Effects of the
CYP3A4 intron 6 C>T (
CYP3A4*22) polymorphism, which has recently been reported to have a critical role
in vivo, were investigated by measuring CYP3A4 protein expression levels and CYP3A4-dependent drug oxidation activities in individual human liver microsomes
in vitro. Prior to protein analysis, analysis of DNA samples indicated that 36 Caucasian subjects were genotyped as
CYP3A4*1/*1 and five subjects were
CYP3A4*1/*22, with a
CYP3A4*22 allelic frequency of 6.1%. No
CYP3A4*22 alleles were found in the Japanese samples (106 alleles). Individual differences in CYP2D6-dependent dextromethorphan
O-demethylation activities in liver microsomes from Caucasians were not affected by either the
CYP3A4*1/*22 or
CYP3A5*1/*3 genotype. Liver microsomes genotyped as
CYP3A4*1/*22 (n = 4) showed significantly lower CYP3A-dependent dextromethorphan
N-demethylation, midazolam 1′-hydroxylation, and testosterone 6β-hydroxylation activities, as well as lower expression levels of CYP3A protein (28% of control), compared with those of the
CYP3A4*1/*1 group (n = 19). The other polymorphism,
CYP3A5*1/*3, did not show these differences (n = 4). The
CYP3A4*22 polymorphism was associated with reduced CYP3A4 protein expression levels and resulted in decreased CYP3A4-dependent activities in human livers. The present results suggest an important role of low expression of CYP3A4 protein associated with the
CYP3A4*22 allele in the individual differences in drug clearance.
View full abstract