Permeability of the Cyanotoxin Microcystin-RR across a Caco-2 Cells Monolayer.

Jérôme Henri,Antoine Huguet,Jean-Michel Delmas,Valérie Fessard,Rachelle Lanceleur

doi:10.3390/toxins13030178

Jérôme Henri, Antoine Huguet + Show 3 more

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https://doi.org/10.3390/toxins13030178

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Abstract

Microcystins (MCs) are toxins produced by several cyanobacterial species found worldwide. While MCs have a common structure, the variation of two amino acids in their structure affects their toxicity. As toxicodynamics are very similar between the MC variants, their differential toxicity could rather be explained by toxicokinetic parameters. Microcystin-RR (MC-RR) is the second most abundant congener and induces toxicity through oral exposure. As intestinal permeability is a key parameter of oral toxicokinetics, the apparent permeability of MC-RR across a differentiated intestinal Caco-2 cell monolayer was investigated. We observed a rapid and large decrease of MC-RR levels in the donor compartment. However, irrespective of the loaded concentration and exposure time, the permeabilities were very low from apical to basolateral compartments (from 4 to 15 × 10−8 cm·s−1) and from basolateral to apical compartments (from 2 to 37 × 10−8 cm·s−1). Our results suggested that MC-RR would be poorly absorbed orally. As similar low permeability was reported for the most abundant congener microcystin-LR, and this variant presented a greater acute oral toxicity than MC-RR, we concluded that the intestinal permeability was probably not involved in the differential toxicity between them, in contrast to the hepatic uptake and metabolism.

Highlights

Over the last century, due to increasing eutrophic conditions of freshwaters, there has been increasing incidence of massive proliferation of photosynthetic prokaryotic cyanobacteria [1]
The integrity of Caco-2 cell monolayers was not affected by MC-RR, irrespective of the time and concentration, with trans-epithelial electrical resistance (TEER) values ranging from 316 to 908 ohm.cm2
We showed similar observations for 25 and 55 μM MC-RR during the first 2 h, with MC-RR amounts below the lower limit of quantification (LOQ)

Summary

Introduction

Due to increasing eutrophic conditions of freshwaters, there has been increasing incidence of massive proliferation of photosynthetic prokaryotic cyanobacteria [1]. Microcystins (MCs) are toxins produced by several cyanobacterial species that can affect humans through several routes of exposure. Parenteral exposure can lead to death, as reported when MC-contaminated water was used for renal dialysis in Brazil, human exposure occurs mainly via the oral route through various sources, such as water, accumulating aquatic organisms, and dietary supplements [2,3,4,5]. Besides the global common structure, MC variants differ mainly by two L-amino-acids in positions 2 and 4, which were shown to affect their toxicity [10,11,12]. The toxicokinetic parameters seem to be affected by the variation of amino acids in positions 2 and 4 and contribute to the toxicity of MC variants [21,22,23]

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