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Research ArticleArticle

Natural Protein Variants of Pregnane X Receptor with Altered Transactivation Activity Toward CYP3A4

Elisabeth Hustert, Arne Zibat, Elena Presecan-Siedel, Regina Eiselt, Romy Mueller, Christine Fuß, Ilka Brehm, Ulrich Brinkmann, Michel Eichelbaum, Leszek Wojnowski and Oliver Burk
Drug Metabolism and Disposition November 2001, 29 (11) 1454-1459;
Elisabeth Hustert
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Arne Zibat
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Elena Presecan-Siedel
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Regina Eiselt
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Romy Mueller
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Christine Fuß
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Ilka Brehm
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Ulrich Brinkmann
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Michel Eichelbaum
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Leszek Wojnowski
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Oliver Burk
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Abstract

Between 45 and 60% of all drugs currently used are metabolized by the CYP3A4 protein. CYP3A4 expression in liver varies up to 60-fold in the general population, which can lead to ineffective drug therapy (high CYP3A4) or, on the other hand, to harmful drug reactions (low CYP3A4). Most of this variability has been attributed to genetic factors, but to date their identity remains unknown. Recently, it was shown that CYP3A expression is largely controlled by the pregnane X receptor (PXR). We, therefore, hypothesized that polymorphisms in PXR may contribute to CYP3A4 variability. The presence of PXR variants was investigated in two ethnic groups, Caucasians and Africans. Six missense mutations leading to variant PXR proteins were identified, and their consequences on CYP3A4 expression were analyzed. Expressed in LS174T cells, three protein variants, V140M, D163G, and A370T, exhibited altered basal and/or induced transactivation of CYP3A promoter reporter genes. Thus, these natural PXR protein variants may play a role in the observed interindividual variability of CYP3A4 expression and may be involved in rare, atypical responses to drugs or altered sensitivities to carcinogens.

Footnotes

  • This work was supported in parts by the Deutsche Forschungsgemeinschaft (Germany), Grant Bu 1249/1–1 (to O.B.), by the Robert Bosch Foundation (Germany), and by Grant 01GG9848–15 from the German Ministry for Education, Science, Research, and Technology.

  • Abbreviations used are::
    CYP
    cytochrome P450
    PXR
    pregnane X receptor
    bp
    base pair
    PCR
    polymerase chain reaction
    DMSO
    dimethyl sulfoxide
    BAC
    bacterial artificial chromosome
    LBD
    ligand-binding domain
    TK
    thymidine kinase
    • Received May 25, 2001.
    • Accepted August 6, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (11)
Drug Metabolism and Disposition
Vol. 29, Issue 11
1 Nov 2001
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Research ArticleArticle

Natural Protein Variants of Pregnane X Receptor with Altered Transactivation Activity Toward CYP3A4

Elisabeth Hustert, Arne Zibat, Elena Presecan-Siedel, Regina Eiselt, Romy Mueller, Christine Fuß, Ilka Brehm, Ulrich Brinkmann, Michel Eichelbaum, Leszek Wojnowski and Oliver Burk
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1454-1459;

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Research ArticleArticle

Natural Protein Variants of Pregnane X Receptor with Altered Transactivation Activity Toward CYP3A4

Elisabeth Hustert, Arne Zibat, Elena Presecan-Siedel, Regina Eiselt, Romy Mueller, Christine Fuß, Ilka Brehm, Ulrich Brinkmann, Michel Eichelbaum, Leszek Wojnowski and Oliver Burk
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1454-1459;
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