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Research ArticleArticle

THE IMPACT OF CYP2C9 GENETICS AND ORAL CONTRACEPTIVES ON CYTOCHROME P450 2C9 PHENOTYPE

Mia Sandberg, Inger Johansson, Magnus Christensen, Anders Rane and Erik Eliasson
Drug Metabolism and Disposition May 2004, 32 (5) 484-489; DOI: https://doi.org/10.1124/dmd.32.5.484
Mia Sandberg
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Inger Johansson
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Magnus Christensen
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Anders Rane
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Erik Eliasson
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Abstract

CYP2C9-dependent drug metabolism is subject to large interindividual variation. To some extent, this is explained by genetic polymorphism with expression of enzyme variants that differ in catalytic activity. The aim of this study was to characterize the variation in CYP2C9 phenotype in relation to genotype, with further analysis of the CYP2C9 gene in metabolic outliers. A study population of 126 healthy white subjects were recruited and genotyped for the variant alleles, CYP2C9*1–3. In CYP2C9 phenotyping with losartan, three subpopulations were distinguished that differed in the number of CYP2C9*3 alleles (0, 1, or 2). A three-fold higher metabolic ratio (MR; urinary losartan/carboxymetabolite) was found comparing CYP2C9*1/*3 (n = 20) to CYP2C9*1/*1 (n = 81), but there was considerable variation within each genotype. Subjects genotyped as CYP2C9*1/*1, but with an unexpectedly slow oxidation of losartan, were selected for DNA-sequencing analysis of the CYP2C9 gene. Interestingly, single nucleotide polymorphisms (SNPs) could not be identified either in the 5′-flanking region, the nine exons, or exon-intron boundaries. However, sequencing of the CYP2C9 gene was also carried out in patients genotyped as CYP2C9*1/*1 but with an exceptionally low steady-state clearance of S-warfarin. Here, five different SNPs were identified. In further analysis of the healthy volunteers, it became evident that women on oral contraceptives (OCs) had slower oxidation of losartan (MR of losartan: 1.7) than women without OCs (MR of losartan: 0.86). This novel finding was not explained by a different frequency of variant alleles. In summary, CYP2C9 genotype and oral contraceptives both contribute to a large interindividual variation in CYP2C9 activity.

Footnotes

  • ↵1 Abbreviations used are: PCR, polymerase chain reaction; ANOVA, analysis of variance; MR, metabolic ratio; OC, oral contraceptive; SNP, single nucleotide polymorphism.

  • This work was supported by grants from the Swedish Science Council, (Medical Research Council Grants 4496 and 5949), and from the National Institutes of Health (National Institute of General Medical Services Grant 1-R01 G60548-01A2) and Pfizer Ltd., Sandwich, UK. E.E. is a recipient of a Merck Sharp & Dohme (Sweden) fellowship and a Pfizer AB research stipend in clinical pharmacology.

  • Part of this work has been presented at the Pharmacogenetics Meeting, 24–28 September, 2003, in Hinxton, Great Britain.

    • Received November 17, 2003.
    • Accepted January 30, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (5)
Drug Metabolism and Disposition
Vol. 32, Issue 5
1 May 2004
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Research ArticleArticle

THE IMPACT OF CYP2C9 GENETICS AND ORAL CONTRACEPTIVES ON CYTOCHROME P450 2C9 PHENOTYPE

Mia Sandberg, Inger Johansson, Magnus Christensen, Anders Rane and Erik Eliasson
Drug Metabolism and Disposition May 1, 2004, 32 (5) 484-489; DOI: https://doi.org/10.1124/dmd.32.5.484

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Research ArticleArticle

THE IMPACT OF CYP2C9 GENETICS AND ORAL CONTRACEPTIVES ON CYTOCHROME P450 2C9 PHENOTYPE

Mia Sandberg, Inger Johansson, Magnus Christensen, Anders Rane and Erik Eliasson
Drug Metabolism and Disposition May 1, 2004, 32 (5) 484-489; DOI: https://doi.org/10.1124/dmd.32.5.484
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