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Research ArticleMetabolism, Transport, and Pharmacogenomics

Estimation of Drug-Metabolizing Capacity by Cytochrome P450 Genotyping and Expression

Manna Temesvári, László Kóbori, József Paulik, Enikő Sárváry, Ales Belic and Katalin Monostory
Journal of Pharmacology and Experimental Therapeutics April 2012, 341 (1) 294-305; DOI: https://doi.org/10.1124/jpet.111.189597
Manna Temesvári
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László Kóbori
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József Paulik
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Enikő Sárváry
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Ales Belic
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Katalin Monostory
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Abstract

Many undesired side effects or therapeutic failures of drugs are the result of differences or changes in drug metabolism, primarily depending on the levels and activities of cytochrome P450 (P450) enzymes. To assess whether P450 expression profiles can reflect hepatic drug metabolism, we compared P450 mRNA levels in the liver or peripheral leukocytes with the corresponding hepatic P450 activities. A preliminary P450 genotyping for the most frequent polymorphisms in white populations (CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2D6*3, CYP2D6*4, CYP2D6*6, and CYP3A5*3) was carried out before P450 phenotyping, excluding the donors with nonfunctional alleles of CYP2C9, CYP2C19, and CYP2D6 and those with a functional CYP3A5*1 allele from a correlation analysis. The hepatic mRNA levels of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 displayed a strong association with P450 activities in the liver, whereas the expression of CYP1A2, CYP2C9, CYP2C19, and CYP3A4 in leukocytes was proven to reflect the hepatic activities of these P450 species. The leukocytes were found to be inappropriate cells for the assessment of hepatic CYP2B6 and CYP2D6 activities. Combining the results of P450 genotyping and phenotyping analyses, patients' drug-metabolizing capacities can be estimated by the P450 expression in the liver and in leukocytes with some limitations. Patients' genetic and nongenetic variations in P450 status can guide the appropriate selection of drugs and the optimal dose, minimizing the risk of harmful side effects and ensuring a successful outcome of drug therapy.

Footnotes

  • This study was supported by the National Development Agency [Grant GOP-1.1.1-09/1-2009-0001], Slovenian-Hungarian Intergovernmental S&T Cooperation Programme [TÉT_10-1-2011-0616], and the Medical Research Council of Hungary [Grant ETT 099-03/2009].

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

    http://dx.doi.org/10.1124/jpet.111.189597.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    GAPDH
    glyceraldehyde 3-phosphate dehydrogenase
    SNP
    single-nucleotide polymorphism
    PCR
    polymerase chain reaction
    CI
    confidence interval
    QD
    quartile deviation.

  • Received November 16, 2011.
  • Accepted January 18, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 341 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 1
1 Apr 2012
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Estimation of Drug-Metabolizing Capacity

Manna Temesvári, László Kóbori, József Paulik, Enikő Sárváry, Ales Belic and Katalin Monostory
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 294-305; DOI: https://doi.org/10.1124/jpet.111.189597

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Estimation of Drug-Metabolizing Capacity

Manna Temesvári, László Kóbori, József Paulik, Enikő Sárváry, Ales Belic and Katalin Monostory
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 294-305; DOI: https://doi.org/10.1124/jpet.111.189597
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