Evaluation of the intestinal permeability and cytotoxic effects of cylindrospermopsin

• Cylindrospermopsin has a limited passage through the intact intestinal epithelium.
• Caco-2 cells showed neither cytotoxicity nor damage on the integrity of the monolayer when incubated with cylindrospermopsin.
• Hepatic Clone-9 cells exposed to cylindrospermopsin showed noticeable cytotoxicity, especially at higher concentrations.
• Alterations in reduced glutathione content were reported in Clone-9 cells exposed to Cylindrospermopsin.
• An increase in glutamate cysteine ligase levels was observed on Clone-9 cells exposed to Cylindrospermopsin.

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.