title: Low in vitro permeability of the cyanotoxin microcystin-LR across a Caco-2 monolayer: with identification of the limiting factors using modelling.
abstract: Microcystins (MCs) are toxins produced by several cyanobacteria species found worldwide. MC-LR is the most frequent. Here, we used the human Caco-2 cell line grown on semi-permeable filter supports as an in vitro model for determining MC-LR intestinal bidirectional transport. In this study, there was very low and time-dependent apparent permeability of MC-LR. To identify the limiting factors involved in the low permeability of MC-LR, a mathematical model was constructed to get physiologically relevant and informative parameters. The apical-to-basolateral transport was characterised by a rapid and substantial decrease in apical MC-LR concentrations (24-40% of the initial amount). In the basolateral compartment, the concentrations increased slowly after a lag time, but represented only a small fraction of the loaded concentrations (0.3-1.3%) after 24 h. This weak permeability was mainly due to a low clearance of efflux (from the cellular to the basolateral compartment) and effective secretion (from the cellular to the apical compartment). During the basolateral-to-apical transport, we observed a slow decrease in basolateral concentrations and a rapid increase in apical concentrations. In conclusion, modelling has the potential to highlight the key mechanisms involved in the complex kinetics of toxin transport.
authors.affiliation: ANSES - French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Fougères, France. Electronic address: jerome.henri@anses.fr.
authors.forename: Jerome
authors.initials: J
authors.lastname: Henri
authors.affiliation: ANSES - French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Fougères, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Huguet
authors.affiliation: ANSES - French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Fougères, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Delmas
authors.affiliation: ANSES - French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Fougères, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Besson
authors.affiliation: ANSES - French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Fougères, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Sanders
authors.affiliation: ANSES - French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Fougères, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Fessard
mesh_terms: D018938:Caco-2 Cells; D006801:Humans; D066298:In Vitro Techniques; D008387:Marine Toxins; D052998:Microcystins / Q000493:pharmacokinetics*; D008954:Models, Biological
chemical_list: D008387:Marine Toxins; D052998:Microcystins; C057862:cyanoginosin LR
keywords: Apparent permeability; Caco-2 monolayer; Mathematical model; Microcystin-LR