ABCC1, ABCC2 and ABCC3 are implicated in the transepithelial transport of the myco-estrogen zearalenone and its major metabolites

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 α- and β-zearalenols (ZOLs), first using human intestinal Caco-2 cells. When exposed to ZEA, α-ZOL or β-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, α-ZOL and β-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, α-ZOL and β-ZOL with or without specific inhibitors, and for competitive studies using fluorescent substrates. The results showed that ZEA, α-ZOL and β-ZOL were substrates for ABCC2. ABCC1 was also involved in ZEA and α-ZOL transport, whereas ABCC3 only interacted with β-ZOL. These specific interactions suggest a role for ABCC1–3 transport proteins in zearalenone exposure and its resulting risk for human health.