European Journal of Clinical Pharmacology

, Volume 59, Issue 4, pp 303–312 | Cite as

Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population

  • Elena A. GaikovitchEmail author
  • Ingolf Cascorbi
  • Przemyslaw M. Mrozikiewicz
  • Jürgen Brockmöller
  • Roland Frötschl
  • Karla Köpke
  • Thomas Gerloff
  • Jury N. Chernov
  • Ivar Roots
Pharmacokinetics and Disposition



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.


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.


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*1×2/*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.


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.


Cytochrome P450 CYP NAT2 MDR1 Russians Haplotypes 



We thank M. Buchneva, Voronezh, for collection of blood samples. The help of O. Landt (Tib Molbiol) in hybridization probes design is gratefully acknowledged. We appreciate critical reading of the manuscript by Dr. G. Laschinski and Dr. J. Kirchheiner.


  1. 1.
    Meisel C, Roots I, Cascorbi I, Brinkmann U, Brockmöller J (2000) How to manage individualized drug therapy: application of pharmacogenetic knowledge of drug metabolism and transport. Clin Chem Lab Med 38:869–876PubMedGoogle Scholar
  2. 2.
    Nebert DW (2000) Drug-metabolizing enzymes, polymorphisms and interindividual response to environmental toxicants. Clin Chem Lab Med 38:857–861PubMedGoogle Scholar
  3. 3.
    Sachse C, Brockmöller J, Bauer S, Roots I (1997) Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 60:284–295Google Scholar
  4. 4.
    Dahl ML, Johansson I, Bertilsson L, Ingelman Sundberg M, Sjöqvist F (1995) Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis. J Pharmacol Exp Ther 274:516–520PubMedGoogle Scholar
  5. 5.
    Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F, Ingelman-Sundberg M (1996) Frequent distribution of ultrarapid metabolizers of debrisoquine in an ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 278:441–446Google Scholar
  6. 6.
    Aynacioglu AS, Sachse C, Bozkurt A, Kortunay S, Nacak M, Schroder T, Kayaalp SO, Roots I, Brockmöller J (1999) Low frequency of defective alleles of cytochrome P450 enzymes 2C19 and 2D6 in the Turkish population. Clin Pharmacol Ther 66:185–192PubMedGoogle Scholar
  7. 7.
    McLellan RA, Oscarson M, Seidegard J, Evans DA, Ingelman-Sundberg M (1997) Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians. Pharmacogenetics 7:187–191PubMedGoogle Scholar
  8. 8.
    Aynacioglu AS, Brockmöller J, Bauer S, Sachse C, Guzelbey P, Ongen Z, Nacak M, Roots I (1999) Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 48:409–415PubMedGoogle Scholar
  9. 9.
    Kimura M, Ieiri I, Mamiya K, Urae A, Higuchi S (1998) Genetic polymorphism of cytochrome P450 s, CYP2C19, and CYP2C9 in a Japanese population. Ther Drug Monit 20:243–247PubMedGoogle Scholar
  10. 10.
    Wang SL, Huang J, Lai MD, Tsai JJ (1995) Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese. Pharmacogenetics 5:37–42PubMedGoogle Scholar
  11. 11.
    Xie HG, Stein CM, Kim RB, Wilkinson GR, Flockhart DA, Wood AJ (1999) Allelic, genotypic and phenotypic distributions of S-mephenytoin 4'-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics 9:539–549PubMedGoogle Scholar
  12. 12.
    Cascorbi I, Brockmöller J, Roots I (1996) A C4887A polymorphism in exon 7 of human CYP1A1: population frequency, mutation linkages, and impact on lung cancer susceptibility. Cancer Res 56:4965–4969PubMedGoogle Scholar
  13. 13.
    Mrozikiewicz PM, Cascorbi I, Brockmöller J, Roots I (1997) CYP1A1 mutations 4887A, 4889G, 5639C and 6235C in the Polish population and their allelic linkage, determined by peptide nucleic acid-mediated PCR clamping. Pharmacogenetics 7:303–307PubMedGoogle Scholar
  14. 14.
