Genetic analysis of the human cytochrome P450 CYP2C9 locus.
Cytochrome P450 CYP2C9 metabolizes a wide variety of clinically important drugs, including phenytoin, tolbutamide, warfarin and a large number of non-steroidal anti-inflammatory drugs. Previous studies have shown that even relatively conservative changes in the amino acid composition of this enzyme can affect both its activity and substrate specificity. To date six different human CYP2C9 cDNA sequences, as well as the highly homologous CYP2C10 sequence have been reported suggesting that the CYP2C9 gene is polymorphic. Only nine single base substitutions in the coding region of CYP2C9 account for the differences seen between the CYP2C9 proteins. In this report we have developed polymerase chain reaction (PCR)-based assays to distinguish all seven sequences, and have determined their allele frequencies in the Caucasian population. Of the seven sequences studied in one hundred individuals only three appeared to be CYP2C9 alleles. These alleles termed CYP2C9*1, CYP2C9*2 and CYP2C9*3 had allele frequencies of 0.79, 0.125 and 0.085 respectively. The CYP2C10 gene could not be found in any of the samples studied. The assays developed here will allow the prediction of CYP2C9 phenotype, thus identifying those individuals who may exhibit different drug pharmacokinetics for CYP2C9 substrates.
Stubbins
M J
MJ
Biomedical Research Centre, University of Dundee, Ninewells Hospital, Tayside, UK.
Harries
L W
LW
Smith
G
G
Tarbit
M H
MH
Wolf
C R
CR
D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases; D003062:Codon; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017931:DNA Primers; D005787:Gene Frequency; D006801:Humans; D008969:Molecular Sequence Data; D004364:Pharmaceutical Preparations / Q000378:metabolism; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics*; D006113:United Kingdom; D044465:White People
D003062:Codon; D017931:DNA Primers; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase