title: Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population.
abstract: OBJECTIVE
  The frequency of functionally important mutations and alleles of genes coding for xenobiotic metabolizing enzymes shows a wide ethnic variation. However, little is known of the frequency distribution of the major allelic variants in the Russian population.
  
  
  METHODS
  Using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) genotyping assays and the real-time PCR with fluorescent probes, the frequencies of functionally important variants of the cytochromes P450 (CYP) 2C9, 2C19, 2D6, 1A1 as well as arylamine N-acetyltransferase 2 (NAT2) and P-glycoprotein (MDR1) were determined in a sample of 290 Russian volunteers derived from Voronezh area.
  
  
  RESULTS
  CYP2C9*2 and * 3 alleles were found with allelic frequencies of 10.5% and 6.7%, respectively. The novel intron-2 T>C mutation at exon 2 +73 bp occurred in 24.8% of alleles. CYP2C19*2 and *3 alleles occurred in 11.4% and 0.3%, respectively. Six persons (2.1%) carried two of these CYP2C19 alleles responsible for poor metabolizing activity. Of all subjects, 5.9% were CYP2D6 poor metabolizers, whereas 3.4% were addressed to ultra-rapid metabolizers (CYP2D6*1x2/*1). The CYP1A1*2A allele was found in 4.7%, *2B in 5.0%, *4 in 2.6%, and the 5'-mutations -3219C>T, -3229G>A, and the novel -4335G>A in 6.0%, 2.9% and 26.0% of alleles, respectively. Genotyping of eight different single nucleotide polymorphisms in the NAT2 gene provided in 58.0% a genotype associated with slow acetylation. The MDR1 triple variants G2677T and G2677A in exon 21 had an allelic frequency of 41.9% and 3.3%, respectively, and the variant C3435T in exon 26 one of 54.3%. Frequencies of functionally important haplotypes were calculated.
  
  
  CONCLUSIONS
  The overview of allele distribution of important xenobiotic-metabolizing enzymes among a Russian population shows similarity to other Caucasians. The data will be useful for clinical pharmacokinetic investigations and for drug dosage recommendations in the Russian population.
authors.affiliation: Institute of Clinical Pharmacology, University Clinic Charité, Humboldt University of Berlin, Schumannstrasse 20/21, 10098 Berlin, Germany. elena.gaikovitch@charite.de
authors.forename: Elena A
authors.initials: EA
authors.lastname: Gaikovitch
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
authors.forename: Przemyslaw M
authors.initials: PM
authors.lastname: Mrozikiewicz
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brockmöller
authors.forename: Roland
authors.initials: R
authors.lastname: Frötschl
authors.forename: Karla
authors.initials: K
authors.lastname: Köpke
authors.forename: Thomas
authors.initials: T
authors.lastname: Gerloff
authors.forename: Jury N
authors.initials: JN
authors.lastname: Chernov
authors.forename: Ivar
authors.initials: I
authors.lastname: Roots
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D011110:Polymorphism, Genetic; D012426:Russia; D044465:White People / Q000235:genetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D019363:Cytochrome P-450 CYP1A1; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human