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Research ArticleArticle

CYP2C9-CYP3A4 Protein-Protein Interactions: Role of the Hydrophobic N Terminus

Murali Subramanian, Harrison Tam, Helen Zheng and Timothy S. Tracy
Drug Metabolism and Disposition June 2010, 38 (6) 1003-1009; DOI: https://doi.org/10.1124/dmd.109.030155
Murali Subramanian
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Harrison Tam
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Helen Zheng
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Timothy S. Tracy
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Abstract

Cytochromes P450 (P450s) interact with redox transfer proteins, including P450 reductase (CPR) and cytochrome b5 (b5), all being membrane-bound. In multiple in vitro systems, P450-P450 interactions also have been observed, resulting in alterations in enzymatic activity. The current work investigated the effects and mechanisms of interaction between CYP2C9 and CYP3A4 in a reconstituted system. CYP2C9-mediated metabolism of S-naproxen and S-flurbiprofen was inhibited up to 80% by coincubation with CYP3A4, although Km values were unchanged. Increasing CYP3A4 concentrations increased the degree of inhibition, whereas increasing CPR concentrations resulted in less inhibition. Addition of b5 only marginally affected the magnitude of inhibition. In contrast, CYP2C9 did not alter the CYP3A4-mediated metabolism of testosterone. The potential role of the hydrophobic N terminus on these interactions was assessed by incubating truncated CYP2C9 with full-length CYP3A4, and vice versa. In both cases, the inhibition was fully abolished, indicating an important role for hydrophobic forces in CYP2C9-CYP3A4 interactions. Finally, a CYP2C9/CYP3A4 heteromer complex was isolated by coimmunoprecipitation techniques, confirming the physical interaction of the proteins. These results show that the N-terminal membrane binding domains of CYP2C9 and CYP3A4 are involved in heteromer complex formation and that at least one consequence is a reduction in CYP2C9 activity.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM063215, GM086891].

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

    doi:10.1124/dmd.109.030155.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    CPR
    cytochrome P450 reductase
    b5
    cytochrome b5
    DOPC
    l-α-dioleoyl-sn-gly-cero-3-phosphocholine
    TBST
    Tris-buffered saline/Tween
    DHT
    dihydrotestosterone
    TST
    testosterone
    rCPR
    rat cytochrome P450 reductase
    hCPR
    human cytochrome P450 reductase
    CYP2C9(t)
    truncated CYP2C9
    CYP3A4(t)
    truncated CYP3A4.

  • Received September 4, 2009.
  • Accepted March 9, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (6)
Drug Metabolism and Disposition
Vol. 38, Issue 6
1 Jun 2010
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Research ArticleArticle

CYP2C9-CYP3A4 Protein-Protein Interactions: Role of the Hydrophobic N Terminus

Murali Subramanian, Harrison Tam, Helen Zheng and Timothy S. Tracy
Drug Metabolism and Disposition June 1, 2010, 38 (6) 1003-1009; DOI: https://doi.org/10.1124/dmd.109.030155

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Research ArticleArticle

CYP2C9-CYP3A4 Protein-Protein Interactions: Role of the Hydrophobic N Terminus

Murali Subramanian, Harrison Tam, Helen Zheng and Timothy S. Tracy
Drug Metabolism and Disposition June 1, 2010, 38 (6) 1003-1009; DOI: https://doi.org/10.1124/dmd.109.030155
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