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

Lada Ivanova,Yelena V Grinkova,Ilia G Denisov,Stephen G Sligar,Christiane K Fæste

doi:10.3390/metabo9080158

Lada Ivanova, Yelena V Grinkova + Show 3 more

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https://doi.org/10.3390/metabo9080158

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Abstract

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.

Highlights

Enniatins (ENNs) are fungal metabolites that occur with high frequency in grain, but for which maximum levels in food and feed have not been established by national and international food safety authorities so far [1]
We have investigated the kinetic profile of enniatin B1 (ENNB1) in human liver microsomes and interactions with other compounds that are hydroxylated by CYP3A4
ENNB1 was metabolised to a significant extent and less than 4% of the unchanged molecule was detectable after incubatiion of 6 μM for 60 min

Summary

Introduction

Enniatins (ENNs) are fungal metabolites that occur with high frequency in grain, but for which maximum levels in food and feed have not been established by national and international food safety authorities so far [1]. In regards to their prevalence and substantial concentrations in grain-based products [2], the determination of their toxicological potency is considered to be important and necessary for the evaluation of human and animal risk from dietary exposure [3]. The lipophilic ENNs have been shown to be carried-over in the food chain [2,4]

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