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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
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A common genetic basis for idiosyncratic toxicity of warfarin and phenytoin

A E Rettie1, R L Haining, M Bajpai

  • 1Department of Medicinal Chemistry, University of Washington, Seattle 98195, USA.

Epilepsy Research
|July 21, 1999
PubMed

Insights

Genetic mutations in CYP2C9 significantly reduce the metabolism of phenytoin and (S)-warfarin. The CYP2C9*3 variant shows drastically impaired metabolic efficiency, potentially explaining drug toxicities.

Area of Science:

  • Pharmacogenetics
  • Drug Metabolism
  • Enzyme Kinetics

Background:

  • Cytochrome P450 2C9 (CYP2C9) is crucial for metabolizing drugs like phenytoin and (S)-warfarin.
  • Previous studies linked CYP2C9 gene mutations to reduced (S)-warfarin metabolism.

Purpose of the Study:

  • To investigate the impact of CYP2C9 gene mutations on phenytoin metabolism.
  • To characterize the metabolic efficiency of mutant CYP2C9 variants using phenytoin and (S)-warfarin.

Main Methods:

  • Determined kinetic parameters for (S)-pHPPH formation, the primary inactive metabolite of phenytoin.
  • Utilized recombinant CYP2C9 variants (including CYP2C9*3) purified from insect cells.

Main Results:

  • The CYP2C9*3 gene product exhibited only 4-6% of the metabolic efficiency of the wild-type CYP2C9*1.
  • This reduced efficiency was observed for both phenytoin and (S)-warfarin metabolism.

Conclusions:

  • Homozygous expression of CYP2C9*3 significantly impairs the metabolism of phenytoin and (S)-warfarin.
  • This genetic variation may underlie the idiosyncratic toxicities observed with these low therapeutic index drugs.

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