Population distribution and effects on drug metabolism of a genetic variant in the 5' promoter region of CYP3A4.
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.
Ball
S E
SE
Drug Metabolism Division, Wyeth-Ayerst Research, Princeton, NJ 08540-8000, USA.
Scatina
J
J
Kao
J
J
Ferron
G M
GM
Fruncillo
R
R
Mayer
P
P
Weinryb
I
I
Guida
M
M
Hopkins
P J
PJ
Warner
N
N
Hall
J
J
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
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