Common allelic variants of cytochrome P4503A4 and their prevalence in different populations.
Marked interindividual variability in expression of CYP3A4 influences the disposition of many endo- and xenobiotics, including the metabolism of steroids, environmental toxins and therapeutically useful drugs. The present study was designed to determine the genetic basis of CYP3A4 variability. We analysed DNA from 82 individuals with known CYP3A4 phenotype including 53 Caucasians and 21 African-American liver donors, seven individuals who were outliers in CYP3A4 metabolism and five individuals in a family of a poor nifedipine metabolizer. In addition, we analysed DNA from the eight person DNA Polymorphism Discovery Resource subset (Coriell Institute) and 89 individuals representing nine ethnic groups. Five non-synonymous mutations in the coding region of CYP3A4 were observed. CYP3A4*14 (T44C) in exon 1 resulted in an L15P change; CYP3A4*15 (G14387A) in exon 6 resulted in a R162Q substitution; CYP3A4*10 (G14422C) in exon 6 resulted in a D174H substitution; CYP3A4*16 (C15721G) in exon 7 resulted in a T185S amino acid substitution; and CYP3A4*12 (C22002T) in exon 11 resulted in a L373F change in the CYP3A4 protein. An additional six single nucleotide polymorphisms (SNPs) in the 5'-UTR, 13 SNPs in the introns and three SNPs in the 3'-UTR were observed. Extensive population differences were observed in the frequencies of various CYP3A4 alleles. None of the 28 CYP3A4 SNPs identified in CYP3A4 phenotyped persons (most individuals being heterozygous for any CYP3A4 variant) was associated with low hepatic CYP3A4 protein expression or low CYP3A4 activity in vivo.
Lamba
Jatinder K
JK
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Lin
Yvonne S
YS
Thummel
Kenneth
K
Daly
Ann
A
Watkins
Paul B
PB
Strom
Stephen
S
Zhang
Jiong
J
Schuetz
Erin G
EG
D000483:Alleles; D015153:Blotting, Western; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D005006:Ethnicity / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007438:Introns; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015995:Prevalence; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D020506:Untranslated Regions
D020506:Untranslated Regions; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human