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Research ArticleArticle

Interindividual Variability and Tissue-Specificity in the Expression of Cytochrome P450 3A mRNA

Ina Koch, Regina Weil, Renzo Wolbold, Jürgen Brockmöller, Elisabeth Hustert, Oliver Burk, Andreas Nuessler, Peter Neuhaus, Michel Eichelbaum, Ulrich Zanger and Leszek Wojnowski
Drug Metabolism and Disposition October 2002, 30 (10) 1108-1114; DOI: https://doi.org/10.1124/dmd.30.10.1108
Ina Koch
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Regina Weil
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Renzo Wolbold
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Jürgen Brockmöller
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Elisabeth Hustert
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Oliver Burk
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Andreas Nuessler
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Peter Neuhaus
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Michel Eichelbaum
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Ulrich Zanger
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Leszek Wojnowski
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Abstract

The elucidation of the individual contributions of the fourCYP3A genes to the overall CYP3A activity has been hampered by similarities in their sequence and function. We investigated the expression of CYP3A mRNA species in the liver and in various other tissues using gene-specific TaqMan probes. CYP3A4 transcripts were the most abundant CYP3A mRNA in each of the 63 white European livers tested and accounted on average for 95% of the combined CYP3A mRNA pool. CYP3A5 and CYP3A7 each contributed on average 2%, whereas CYP3A43 contributed 0.3% transcripts to this pool. Fourteen percent of livers exhibited an increased share of CYP3A5 transcripts (range 4–20%). These livers were either heterozygous for the marker of the CYP3A5 polymorphism, the CYP3A5*1A allele, or expressed very low levels of CYP3A4 mRNA. The CYP3A7 expression was bimodal, and it was increased in 15% livers. CYP3A4 was the dominant CYP3A in the intestine, followed by CYP3A5. CYP3A5 and CYP3A7, but not CYP3A4, were also expressed in the adrenal gland and in the prostate, whereas only CYP3A5 was detected in the kidney. These three tissues were shown to express much lower levels of pregnane X receptor mRNA than the intestine, indicating possibly a different mode of regulation of CYP3A expression. Expression of CYP3A genes was undetectable in peripheral blood lymphocytes. In summary, these assays and results should aid in our efforts to further dissect the regulation and the physiological and pharmacological significance of CYP3A isozymes.

Footnotes

  • ↵1 Present address: Department of Clinical Pharmacology, Georg-August University Goettingen, Robert-Koch-Str. 40, D-37075 Goettingen, Germany. E-mail:Leszek.Wojnowski{at}med.uni-goettingen.de

  • Parts of this work were supported by Grants 01GG9846 and 01GG9848 from the German Federal Ministry for Education and Science (BMBF) and by the Robert Bosch Foundation, Stuttgart, Germany.

  • Abbreviations used are::
    PCR
    polymerase chain reaction
    cDNA
    complementary DNA
    PXR
    pregnane X receptor
    rRNA
    ribosomal RNA
    GAPDH
    glyceraldehyde 3-phosphate dehydrogenase
    HPRT
    hypoxanthine-guanine phosphoribosyl transferase
    TBP
    TATA-box binding protein
    GUS
    β-glucuronidase
    • Received March 20, 2002.
    • Accepted July 2, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (10)
Drug Metabolism and Disposition
Vol. 30, Issue 10
1 Oct 2002
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Research ArticleArticle

Interindividual Variability and Tissue-Specificity in the Expression of Cytochrome P450 3A mRNA

Ina Koch, Regina Weil, Renzo Wolbold, Jürgen Brockmöller, Elisabeth Hustert, Oliver Burk, Andreas Nuessler, Peter Neuhaus, Michel Eichelbaum, Ulrich Zanger and Leszek Wojnowski
Drug Metabolism and Disposition October 1, 2002, 30 (10) 1108-1114; DOI: https://doi.org/10.1124/dmd.30.10.1108

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Research ArticleArticle

Interindividual Variability and Tissue-Specificity in the Expression of Cytochrome P450 3A mRNA

Ina Koch, Regina Weil, Renzo Wolbold, Jürgen Brockmöller, Elisabeth Hustert, Oliver Burk, Andreas Nuessler, Peter Neuhaus, Michel Eichelbaum, Ulrich Zanger and Leszek Wojnowski
Drug Metabolism and Disposition October 1, 2002, 30 (10) 1108-1114; DOI: https://doi.org/10.1124/dmd.30.10.1108
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