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Research ArticleArticle

In Vitro Metabolism of the Mycotoxin Enniatin B in Different Species and Cytochrome P450 Enzyme Phenotyping by Chemical Inhibitors

Christiane K. Fæste, Lada Ivanova and Silvio Uhlig
Drug Metabolism and Disposition September 2011, 39 (9) 1768-1776; DOI: https://doi.org/10.1124/dmd.111.039529
Christiane K. Fæste
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Lada Ivanova
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Silvio Uhlig
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Abstract

Enniatins are cyclic hexapeptidic mycotoxins produced by fungi growing on field grains, especially in wet climates. They show considerable resistance to food and feed processing technologies and might cause intoxication of humans and animals. Enniatins are also under exploration as anticancer drugs. The observed difference of in vitro and in vivo toxicities suggests low absorption or fast elimination of the enniatins after oral uptake. In the study presented here, in vitro metabolism studies of enniatin B were performed using rat, dog, and human liver microsomes under conditions of linear kinetics to estimate the respective elimination rates. Furthermore, cytochrome P450 reaction phenotyping with chemical inhibitors selective for human enzymes was carried out. Twelve metabolites were separated and characterized by multiple high-performance liquid chromatographic/mass spectrometric analyses as products of oxidation and demethylation reactions. Biotransformation rates and metabolite patterns varied considerably in the three species. The intrinsic clearances determined in assays with rat, dog, and human liver microsomes were 1.16, 8.23, and 1.13 l/(h · kg), respectively. The predicted enniatin B in vivo blood clearances were 1.57 l/(h · kg) in rats, 1.67 l/(h · kg) in dogs, and 0.63 l/(h · kg) in humans. CYP3A4 was important for enniatin B metabolism in human microsomes as shown by 80% inhibition and impaired metabolite formation in the presence of troleandomycin. CYP1A2 and CYP2C19 were additionally involved. Preliminary results showed that CYP3A and CYP1A might also be relevant in rats and dogs. The extensive hepatic metabolism could explain the reduced in vivo potential of enniatin B.

Footnotes

  • This work was supported in part by the Norwegian Research Council [Grant 200349/I10] within the project “Mycotoxin 2—biomarkers for adverse endocrine effects of fungal extrolites and mycotoxins—characterisation of molecular mechanisms using cell assays, chemical analyses and proteomics.”

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.111.039529.

  • ABBREVIATIONS:

    EnnB
    enniatin B
    M1
    metabolite 1
    N-Me-Val
    N-methyl-l-valines
    HPLC
    high-performance liquid chromatography
    HLM
    human liver microsomes
    P450
    cytochrome P450
    DLM
    dog liver microsomes
    RLM
    rat liver microsomes
    LC-MS
    high-performance liquid chromatography-coupled mass spectrometry
    RLW
    relative liver weights
    MRI
    microsomal recovery indexes
    Fur
    furafylline
    TAO
    troleandomycin
    AUC
    area under the concentration-time curve.

  • Received March 15, 2011.
  • Accepted May 26, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (9)
Drug Metabolism and Disposition
Vol. 39, Issue 9
1 Sep 2011
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Research ArticleArticle

In Vitro Metabolism of the Mycotoxin Enniatin B in Different Species and Cytochrome P450 Enzyme Phenotyping by Chemical Inhibitors

Christiane K. Fæste, Lada Ivanova and Silvio Uhlig
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1768-1776; DOI: https://doi.org/10.1124/dmd.111.039529

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Research ArticleArticle

In Vitro Metabolism of the Mycotoxin Enniatin B in Different Species and Cytochrome P450 Enzyme Phenotyping by Chemical Inhibitors

Christiane K. Fæste, Lada Ivanova and Silvio Uhlig
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1768-1776; DOI: https://doi.org/10.1124/dmd.111.039529
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