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Research ArticleArticle

Exploration of Catalytic Properties of CYP2D6 and CYP3A4 Through Metabolic Studies of Levorphanol and Levallorphan

Britta Bonn, Collen M. Masimirembwa and Neal Castagnoli Jr.
Drug Metabolism and Disposition January 2010, 38 (1) 187-199; DOI: https://doi.org/10.1124/dmd.109.028670
Britta Bonn
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Collen M. Masimirembwa
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Neal Castagnoli Jr.
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Abstract

CYP2D6 and CYP3A4, two members of the cytochrome P450 superfamily of monooxygenases, mediate the biotransformation of a variety of xenobiotics. The two enzymes differ in substrate specificity and size and characteristics of the active site cavity. The aim of this study was to determine whether the catalytic properties of these isoforms, reflected by the differences observed from crystal structures and homology models, could be confirmed with experimental data. Detailed metabolite identification, reversible inhibition, and time-dependent inhibition were examined for levorphanol and levallorphan with CYP2D6 and CYP3A4. The studies were designed to provide a comparison of the orientations of substrates, the catalytic sites of the two enzymes, and the subsequent outcomes on metabolism and inhibition. The metabolite identification revealed that CYP3A4 catalyzed the formation of a variety of metabolites as a result of presenting different parts of the substrates to the heme. CYP2D6 was a poorer catalyst that led to a more limited number of metabolites that were interpreted in terms to two orientations of the substrates. The inhibition studies showed evidence for strong reversible inhibition of CYP2D6 but not for CYP3A4. Levallorphan acted as a time-dependent inhibitor on CYP3A4, indicating a productive binding mode with this enzyme not observed with CYP2D6 that presumably resulted from close interactions of the N-allyl moiety oriented toward the heme. All the results are in agreement with the large and flexible active site of CYP3A4 and the more restricted active site of CYP2D6.

Footnotes

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

    doi:10.1124/dmd.109.028670

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • P450
    cytochrome P450
    TDI
    time-dependent inhibition
    AMMC
    4-aminomethyl-7-methoxycoumarine
    BFC
    7-benzyloxy-4-trifluoromethylcoumarine
    HPLC
    high-performance liquid chromatography
    MS
    mass spectrometry
    XIC
    extracted ion chromatogram
    TIC
    total ion current chromatogram
    NR
    normalized ratio
    Clint
    intrinsic clearance.

    • Received May 31, 2009.
    • Accepted September 29, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (1)
Drug Metabolism and Disposition
Vol. 38, Issue 1
1 Jan 2010
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Research ArticleArticle

Exploration of Catalytic Properties of CYP2D6 and CYP3A4 Through Metabolic Studies of Levorphanol and Levallorphan

Britta Bonn, Collen M. Masimirembwa and Neal Castagnoli
Drug Metabolism and Disposition January 1, 2010, 38 (1) 187-199; DOI: https://doi.org/10.1124/dmd.109.028670

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Research ArticleArticle

Exploration of Catalytic Properties of CYP2D6 and CYP3A4 Through Metabolic Studies of Levorphanol and Levallorphan

Britta Bonn, Collen M. Masimirembwa and Neal Castagnoli
Drug Metabolism and Disposition January 1, 2010, 38 (1) 187-199; DOI: https://doi.org/10.1124/dmd.109.028670
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