Carrier-Mediated and Energy-Dependent Uptake and Efflux of Deoxynivalenol in Mammalian Cells

Abstract

Deoxynivalenol (DON) is one of the most abundant mycotoxins and exerts many adverse effects on humans and animals. To date, the transporting mechanism of DON in mammalian cells remains unclear. In this study, the parallel artificial membrane permeability assay (PAMPA), Transwell models and metabolic inhibitors were used to determine the possible transporting mechanisms of DON in Caco-2, MDCK and HepG2 cells. PAMPA and Transwell models showed reduced passive transport and increased intestinal absorption, indicating a carrier-mediated transporting mechanism. Furthermore, higher unidirectional transport of DON was observed in the basolateral-to-apical direction than in the apical-to-basolateral direction, indicating the existence of efflux proteins. Interestingly, DON was accumulated in the nucleus, and no DON was detected in mitochondria, indicating that the nucleus may be the main target organelle of DON. Moreover, the use of various transporter inhibitors in different cells shows that organic anion transporters, organic cation transporters, and organic anion-transporting polypeptides participate in DON uptake, and P-glycoprotein is the major efflux protein. Importantly, DON uptake is strongly inhibited by metabolic inhibitors and is highly dependent on temperature. In summary, carrier-mediated and energy-dependent uptake and efflux mechanisms for DON in mammalian cells are reported, aiding in improving our understanding of its toxicological mechanisms.

Analysis of the interactions between environmental and food contaminants, cadmium and deoxynivalenol, in different target organs

“…Among the four cell types, HL-60 and HepG2 demonstrated the more contrasted response depending on the dose of the mixture. That could be related to the particular resistance of HepG2 to DON and of HL-60 to Cd as already observed by others (Juan-García et al, 2016;Li et al, 2017).…”

1H-NMR metabolomics response to a realistic diet contamination with the mycotoxin deoxynivalenol: Effect of probiotics supplementation

“…Feeding S. cerevisiae boulardii as a supplement to rats exposed to carbon tetrachloride resulted in significant changes in intestinal permeability, and the protective effect of the yeast was partially attributed to the improvement of the toxic-induced alteration of the barrier function [19]. Both paracellular and transcellular paths have been reported for the intestinal transfer of DON to the systemic compartment, though DON transiting via transcellular pathmay be substrate to efflux systems involving the P-glycoprotein, and the multi-drug resistance-associated protein 2 [1,67,68]. Moreover, DON transport from the apical to the basolateral side of Caco-2 cells and, inversely, from the basolateral to the apical side have been shown to be directly proportional to its initial concentration as well as to the duration of the incubation, suggesting that, in contrast to the paracellular flux, the overall contribution of the transcellular passage, may be limited [69].…”

In Silico and In Vitro Studies of Mycotoxins and Their Cocktails; Their Toxicity and Its Mitigation by Silibinin Pre-Treatment

“…T-2 toxin caused the most significant increase in ATP consumption, suggesting its P-gp-mediated transport ( Figure 2). Li et al [82] and Videman et al [83] proposed that P-gp is the foremost transporter of DON in Caco-2, HepG2, and MDCK cells. Different models indicate that P-gp is directly involved in the efflux of ZEA [84][85][86].…”