The mycotoxin patulin alters the barrier function of the intestinal epithelium: mechanism of action of the toxin and protective effects of glutathione.
Patulin is a mycotoxin mainly found in apple and apple products. In addition to being toxic for animals, mutagenic, carcinogenic and teratogenic, patulin induces intestinal injuries, including epithelial cell degeneration, inflammation, ulceration, and hemorrhages. In a study of the cellular mechanisms associated with the intestinal toxicity of patulin, two human epithelial intestinal cell lines (HT-29-D4 and Caco-2-14) were exposed to the mycotoxin. Micromolar concentrations of patulin were found to induce a rapid and dramatic decrease of transepithelial resistance (TER) in both cell lines without major signs of toxicity as assessed by the LDH release assay. Since TER reflects the organization of tight junctions, these data indicate that patulin affected the barrier function of the intestinal epithelium. The inhibitory effect of patulin on TER was closely associated with its reactivity for SH groups: (i) cysteine and glutathione prevented the cells from patulin injury; (ii) patulin toxicity was potentiated by buthionine sulfoximine, a specific glutathione-depleting agent; (iii) treatment of the cells with N-ethylmaleimide, a compound known to react with SH groups, resulted in a marked decrease of TER. Moreover, the inhibitory effect of patulin on TER was mimicked and potentiated by phenylarsine oxide, a specific inhibitor of protein tyrosine phosphatase (PTP). This cellular enzyme is a key regulator of intestinal epithelial barrier function. The active site of PTP contains a cysteine residue (Cys215) that is essential for phosphatase activity. Sulfhydryl-reacting compounds such as acetaldehyde decrease TER through covalent modification of Cys215 of PTP. We propose that the toxicity of patulin for intestinal cells involves, among other potential mechanisms, an inactivation of the active site of PTP.
Mahfoud
Radhia
R
Institut Méditerranéen de Recherche en Nutrition, UMR-INRA 1111, Faculté des Sciences de St Jérôme, 13397 Marseille Cedex 20, France.
Maresca
Marc
M
Garmy
Nicolas
N
Fantini
Jacques
J
D000931:Antidotes / Q000494:pharmacology*; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D004336:Drug Antagonism; D004594:Electrophysiology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005033:Ethylmaleimide / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000494:pharmacology*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009183:Mycotoxins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010365:Patulin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles
D000931:Antidotes; D002712:Chlorides; D009183:Mycotoxins; D013438:Sulfhydryl Compounds; D013778:Tetrazolium Salts; D013844:Thiazoles; D010365:Patulin; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue; D005978:Glutathione; D005947:Glucose; D005033:Ethylmaleimide