A common genetic basis for idiosyncratic toxicity of warfarin and phenytoin

Epilepsy Res. 1999 Jul;35(3):253-5. doi: 10.1016/s0920-1211(99)00017-0.


CYP2C9 is mainly responsible for the metabolic clearance of phenytoin and (S)-warfarin. We have shown previously that mutations in the CYP2C9 gene are associated with diminished metabolism of (S)-warfarin, and so we have now studied the metabolism of phenytoin to its primary inactive metabolite, (S)-pHPPH, by these mutant enzymes. Kinetic parameters were determined for (S)-pHPPH formation using recombinant CYP2C9 variants purified from insect cells. The data demonstrate that the CYP2C9*3 gene product retains only 4-6% of the metabolic efficiency of the wild-type protein, CYP2C9*1, towards phenytoin and (S)-warfarin. Consequently, we suggest that homozygous expression of CYP2C9*3 may represent a common genetic basis for (apparently) idiosyncratic toxicities that have been reported for these two low therapeutic index drugs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anticoagulants / toxicity*
  • Anticonvulsants / toxicity*
  • Aryl Hydrocarbon Hydroxylases*
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • Genotype
  • Insecta
  • Kinetics
  • Phenotype
  • Phenytoin / toxicity*
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / genetics*
  • Steroid Hydroxylases / metabolism
  • Warfarin / toxicity*


  • Anticoagulants
  • Anticonvulsants
  • Warfarin
  • Phenytoin
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • Steroid 16-alpha-Hydroxylase