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Clin Pharmacol Ther. 1999 Sep;66(3):288-94.

Population distribution and effects on drug metabolism of a genetic variant in the 5' promoter region of CYP3A4.

Author information

1
Drug Metabolism Division, Wyeth-Ayerst Research, Princeton, NJ 08540-8000, USA.

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.

PMID:
10511065
DOI:
10.1016/S0009-9236(99)70037-8
[Indexed for MEDLINE]

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