the nuclear envelope does not appear to be altered by high concentrations of palytoxin. However, palytoxin-treated cells showed electron-dense and damaged mitochondria. Toxin exposure also induced the disappearance of the differentiated Caco-2 microvilli and organelles, as well as chromatin de-condensation. Permeability assays showed that palytoxin could not significantly pass the Caco-2 monolayer, despite the lack of epithelium integrity, suggesting that palytoxins would be poorly transported to blood, which may explain its lower oral toxicity. These data can help to achieve a better understanding of palytoxin poisoning. However, more studies regarding its repeated administration and chronic effects are needed.
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Fernández
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Louzao
authors.forename: Natalia
authors.initials: N
authors.lastname: Vilariño
authors.forename: Begoña
authors.initials: B
authors.lastname: Espiña
authors.forename: María
authors.initials: M
authors.lastname: Fraga
authors.forename: Mercedes R
authors.initials: MR
authors.lastname: Vieytes
authors.forename: Albina
authors.initials: A
authors.lastname: Román
authors.forename: Mark
authors.initials: M
authors.lastname: Poli
authors.forename: Luis M
authors.initials: LM
authors.lastname: Botana
mesh_terms: D000178:Acrylamides / Q000378:metabolism / Q000633:toxicity*; D018938:Caco-2 Cells; D002454:Cell Differentiation; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D003064:Cnidarian Venoms; D017097:Electric Impedance; D020895:Enterocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D005765:Gastrointestinal Agents / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D007700:Kinetics; D008387:Marine Toxins / Q000378:metabolism / Q000633:toxicity*; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008871:Microvilli / Q000187:drug effects* / Q000648:ultrastructure; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D009685:Nuclear Envelope / Q000187:drug effects / Q000648:ultrastructure; D062793:Occludin / Q000378:metabolism; D015388:Organelles / Q000187:drug effects / Q000648:ultrastructure; D009994:Osmolar Concentration; D010539:Permeability; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D000095702:Polyether Toxins
chemical_list: D000178:Acrylamides; D003064:Cnidarian Venoms; D005765:Gastrointestinal Agents; D008387:Marine Toxins; D062793:Occludin; C568985:OCLN protein, human; C010272:palytoxin; D000095702:Polyether Toxins
keywords: Caco-2; intestinal permeability; occludin; palytoxin; trans-epithelial electric resistance