Common allelic variants of cytochrome P4503A4 and their prevalence in different populations

Abstract

Marked interindividual variability in expression of CYP3A4 influences the disposition of many endo- and xenobiotics, including the metabolism of steroids, environmental toxins and therapeutically useful drugs. The present study was designed to determine the genetic basis of CYP3A4 variability. We analysed DNA from 82 individuals with known CYP3A4 phenotype including 53 Caucasians and 21 African-American liver donors, seven individuals who were outliers in CYP3A4 metabolism and five individuals in a family of a poor nifedipine metabolizer. In addition, we analysed DNA from the eight person DNA Polymorphism Discovery Resource subset (Coriell Institute) and 89 individuals representing nine ethnic groups. Five non-synonymous mutations in the coding region of CYP3A4 were observed. CYP3A4*14 (T44C) in exon 1 resulted in an L15P change; CYP3A4*15 (G14387A) in exon 6 resulted in a R162Q substitution; CYP3A4*10 (G14422C) in exon 6 resulted in a D174H substitution; CYP3A4*16 (C15721G) in exon 7 resulted in a T185S amino acid substitution; and CYP3A4*12 (C22002T) in exon 11 resulted in a L373F change in the CYP3A4 protein. An additional six single nucleotide polymorphisms (SNPs) in the 5'-UTR, 13 SNPs in the introns and three SNPs in the 3'-UTR were observed. Extensive population differences were observed in the frequencies of various CYP3A4 alleles. None of the 28 CYP3A4 SNPs identified in CYP3A4 phenotyped persons (most individuals being heterozygous for any CYP3A4 variant) was associated with low hepatic CYP3A4 protein expression or low CYP3A4 activity in vivo.

Polymorphisms of drug‐metabolizing enzymes and risk of childhood acute lymphoblastic leukemia

“…Felix et al [8] have reported that patients with CYP 3A4 wild type receiving epipodophyllotoxin are at increased risk for treatment-related leukemia. Because the frequency of CYP 3A4*1B is very low in Asians, it is not surprising that the effect of this polymorphism is not seen in Japanese patients with acute myeloid leukemia, treatment-related leukemias, or myelodysplastic syndrome [21,22]. Similar to the Japanese study, we showed that the frequency of the CYP 3A4*1B allele was only 0.8% in Thais, and no homozygous variant was found.…”

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

“…19 Polymorphisms in the CYP3A enzyme family were not considered, since CYP3A4 genetic variants have little effects on function or are rare in most populations. 20 Whether or not the polymorphisms in CYP3A5 and CYP3A7 play a medically relevant role is questionable since expression levels are low and a psychotropic drug selectively metabolized by either CYP3A5 or CYP3A7, but not by CYP3A4, still remains to be identified. 21 Studies using CYP inhibiting substances such as quinidine to mimic poor metabolizer status were not included.…”

The effect of CYP3A5 polymorphism on dose-adjusted cyclosporine concentration in renal transplant recipients: a meta-analysis

“…7 Although a number of singlenucleotide polymorphisms for CYP3A4 have been identified, most of them are rare and not reported to affect its activity. 8 Inversely, CYP3A5 is polymorphically expressed with high activity in 50% of African Americans and in approximately 30% of Caucasians. 9 Therefore, the variable expression of CYP3A5 was supposed to be an important reason for inter-individual pharmacokinetic variability of CsA.…”