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Research ArticleArticle

Proluciferin Acetals as Bioluminogenic Substrates for Cytochrome P450 Activity and Probes for CYP3A Inhibition

Poncho L. Meisenheimer, H. Tetsuo Uyeda, Dongping Ma, Mary Sobol, Mark G. McDougall, Cesear Corona, Dan Simpson, Dieter H. Klaubert and James J. Cali
Drug Metabolism and Disposition December 2011, 39 (12) 2403-2410; DOI: https://doi.org/10.1124/dmd.111.041541
Poncho L. Meisenheimer
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H. Tetsuo Uyeda
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Dongping Ma
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Mary Sobol
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Mark G. McDougall
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Cesear Corona
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Dan Simpson
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Dieter H. Klaubert
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James J. Cali
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Abstract

Cytochrome P450 (P450) assays use probe substrates to interrogate the influence of new chemical entities toward P450 enzymes. We report the synthesis and study of a family of bioluminogenic luciferin acetal substrates that are oxidized by P450 enzymes to form luciferase substrates. The luciferin acetals were screened against a panel of purified P450 enzymes. In particular, one proluciferin acetal has demonstrated sensitive and selective CYP3A4-catalyzed oxidation to a luciferin ester—Km and kcat are 2.88 μM and 5.87 pmol metabolite · min−1 · pmol enzyme−1, respectively. The proluciferin acetal was used as a probe substrate to measure IC50 values of known inhibitors against recombinant CYP3A4 or human liver microsomes. IC50 values for the known inhibitors correlate strongly with IC50 values calculated from the traditional high-performance liquid chromatography-based probe substrate testosterone. Luciferin acetals are rapidly oxidized to unstable hemi-orthoesters by CYP3A resulting in luciferin esters and, therefore, are conducive to simple rapid CYP3A bioluminescent assays.

Footnotes

  • This work was financially supported by Promega Corporation and Promega Biosciences.

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

    doi:10.1124/dmd.111.041541.

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

  • ABBREVIATIONS:

    P450
    cytochrome P450
    NCE
    new chemical entity
    HPLC
    high-performance liquid chromatography
    RLU
    relative light units
    HLMs
    human liver microsomes
    KPO4
    potassium phosphate buffered to the stated pH
    LOD
    limit of detection.

  • Received July 11, 2011.
  • Accepted September 2, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (12)
Drug Metabolism and Disposition
Vol. 39, Issue 12
1 Dec 2011
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Research ArticleArticle

PROLUCIFERIN ACETALS AS CYP3A PROBES

Poncho L. Meisenheimer, H. Tetsuo Uyeda, Dongping Ma, Mary Sobol, Mark G. McDougall, Cesear Corona, Dan Simpson, Dieter H. Klaubert and James J. Cali
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2403-2410; DOI: https://doi.org/10.1124/dmd.111.041541

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Research ArticleArticle

PROLUCIFERIN ACETALS AS CYP3A PROBES

Poncho L. Meisenheimer, H. Tetsuo Uyeda, Dongping Ma, Mary Sobol, Mark G. McDougall, Cesear Corona, Dan Simpson, Dieter H. Klaubert and James J. Cali
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2403-2410; DOI: https://doi.org/10.1124/dmd.111.041541
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