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Research ArticleArticle

Mechanism-Based Inactivation of Human CYP2E1 by Diethyldithocarbamate

Matthew Pratt-Hyatt, Hsia-lien Lin and Paul F. Hollenberg
Drug Metabolism and Disposition December 2010, 38 (12) 2286-2292; DOI: https://doi.org/10.1124/dmd.110.034710
Matthew Pratt-Hyatt
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Hsia-lien Lin
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Paul F. Hollenberg
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Abstract

Although the ability of disulfiram to inactivate CYP2E1 has been known for more than 20 years, the mechanism has not yet been elucidated. A metabolite of disulfiram, diethyldithocarbamate (DDC), is converted by CYP2E1 to a reactive intermediate that subsequently inactivates the protein, leading to mechanism-based inactivation. Mass spectral analysis of the inactivated human 2E1 protein demonstrates that the inactivation is due to the formation of an adduct of the reactive metabolite of DDC with the apoprotein. These data, along with mass spectral analysis of a reactive intermediate trapped with GSH, indicate the involvement of a reactive intermediate with a molecular mass of 116 Da. Our results suggest that this binding involves formation of a disulfide bond with one of the eight cysteines in CYP2E1. The inactivation of wild-type CYP2E1 as well as two of its polymorphic mutants, CYP2E1*2 and CYP2E1*4, was also investigated. For wild-type CYP2E1, the KI was 12.2 μM and the kinact was 0.02 min−1. The KI values for the two polymorphic mutants were 227.6 and 12.4 μM for CYP2E1.2 and CYP2E1.4, and the kinact values were 0.0061 and 0.0187 min−1, respectively. These data indicate that DDC is a much less efficient inactivator of CYP2E1.2 than it is of either the wild-type or the CYP2E1.4 variant.

Footnotes

  • This work was supported in part by the National Institutes of Health National Cancer Institute [Grant CA16954] (to P.F.H.); and the National Institutes of Health National Institute on Drug Abuse [Biology of Drug Abuse Postdoctoral Training Fellowship DA007268-18] (to M.P.-H.).

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

    doi:10.1124/dmd.110.034710.

  • ABBREVIATIONS:

    ALDH
    aldehyde dehydrogenase
    DBH
    dopamine-β-hydroxylase
    DDC
    diethyldithiocarbamate
    P450
    cytochrome P450
    7-EFC
    7-ethoxy-4-(trifluoromethyl)-coumarin
    HPLC
    high-performance liquid chromatography
    ESI
    electrospray ionization
    LC
    liquid chromatography
    MS
    mass spectrometry
    MS/MS
    tandem mass spectrometry
    DTT
    dithiothreitol.

  • Received May 25, 2010.
  • Accepted September 8, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (12)
Drug Metabolism and Disposition
Vol. 38, Issue 12
1 Dec 2010
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Research ArticleArticle

Mechanism-Based Inactivation of Human CYP2E1 by Diethyldithocarbamate

Matthew Pratt-Hyatt, Hsia-lien Lin and Paul F. Hollenberg
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2286-2292; DOI: https://doi.org/10.1124/dmd.110.034710

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Research ArticleArticle

Mechanism-Based Inactivation of Human CYP2E1 by Diethyldithocarbamate

Matthew Pratt-Hyatt, Hsia-lien Lin and Paul F. Hollenberg
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2286-2292; DOI: https://doi.org/10.1124/dmd.110.034710
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