In Vitro Evaluation of the Potential Interactions of Zearalenone-14-sulfate and Zearalenone-14-glucuronide with Human Cytochrome P450 Enzymes, Organic Anion Transporting Polypeptides, and ATP-Binding Cassette Multidrug Transporters.

Zearalenone (ZEN) is a mycotoxin that is typically produced by Fusarium strains. ZEN and its derivatives are common food contaminants and known xenoestrogens. Previous studies demonstrated the interactions of ZEN and zearalenols with certain cytochrome P450 (CYP) enzymes, organic anion transporting polypeptides (OATPs), and ATP-binding cassette (ABC) multidrug transporters. However, no data are available regarding the conjugated metabolites of the mycotoxin. Therefore, in the current study, we aimed to investigate the potential interactions of zearalenone-14-sulfate (Z14S) and zearalenone-14-glucuronide (Z14GA) with these proteins using in vitro assays. Our major observations/conclusions are the following: Z14S was a weak inhibitor of CYP2C9 and CYP3A4, while Z14GA did not affect the activity of the CYP enzymes examined. Z14S inhibited OATP1A2 and OATP1B3 at low micromolar concentrations, and it showed even stronger effects on OATP1B1 and OATP2B1 with nanomolar IC50 values. In contrast, Z14GA proved to be a weak inhibitor of OATPs tested, except OATP2B1. Among the ABC transporters investigated, we noticed the most relevant interactions of ZEN with MDR1, Z14S with BCRP, and Z14GA with MRP2. Our novel observations may contribute to the deeper understanding of the toxicokinetic interactions of Z14S and Z14GA.