# 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

## TL;DR

This study examines how two Zearalenone metabolites interact with enzymes and transporters in the body, revealing their potential to affect drug metabolism and transport.

## Contribution

The study is the first to investigate interactions of Zearalenone-14-sulfate and Zearalenone-14-glucuronide with CYP enzymes and transporters.

## Key findings

- Z14S weakly inhibits CYP2C9 and CYP3A4, while Z14GA does not affect CYP enzymes.
- Z14S strongly inhibits OATP1B1 and OATP2B1 at nanomolar concentrations.
- Z14GA shows weak inhibition of OATPs except for OATP2B1, and interacts with MRP2 among ABC transporters.

## Abstract

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.