title: CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with reduced CYP3A4 protein level and function in human liver microsomes.
abstract: 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.
authors.affiliation: Showa Pharmaceutical University, Tokyo, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Okubo
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shimada
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D000483:Alleles; D044466:Asian People; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics*; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism*; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011110:Polymorphism, Genetic
chemical_list: D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human