title: Evaluation of the intestinal permeability and cytotoxic effects of cylindrospermopsin.
abstract: Cylindrospermopsin is a freshwater and widespread cyanotoxin considered hazardous for human health. Climate change and eutrophication are the main factors influencing the increasing presence of cylindrospermopsin producers that can contaminate human and animal drinking waters, leading to a rise in ecological and human risk. In order to reach the bloodstream and thus the target receptor, an orally administered drug must first cross the intestinal barrier. The goal of this study was to examine the cylindrospermopsin intestinal permeability and its cellular effects on intestinal and hepatic cells. We explored the human intestinal permeability of cylindrospermopsin by performing in vitro permeation studies across the Caco-2 cell monolayer. Cell permeability data indicated a limited passage of the toxin through the intact intestinal epithelium in a time and concentration dependent way. Cylindrospermopsin induced neither damage on the integrity of the monolayer nor cytotoxicity in tests performed with Caco-2 even at micromolar concentration. Opposite, when hepatic Clone 9 cells were exposed to cylindrospermopsin, a noticeable cytotoxicity was observed being more marked at the higher concentrations used. In addition, this cell line showed alterations in reduced glutathione content due to cylindrospermopsin over time. Meanwhile glutamate cysteine ligase levels, the first rate-limiting enzyme of the glutathione route, showed a significant increase. Therefore our results indicate that cylindrospermopsin cytotoxicity is unrelated to protein inhibition or a decrease of reduced glutathione levels in Clone 9 cells.
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Campus Universitario, 27002 Lugo, Spain.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Fernández
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Campus Universitario, 27002 Lugo, Spain. Electronic address: mcarmen.louzao@usc.es.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Louzao
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Campus Universitario, 27002 Lugo, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Vilariño
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Campus Universitario, 27002 Lugo, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Fraga
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Campus Universitario, 27002 Lugo, Spain; International Iberian Nanotechnology Laboratory (INL), Avenida Mestre José Veiga s/n, 4715-330 Braga, Portugal.
authors.forename: Begoña
authors.initials: B
authors.lastname: Espiña
authors.affiliation: Departamento de Fisiología Animal, Facultad de Veterinaria, Universidad de Santiago de Compostela, Campus Universitario, 27002 Lugo, Spain.
authors.forename: Mercedes R
authors.initials: MR
authors.lastname: Vieytes
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Campus Universitario, 27002 Lugo, Spain. Electronic address: luis.botana@usc.es.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Botana
mesh_terms: D000470:Alkaloids; D001427:Bacterial Toxins; D018938:Caco-2 Cells; D000087522:Cyanobacteria Toxins; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D010539:Permeability; D014498:Uracil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity
chemical_list: D000470:Alkaloids; D001427:Bacterial Toxins; D000087522:Cyanobacteria Toxins; C089595:cylindrospermopsin; D014498:Uracil; D005978:Glutathione
keywords: Caco-2; Clone 9; Cylindrospermopsin; Glutamate cysteine ligase; Glutathione; Intestinal permeability