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Arch Toxicol. 2019 Jun;93(6):1729-1743. doi: 10.1007/s00204-019-02459-w. Epub 2019 May 2.

The Fusarium metabolite culmorin suppresses the in vitro glucuronidation of deoxynivalenol.

Author information

1
Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währingerstrasse 38, 1090, Vienna, Austria.
2
Christian Doppler Laboratory for Mycotoxin Metabolism and Center for Analytical Chemistry, Department of Agrobiotechnology (IFA-Tulln), University of Natural Resources and Life Sciences, Vienna (BOKU), Konrad-Lorenz-Strasse 20, 3430, Tulln, Austria.
3
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, 1060, Vienna, Austria.
4
BIOMIN Research Center, Technopark 1, 3430, Tulln, Austria.
5
Department of Applied Chemistry and Ecology, Faculty of Food Technology, Josip Juraj Strossmayer University of Osijek, Franje Kuhača 20, 31000, Osijek, Croatia.
6
Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, Vienna (BOKU), Konrad-Lorenz-Strasse 24, 3430, Tulln, Austria.
7
Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währingerstrasse 38, 1090, Vienna, Austria. doris.marko@univie.ac.at.

Abstract

Glucuronidation is a major phase II conjugation pathway in mammals, playing an important role in the detoxification and biotransformation of xenobiotics including mycotoxins such as deoxynivalenol (DON). Culmorin (CUL), a potentially co-occurring Fusarium metabolite, was recently found to inhibit the corresponding detoxification reaction in plants, namely DON-glucoside formation, raising the question whether CUL might affect also the mammalian counterpart. Using cell-free conditions, CUL when present equimolar (67 µM) or in fivefold excess, suppressed DON glucuronidation by human liver microsomes, reducing the formation of DON-15-glucuronide by 15 and 50%, and DON-3-glucuronide by 30 and 50%, respectively. Substantial inhibitory effects on DON glucuronidation up to 100% were found using the human recombinant uridine 5'-diphospho-glucuronosyltransferases (UGT) 2B4 and 2B7, applying a tenfold excess of CUL (100 µM). In addition, we observed the formation of a novel metabolite of CUL, CUL-11-glucuronide, identified for the first time in vitro as well as in vivo in piglet and human urine samples. Despite the observed potency of CUL to inhibit glucuronidation, no significant synergistic toxicity on cell viability was observed in combinations of CUL (0.1-100 µM) and DON (0.01-10 µM) in HT-29 and HepG2 cells, presumably reflecting the limited capacity of the tested cell lines for DON glucuronidation. However, in humans, glucuronidation is known to represent the main detoxification pathway for DON. The present results, including the identification of CUL-11-glucuronide in urine samples of piglets and humans, underline the necessity of further studies on the relevance of CUL as a potentially co-occurring modulator of DON toxicokinetics in vivo.

KEYWORDS:

Chemical mixtures; Drug metabolism; Drug–exposome interactions; Fungal metabolites; Natural contaminants

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