3 research outputs found
CYP3A5 variant allele frequencies in Dutch Caucasians
BACKGROUND: Enzymes of the cytochrome P450 3A (CYP3A) family are
responsible for the metabolism of >50% of currently prescribed drugs.
CYP3A5 is expressed in a limited number of individuals. The absence of
CYP3A5 expression in approximately 70% of Caucasians was recently
correlated to a genetic polymorphism (CYP3A5*3). Because CYP3A5 may
represent up to 50% of total CYP3A protein in individuals polymorphically
expressing CYP3A5, it may have a major role in variation of CYP3A-mediated
drug metabolism. Using sequencing, have been identified (Hustert et al.
Pharmacogenetics 2001;11:773-9; Kuehl et al. Nat Genet 2001;27:383-91)
variant alleles *2 through *7 for CYP3A5. Detection of CYP3A5 variant
alleles, and knowledge about their allelic frequency in specific ethnic
groups, is important to establish the clinical relevance of screening for
these polymorphisms to optimize pharmacotherapy. METHODS: In a group of
500 healthy Dutch Caucasian blood donors, we determined the allelic
frequency of the CYP3A5*2, *3, *4, *5, *6, and *7 alleles by use of newly
developed PCR-restriction fragment length polymorphism assays. RESULTS:
The frequency of the defective CYP3A5*3 allele in the Dutch Caucasian
population was 91%, followed by the CYP3A5*2 (1%) and CYP3A5*6 (0.1%)
alleles. The CYP3A5*4, *5, and *7 alleles were not detected. CONCLUSIONS:
On the basis of its allelic frequency, screening for the CYP3A5*3 allele
in the Caucasian population is extremely relevant. In addition, screening
for the CYP3A5*2 allele may be taken into consideration in individuals
heterozygous for the CYP3A5*3 allele. The CYP3A5*4, *5, *6, and *7 alleles
have low allelic frequencies that do not support initial screening
A new CYP3A5 variant, CYP3A5*11, is shown to be defective in nifedipine metabolism in a recombinant cDNA expression system
A new CYP3A5 variant, CYP3A5*11, was found in a white European subject by DNA sequencing. The CYP3A5*11 allele contains a single nucleotide polymorphism (SNP) (g.3775A>G) in exon 2, which results in a Tyr53Cys substitution, and a g.6986A>G splice change, the latter SNP previously reported in the defective CYP3A5*3 allele. However, the CYP3A5*3 is not a null allele because this variant is associated with leaky splicing, resulting in small amounts of functional protein still being produced. Therefore, we constructed a cDNA coding for the newly identified CYP3A5.11 protein by site-directed mutagenesis, expressed it in Escherichia coli, and partially purified it. Whereas bacteria transformed with wild-type CYP3A5*1 cDNA expressed predominantly cytochrome P450 (P450), those transfected with CYP3A5*11 expressed a significant amount of denatured cytochrome P420 in addition to P450, suggesting the protein to be unstable. CYP3A5.11 exhibited a 38% decrease in the Vmaxfor nifedipine metabo