title: Experimental basis for the high oral toxicity of dinophysistoxin 1: a comparative study of DSP.
abstract: Okadaic acid (OA) and its analogues, dinophysistoxin 1 (DTX1) and dinophysistoxin 2 (DTX2), are lipophilic and heat-stable marine toxins produced by dinoflagellates, which can accumulate in filter-feeding bivalves. These toxins cause diarrheic shellfish poisoning (DSP) in humans shortly after the ingestion of contaminated seafood. Studies carried out in mice indicated that DSP poisonous are toxic towards experimental animals with a lethal oral dose 2-10 times higher than the intraperitoneal (i.p.) lethal dose. The focus of this work was to study the absorption of OA, DTX1 and DTX2 through the human gut barrier using differentiated Caco-2 cells. Furthermore, we compared cytotoxicity parameters. Our data revealed that cellular viability was not compromised by toxin concentrations up to 1 μM for 72 h. Okadaic acid and DTX2 induced no significant damage; nevertheless, DTX1 was able to disrupt the integrity of Caco-2 monolayers at concentrations above 50 nM. In addition, confocal microscopy imaging confirmed that the tight-junction protein, occludin, was affected by DTX1. Permeability assays revealed that only DTX1 was able to significantly cross the intestinal epithelium at concentrations above 100 nM. These data suggest a higher oral toxicity of DTX1 compared to OA and DTX2.
authors.affiliation: Department of Pharmacology, Faculty of Veterinary, University of Santiago de Compostela, University Campus, Lugo 27002, Spain. alberto.fernandez@usc.es.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Fernández
authors.affiliation: Department of Pharmacology, Faculty of Veterinary, University of Santiago de Compostela, University Campus, Lugo 27002, Spain. mcarmen.louzao@usc.es.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Louzao
authors.affiliation: Department of Pharmacology, Faculty of Veterinary, University of Santiago de Compostela, University Campus, Lugo 27002, Spain. maria.fraga@usc.es.
authors.forename: María
authors.initials: M
authors.lastname: Fraga
authors.affiliation: Department of Pharmacology, Faculty of Veterinary, University of Santiago de Compostela, University Campus, Lugo 27002, Spain. natalia.vilarino@usc.es.
authors.forename: Natalia
authors.initials: N
authors.lastname: Vilariño
authors.affiliation: Department of Pharmacology, Faculty of Veterinary, University of Santiago de Compostela, University Campus, Lugo 27002, Spain. mmercedes.rodriguez@usc.es.
authors.forename: Mercedes R
authors.initials: MR
authors.lastname: Vieytes
authors.affiliation: Department of Pharmacology, Faculty of Veterinary, University of Santiago de Compostela, University Campus, Lugo 27002, Spain. luis.botana@usc.es.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Botana
mesh_terms: D018938:Caco-2 Cells; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007928:Lethal Dose 50; D008387:Marine Toxins / Q000493:pharmacokinetics / Q000633:toxicity*; D018613:Microscopy, Confocal; D019319:Okadaic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity*; D011714:Pyrans / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D008387:Marine Toxins; D011714:Pyrans; D019319:Okadaic Acid; C051904:dinophysistoxin 1; C076221:dinophysistoxin 2