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Open AccessArticle

Biotransformation of the Mycotoxin Enniatin B1 by CYP P450 3A4 and Potential for Drug-Drug Interactions

1
Chemistry and Toxinology Research Group, Norwegian Veterinary Institute, P.O. Box 750 Sentrum, 0106 Oslo, Norway
2
Department of Biochemistry, University of Illinois, Urbana, IL 61802, USA
*
Author to whom correspondence should be addressed.
Metabolites 2019, 9(8), 158; https://doi.org/10.3390/metabo9080158
Received: 20 June 2019 / Revised: 16 July 2019 / Accepted: 23 July 2019 / Published: 27 July 2019
(This article belongs to the Special Issue Fungal and Mycotoxin Metabolism)
Enniatins (ENNs) are fungal secondary metabolites that frequently occur in grain in temperate climates. Their toxic potency is connected to their ionophoric character and lipophilicity. The biotransformation of ENNs predominantly takes place via cytochrome P450 3A (CYP 3A)-dependent oxidation reactions. Possible interaction with ENNs is relevant since CYP3A4 is the main metabolic enzyme for numerous drugs and contaminants. In the present study, we have determined the kinetic characteristics and inhibitory potential of ENNB1 in human liver microsomes (HLM) and CYP3A4-containing nanodiscs (ND). We showed in both in vitro systems that ENNB1 is mainly metabolised by CYP3A4, producing at least eleven metabolites. Moreover, ENNB1 significantly decreased the hydroxylation rates of the typical CYP3A4-substrate midazolam (MDZ). Deoxynivalenol (DON), which is the most prevalent mycotoxin in grain and usually co-occurrs with the ENNs, was not metabolised by CYP3A4 or binding to its active site. Nevertheless, DON affected the efficiency of this biotransformation pathway both in HLM and ND. The metabolite formation rates of ENNB1 and the frequently used drugs progesterone (PGS) and atorvastatin (ARVS) lactone were noticeably reduced, which indicated a certain affinity of DON to the enzyme with subsequent conformational changes. Our results emphasise the importance of drug–drug interaction studies, also with regard to natural toxins. View Full-Text
Keywords: enniatin B1; deoxynivalenol; cytochrome P450 3A4; functional nanodiscs; biotransformation; inhibition; human liver microsomes enniatin B1; deoxynivalenol; cytochrome P450 3A4; functional nanodiscs; biotransformation; inhibition; human liver microsomes
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Ivanova, L.; Denisov, I.G.; Grinkova, Y.V.; Sligar, S.G.; Fæste, C.K. Biotransformation of the Mycotoxin Enniatin B1 by CYP P450 3A4 and Potential for Drug-Drug Interactions. Metabolites 2019, 9, 158.

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