title: Transepithelial transport of fusariotoxin nivalenol: mediation of secretion by ABC transporters.
abstract: Mycotoxin nivalenol (NIV) is a natural contaminant of various cereal crops, animal feed and processed grains throughout the world. Human and animal contamination occurs mainly orally, and the toxin must traverse the intestinal epithelial barrier before inducing potential health effects. In this study, we investigated the mechanisms involved in NIV transepithelial transfer. The human intestinal Caco-2 cell line showed a basal-to-apical polarized transport of NIV. Using metabolic inhibitors and temperature-dependent experiments, we demonstrated that basolateral-apical (BL-AP) transfer of NIV involved an energy-dependent transport whereas apical-basolateral (AP-BL) transfer was governed by passive diffusion. NIV efflux was significantly decreased in the presence of the P-glycoprotein (P-gp) inhibitor valspodar, the multi-drug resistance-associated proteins (MRPs) inhibitor MK571, but was not modified by the breast cancer resistance protein (BCRP) inhibitor Ko143. Intracellular NIV accumulation was investigated using epithelial cell lines transfected with either human P-glycoprotein or MRP2. This accumulation was significantly decreased in LLCPK1/MDR1 and MDCKII/MRP2 cells, compared to wild-type cells, and this effect was reversed by valspodar and MK571, respectively. These in vitro results suggested that NIV was a substrate for both P-glycoprotein and MRP2. This interaction may play a key role in weak intestinal absorption of NIV and the mainly predominant excretion of NIV in faeces in animal studies.
authors.affiliation: UMR 1233, Métabolisme et Toxicologie Comparée des Xénobiotiques, INRA-DGER, Ecole Nationale Vétérinaire de Lyon, 1 av. Bourgelat, 69280 Marcy l'Etoile, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tep
authors.forename: Bernadette
authors.initials: B
authors.lastname: Videmann
authors.forename: Michèle
authors.initials: M
authors.lastname: Mazallon
authors.forename: Sabine
authors.initials: S
authors.lastname: Balleydier
authors.forename: Séverine
authors.initials: S
authors.lastname: Cavret
authors.forename: Sylvaine
authors.initials: S
authors.lastname: Lecoeur
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000502:physiology; D001693:Biological Transport, Active / Q000187:drug effects; D018938:Caco-2 Cells; D002460:Cell Line; D002849:Chromatography, Gas; D004563:Electrochemistry; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009183:Mycotoxins / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013696:Temperature; D013778:Tetrazolium Salts; D013844:Thiazoles; D014255:Trichothecenes / Q000378:metabolism*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009183:Mycotoxins; D011422:Propionates; D011804:Quinolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D014255:Trichothecenes; C000715087:ABCC2 protein, human; C059141:verlukast; C038405:nivalenol; C022616:thiazolyl blue