title: Population distribution and effects on drug metabolism of a genetic variant in the 5' promoter region of CYP3A4.
abstract: BACKGROUND
  There are large interindividual differences in CYP3A4 expression and in the metabolism of drug substrates for this enzyme. We and others have identified a polymorphism in the 5' promotor region of the CYP3A4 gene; however, its functional significance is not currently known. This study was conducted to determine whether this polymorphism plays a clinically important role in determining CYP3A4 phenotype.
  
  
  METHODS
  An adenine (A) to guanine (G) transition was identified in the 5' promotor region of the CYP3A4 gene at position -292 (from the start codon), in a sequence motif known as the nifedipine-specific element. The frequency of this polymorphism was assessed in 802 healthy volunteers from five broadly defined racial groups. The population distribution of the G allele in these groups was as follows: white Americans (3.6%; n = 273), black Americans (54.6%, n = 186), Hispanic Americans (9.3%; n = 188), Japanese Americans (0.0%; n = 77), and Chinese Americans (0.0%; n = 78). In a subsequent study, 90 additional black Americans were genotyped, and a subset of the homozygous subjects (AA, n = 8; GG, n = 23) were given the CYP3A4 probe substrates erythromycin and nifedipine to allow genotype-phenotype comparisons to be made.
  
  
  RESULTS
  There was no difference in the rate of CYP3A4-dependent demethylation of erythromycin (erythromycin breath test) or the pharmacokinetics of nifedipine or its CYP3A4-dependent metabolite dehydronifedipine between the two genotype groups (AA or GG).
  
  
  CONCLUSIONS
  This promotor region polymorphism does not appear to play a major role in determining constitutive CYP3A4 expression.
authors.affiliation: Drug Metabolism Division, Wyeth-Ayerst Research, Princeton, NJ 08540-8000, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Ball
authors.forename: J
authors.initials: J
authors.lastname: Scatina
authors.forename: J
authors.initials: J
authors.lastname: Kao
authors.forename: G M
authors.initials: GM
authors.lastname: Ferron
authors.forename: R
authors.initials: R
authors.lastname: Fruncillo
authors.forename: P
authors.initials: P
authors.lastname: Mayer
authors.forename: I
authors.initials: I
authors.lastname: Weinryb
authors.forename: M
authors.initials: M
authors.lastname: Guida
authors.forename: P J
authors.initials: PJ
authors.lastname: Hopkins
authors.forename: N
authors.initials: N
authors.lastname: Warner
authors.forename: J
authors.initials: J
authors.lastname: Hall
mesh_terms: D019540:Area Under Curve; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D001944:Breath Tests; D002121:Calcium Channel Blockers / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017931:DNA Primers; D004917:Erythromycin / Q000378:metabolism; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009543:Nifedipine / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D044469:Racial Groups / Q000235:genetics*; D012016:Reference Values; D044465:White People / Q000235:genetics; D001741:Black or African American
chemical_list: D002121:Calcium Channel Blockers; D017931:DNA Primers; D011500:Protein Synthesis Inhibitors; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009543:Nifedipine