title: ABCC1, ABCC2 and ABCC3 are implicated in the transepithelial transport of the myco-estrogen zearalenone and its major metabolites.
abstract: The myco-estrogene zearalenone (ZEA) is a worldwide cereal contaminant, implicated in reproductive disorders in animals and humans. Intestinal cells constitute a first barrier to mycotoxins exposure, since they express membrane ABC transporters that may affect the bioavailability of food xenobiotics. In this study, we investigated the mechanisms involved in the transepithelial transfer of ZEA and its major metabolites alpha- and beta-zearalenols (ZOLs), first using human intestinal Caco-2 cells. When exposed to ZEA, alpha-ZOL or beta-ZOL either in the apical (AP) or basolateral (BL) compartment, cells showed asymmetry in the AP-BL and BL-AP transfer of mycotoxins. Metabolic inhibitors increased ZEA, alpha-ZOL and beta-ZOL intracellular accumulation. Caco-2 cells apically exposed to ZEA produced metabolites (ZOLs and glucuronides) whose distribution between AP, BL and intracellular compartments was significantly modified by ABCCs inhibitor MK571. ABCB1-, ABCC1-, ABCC2 and ABCC3-transfected cells were used for studies of intracellular accumulation of ZEA, alpha-ZOL and beta-ZOL with or without specific inhibitors, and for competitive studies using fluorescent substrates. The results showed that ZEA, alpha-ZOL and beta-ZOL were substrates for ABCC2. ABCC1 was also involved in ZEA and alpha-ZOL transport, whereas ABCC3 only interacted with beta-ZOL. These specific interactions suggest a role for ABCC1-3 transport proteins in zearalenone exposure and its resulting risk for human health.
authors: UMR 1233 INRA-ENVL, MTCX, Ecole Nationale Vétérinaire de Lyon, 1 av. Bourgelat, 69280 Marcy l'Etoile, France.
authors: Bernadette
authors: B
authors: Videmann
authors: M
authors: M
authors: Mazallon
authors: C
authors: C
authors: Prouillac
authors: Marcel
authors: M
authors: Delaforge
authors: Sylvaine
authors: S
authors: Lecoeur
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004848:Epithelium / Q000378:metabolism; D004968:Estrogens, Non-Steroidal / Q000493:pharmacokinetics*; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D018374:LLC-PK1 Cells; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020112:Rhodamine 123 / Q000378:metabolism; D013552:Swine; D015025:Zearalenone / Q000493:pharmacokinetics*
chemical_list: D004968:Estrogens, Non-Steroidal; D005452:Fluoresceins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D020112:Rhodamine 123; D015025:Zearalenone; C000715087:ABCC2 protein, human; C114462:multidrug resistance-associated protein 3; C007740:fluorexon; C421109:multidrug resistance-associated protein 1