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Research ArticleArticle

Bupropion Hydroxylation as a Selective Marker of Rat CYP2B1 Catalytic Activity

Dumrongsak Pekthong, Coraline Desbans, Hélène Martin and Lysiane Richert
Drug Metabolism and Disposition January 2012, 40 (1) 32-38; DOI: https://doi.org/10.1124/dmd.111.041368
Dumrongsak Pekthong
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Coraline Desbans
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Hélène Martin
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Lysiane Richert
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Abstract

Benzyloxyresorufin-O-dealkylation (BROD) is usually used as a marker of cytochrome P450 (P450) 2B1 in rat. However, some reports show that CYP1A2 is also highly implicated. The purpose of the present study was to establish bupropion (BUP) hydroxylation, but not BROD, as a selective in vitro marker of CYP2B1 catalytic activity. IC50 for BROD and BUP hydroxylation were equivalent (40.8 ± 4.6 and 41.8 ± 3.4 μM, respectively) when using liver microsomes from β-naphthoflavone-pretreated rats in the presence of metyrapone (CYP2B1 inhibitor). When using the same microsomes in the presence of CYP1A1/2-selective inhibitor α-naphthoflavone, we found an IC50 of 2.5 × 10−3 ± 0.8 × 10−3 μM for BROD and >100 μM for BUP hydroxylation. These results suggest that CYP2B1 is similarly involved in both activities, whereas CYP1A2 is involved in BROD activity but not in BUP hydroxylation. BUP hydroxylation was assessed in microsomes from baculovirus-infected insect cells coexpressing NADPH-P450 oxidoreductase, and 14 rat P450s and kinetic parameters (Km and Vmax) were determined. BUP hydroxylation was predominantly catalyzed by CYP2B1 (75% of total hydroxybupropion formation), low activity was detected with CYP2E1 and CYP2C11 (10.9 and 8.7% of total hydroxybupropion, respectively), and activity was almost undetectable with the other P450 isoforms at saturating substrate concentrations (2500 μM), thereby validating the use of BUP as a diagnostic in vitro marker of CYP2B1 catalytic activity in rat.

Footnotes

  • This work was funded by KaLy-Cell [Grant Université de Franche-Comté-KaLy-Cell, number I233].

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

    http://dx.doi.org/10.1124/dmd.111.041368.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    ANF
    α-naphthoflavone
    BNF
    β-naphthoflavone
    BROD
    benzyloxyresorufin-O-dealkylase
    BUP
    bupropion
    HBUP
    hydroxybupropion
    PB
    phenobarbital
    RHM
    rat hepatocyte microsomes
    RLM
    rat liver microsomes
    BSA
    bovine serum albumin
    DEX
    dexamethasone
    3-MC
    3-methylcholantrene
    FEN
    fenofibrate
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    HPLC
    high-performance liquid chromatography
    ESI
    electrospray ionization.

  • Received June 24, 2011.
  • Accepted September 30, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (1)
Drug Metabolism and Disposition
Vol. 40, Issue 1
1 Jan 2012
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Research ArticleArticle

BUPROPION HYDROXYLATION A MARKER OF RAT CYP2B1 ACTIVITY

Dumrongsak Pekthong, Coraline Desbans, Hélène Martin and Lysiane Richert
Drug Metabolism and Disposition January 1, 2012, 40 (1) 32-38; DOI: https://doi.org/10.1124/dmd.111.041368

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Research ArticleArticle

BUPROPION HYDROXYLATION A MARKER OF RAT CYP2B1 ACTIVITY

Dumrongsak Pekthong, Coraline Desbans, Hélène Martin and Lysiane Richert
Drug Metabolism and Disposition January 1, 2012, 40 (1) 32-38; DOI: https://doi.org/10.1124/dmd.111.041368
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