Population Distribution and Effects on Drug Metabolism of a Genetic Variant in the 5' Promoter Region of CYP3A4

Clin Pharmacol Ther. 1999 Sep;66(3):288-94. doi: 10.1016/S0009-9236(99)70037-8.

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.

MeSH terms

  • African Continental Ancestry Group / genetics
  • Area Under Curve
  • Asian Continental Ancestry Group / genetics
  • Breath Tests
  • Calcium Channel Blockers / metabolism
  • Continental Population Groups / genetics*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • DNA Primers
  • Erythromycin / metabolism
  • European Continental Ancestry Group / genetics
  • Genotype
  • Hispanic Americans / genetics
  • Humans
  • Mixed Function Oxygenases / genetics*
  • Nifedipine / metabolism
  • Phenotype
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic / genetics*
  • Protein Synthesis Inhibitors / metabolism
  • Reference Values

Substances

  • Calcium Channel Blockers
  • DNA Primers
  • Protein Synthesis Inhibitors
  • Erythromycin
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Nifedipine