A common genetic basis for idiosyncratic toxicity of warfarin and phenytoin.
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.
Department of Medicinal Chemistry, University of Washington, Seattle 98195, USA.
A E
AE
Rettie
R L
RL
Haining
M
M
Bajpai
R H
RH
Levy
D000818:Animals; D000925:Anticoagulants / Q000633:toxicity*; D000927:Anticonvulsants / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D007313:Insecta; D007700:Kinetics; D010641:Phenotype; D010672:Phenytoin / Q000633:toxicity*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism; D014859:Warfarin / Q000633:toxicity*
D000925:Anticoagulants; D000927:Anticonvulsants; D014859:Warfarin; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase