Ochratoxin A secretion by ATP-dependent membrane transporters in Caco-2 cells

Abstract

The ATP-dependent membrane transporters, P-gp, MRP2 and BCRP, localized in the luminal membranes of the intestines, liver and kidney, counteract absorption and increase excretion of xenobiotics and drugs. Previously, it has been suggested that the mycotoxin ochratoxin A (OTA) is a substrate for ATP-dependent transporters, and hence the absorption and secretion of OTA in the Caco-2 cell model was investigated. To this end, Caco-2 cells were cultured as confluent monolayers in bicameral inserts and the transepithelial transport of the mycotoxin was assessed. Caco-2 cells secreted OTA to the luminal side in a concentration-dependent manner. This secretory permeability was higher than the absorptive permeability, while the absorptive permeability remained constant for all OTA concentrations tested. The secretion decreased and absorption increased in the presence of the MRP-inhibitor MK571, the P-gp and BCRP inhibitor GF120918, and the BCRP-inhibitor Ko143, suggesting that the secretion of OTA is mediated by MRP2 and BCRP. Cyclosporine A also decreased the secretory permeability, but did not affect absorptive permeability, while PSC833 did neither change absorption nor secretion of OTA. Hence it can be suggested that OTA is a substrate for MRP2 as well as BCRP. These findings are of interest in evaluating mycotoxin absorption after oral ingestion, tissue distribution and particularly excretion pathways, including renal, biliary and mammary gland excretion.

New Insight into the Ochratoxin A Biosynthetic Pathway through Deletion of a Nonribosomal Peptide Synthetase Gene in Aspergillus carbonarius

“…From the results of this experiment, it was not possible to have an indication of whether the hydrolysis activity occurred in the medium due to an enzyme excreted out of the cell or if externally applied OTA was absorbed into the cell where the degradation process would have taken place. Previous studies have indicated that OTA is a substrate for different kinds of transporters facilitating not only the efflux of compounds but also cellular uptake (49). Actually, contradictory findings have been reported about the excretion of OTA-degrading enzymes by different fungal species.…”

Effects of fasting and gender on ochratoxin A toxicokinetics in F344 rats

“…Dietrich et al (2005) suggested the presence of organic anion transporters with the capacity to transport OTA in the jejunum, but Berger et al (2003) showed that these transporters were not implicated in OTA transport across Caco-2-cells. Another factor that may influence the OTA bioavailability is the finding that OTA is a substrate for the ATPBinding Cassette efflux-proteins MRP2 and BCRP in Caco-2-cells (Schrickx et al, 2006).…”

Mycotoxins in cattle feeds and carry-over to dairy milk: A review

“…Substrates for these transporters are likely to appear in high concentrations in milk. Recently, it was shown that, for example, ochratoxin A is a substrate for BCRP (Schrickx et al 2006), which correlates with the high prevalence of ochratoxin A in human breast milk samples. In addition, it has been shown that aflatoxin B1 is a substrate for BCRP, making it likely that aflatoxin M 1 and aflatoxicol are also excreted actively into milk (Van Herwaarden et al 2006).…”