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Research ArticleArticle

Debrisoquine Metabolism and CYP2D Expression in Marmoset Liver Microsomes

Brian R. Cooke, S. W. Annie Bligh, Z. Richard Cybulski, Costas Ioannides and Michael Hall
Drug Metabolism and Disposition January 2012, 40 (1) 70-75; DOI: https://doi.org/10.1124/dmd.111.041566
Brian R. Cooke
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S. W. Annie Bligh
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Z. Richard Cybulski
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Costas Ioannides
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Michael Hall
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Abstract

The objective of this study was to define CYP2D enzymes in marmoset (Callithrix jacchus) liver microsomes, both at the activity level using debrisoquine as the model substrate and at the protein level using antibodies raised to human CYP2D6. Marmoset liver microsomes were incubated with [14C]debrisoquine, and the structure of the generated metabolites was determined using liquid chromatography-tandem mass spectrometry and NMR. Marmoset liver microsomes were very effective in hydroxylating debrisoquine at various positions. Although 4-hydroxydebrisoquine was formed, in contrast to rat and human it was only a minor metabolite. Debrisoquine was more extensively hydroxylated in the 7, 5, 6, and 8 positions. In addition to the monohydroxylated metabolites, a dihydroxy metabolite, namely 6,7-dihydroxydebrisoquine, was identified. Finally, metabolites that had undergone ring opening were also detected but were not investigated further. Antibodies to CYP2D6 immunoreacted with protein in marmoset and human but not rat hepatic microsomes. In conclusion, we demonstrate that marmoset liver microsomes are effective in hydroxylating debrisoquine at various positions and that they contain a protein that is immunorelated to human CYP2D6.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.041566.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    ESI
    electrospray ionization
    HPLC
    high-performance liquid chromatography
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    MF
    metabolic fractions.

  • Received July 12, 2011.
  • Accepted October 5, 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

MARMOSET DEBRISOQUINE METABOLISM AND CYP2D EXPRESSION

Brian R. Cooke, S. W. Annie Bligh, Z. Richard Cybulski, Costas Ioannides and Michael Hall
Drug Metabolism and Disposition January 1, 2012, 40 (1) 70-75; DOI: https://doi.org/10.1124/dmd.111.041566

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Research ArticleArticle

MARMOSET DEBRISOQUINE METABOLISM AND CYP2D EXPRESSION

Brian R. Cooke, S. W. Annie Bligh, Z. Richard Cybulski, Costas Ioannides and Michael Hall
Drug Metabolism and Disposition January 1, 2012, 40 (1) 70-75; DOI: https://doi.org/10.1124/dmd.111.041566
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