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Rapid CommunicationShort Communication

CYP3A5 Genotype-Phenotype Analysis in the Human Kidney Reveals a Strong Site-Specific Expression of CYP3A5 in the Proximal Tubule in Carriers of the CYP3A5*1 Allele

Juliane Bolbrinker, Stefanie Seeberg, Martin Schostak, Carsten Kempkensteffen, Hans Baelde, Emile de Heer and Reinhold Kreutz
Drug Metabolism and Disposition April 2012, 40 (4) 639-641; DOI: https://doi.org/10.1124/dmd.111.042648
Juliane Bolbrinker
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Stefanie Seeberg
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Martin Schostak
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Carsten Kempkensteffen
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Hans Baelde
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Emile de Heer
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Reinhold Kreutz
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Abstract

Interindividual variability in the drug-metabolizing activity of the CYP3A5 enzyme is mainly due to a single nucleotide polymorphism in CYP3A5, leading to low expression in homozygous CYP3A5*3/*3 individuals compared with CYP3A5*1 allele carriers. In the human kidney, expression of CYP3A5 has been implicated in blood pressure regulation and calcineurin inhibitor-associated nephrotoxicity. The effect of the CYP3A5*1/*3 polymorphism on the expression level and protein distribution within the human kidney is not well characterized. Therefore, we performed a genotype-phenotype analysis of CYP3A5 mRNA and protein expression in the human kidney. To this end, we analyzed sections of normal kidney tissue obtained from 93 white individuals undergoing nephrectomy by quantitative mRNA expression analysis. Qualitative protein expression analysis of CYP3A5 was performed by immunohistochemistry. Mean renal mRNA expression of carriers of the CYP3A5*1 (n = 12) allele was more than 18-fold higher than that of CYP3A5*3/*3 carriers (n = 81, p < 0.001). Immunohistochemical analysis demonstrated CYP3A5 protein in all epithelia of the nephron in kidney sections with the CYP3A5*3/*3 genotype. In carriers of the CYP3A5*1 allele, a strong increase in protein expression of CYP3A5 was detected, and this was confined to the proximal tubule. This study confirms a significant effect of the CYP3A5*1/*3 polymorphism on CYP3A5 expression in the normal human kidney and reveals a strong nephron segment-specific difference in the CYP3A5 protein expression limited to the proximal tubule.

Footnotes

  • This study was supported by the Deutsche Hochdruckliga.

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

    http://dx.doi.org/10.1124/dmd.111.042648.

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

  • ABBREVIATIONS:

    ABCB1
    ATP-binding cassette, subfamily B, member 1
    HMBS
    hydroxymethylbilane synthase.

  • Received September 5, 2011.
  • Accepted January 3, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (4)
Drug Metabolism and Disposition
Vol. 40, Issue 4
1 Apr 2012
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Rapid CommunicationShort Communication

CYP3A5 GENOTYPE-PHENOTYPE CORRELATION IN THE HUMAN KIDNEY

Juliane Bolbrinker, Stefanie Seeberg, Martin Schostak, Carsten Kempkensteffen, Hans Baelde, Emile de Heer and Reinhold Kreutz
Drug Metabolism and Disposition April 1, 2012, 40 (4) 639-641; DOI: https://doi.org/10.1124/dmd.111.042648

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Rapid CommunicationShort Communication

CYP3A5 GENOTYPE-PHENOTYPE CORRELATION IN THE HUMAN KIDNEY

Juliane Bolbrinker, Stefanie Seeberg, Martin Schostak, Carsten Kempkensteffen, Hans Baelde, Emile de Heer and Reinhold Kreutz
Drug Metabolism and Disposition April 1, 2012, 40 (4) 639-641; DOI: https://doi.org/10.1124/dmd.111.042648
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