    Inoue K, Asao T, Shimada T (2000) Ethnic-related differences in the frequency distribution of genetic polymorphisms in the CYP1A1 and CYP1B1 genes in Japanese and Caucasian populations. Xenobiotica 30:285–295PubMedGoogle Scholar
  15. 15.
    Cascorbi I, Drakoulis N, Brockmöller J, Maurer A, Sperling K, Roots I (1995) Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: correlation with phenotypic activity. Am J Hum Genet 57:581–592Google Scholar
  16. 16.
    Mrozikiewicz PM, Cascorbi I, Brockmöller J, Roots I (1996) Determination and allelic allocation of seven nucleotide transitions within the arylamine N-acetyltransferase gene in the Polish population. Clin Pharmacol Ther 59:376–382PubMedGoogle Scholar
  17. 17.
    Aynacioglu AS, Cascorbi I, Mrozikiewicz PM, Roots I (1997) Arylamine N-acetyltransferase (NAT2) genotypes in a Turkish population. Pharmacogenetics 7:327–331PubMedGoogle Scholar
  18. 18.
    Lee EJ, Zhao B, Seow-Choen F (1998) Relationship between polymorphism of N-acetyltransferase gene and susceptibility to colorectal carcinoma in a Chinese population. Pharmacogenetics 8:513–517PubMedGoogle Scholar
  19. 19.
    Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmöller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 97:3473–3478PubMedGoogle Scholar
  20. 20.
    Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M, Schaeffeler E, Eichelbaum M, Brinkmann U, Roots I (2001) Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 69:169–174CrossRefPubMedGoogle Scholar
  21. 21.
    Johne A, Kopke K, Gerloff T, Mai I, Rietbrock S, Meisel C, Hoffmeyer S, Kerb R, Fromm MF, Brinkmann U, Eichelbaum M, Brockmoller J, Cascorbi I, Roots I (2002) Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin Pharmacol Ther 72:584–594CrossRefPubMedGoogle Scholar
  22. 22.
    Schaeffeler E, Eichelbaum M, Brinkmann U, Penger A, Asante-Poku S, Zanger UM, Schwab M (2001) Frequency of C3435T polymorphism of MDR1 gene in African people. Lancet 358:383–384CrossRefPubMedGoogle Scholar
  23. 23.
    Ito S, Ieiri I, Tanabe M, Suzuki A, Higuchi S, Otsubo K (2001) Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics 11:175–184CrossRefPubMedGoogle Scholar
  24. 24.
    Ameyaw MM, Regateiro F, Li T, Liu X, Tariq M, Mobarek A, Thornton N, Folayan GO, Githang'a J, Indalo A, Ofori-Adjei D, Price-Evans DA, McLeod HL (2001) MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics 11:217–221CrossRefPubMedGoogle Scholar
  25. 25.
    Marandi T, Dahl ML, Rago L, Kiivet R, Sjöqvist F (1997) Debrisoquine and S-mephenytoin hydroxylation polymorphisms in a Russian population living in Estonia. Eur J Clin Pharmacol 53:257–260PubMedGoogle Scholar
  26. 26.
    Duzhak T, Mitrofanov D, Ostashevskii V, Gutkina N, Chasovnikova O, Posukh O, Osipova L, Lyakhovich VV (2000) Genetic polymorphisms of CYP2D6, CYP1A1, GSTM1 and p53 genes in a unique Siberian population of Tundra Nentsi. Pharmacogenetics 10:531–537CrossRefPubMedGoogle Scholar
  27. 27.
    Cascorbi I, Ackermann E, Sachse C, Brockmöller J, Roots I (1998) A novel CYP2C9 intron 2 T/C transition and linkage to mutations Leu359 and Cys144 (abstract). Clin Pharmacol Ther 63:198Google Scholar
  28. 28.
    de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA (1994) The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 269:15419–15422PubMedGoogle Scholar
  29. 29.
    Borlak J, Thum T (2002) Identification of major CYP2C9 and CYP2C19 polymorphisms by fluorescence resonance energy transfer analysis. Clin Chem 48:1592–1594PubMedGoogle Scholar
  30. 30.
    Smart J, Daly AK (2000) Variation in induced CYP1A1 levels: relationship to CYP1A1, Ah receptor and GSTM1 polymorphisms. Pharmacogenetics 10:11–24CrossRefPubMedGoogle Scholar
  31. 31.
    Leff MA, Fretland AJ, Doll MA, Hein DW (1999) Novel human N-acetyltransferase 2 alleles that differ in mechanism for slow acetylator phenotype. J Biol Chem 274:34519–34522CrossRefPubMedGoogle Scholar
  32. 32.
    Hein D (2002) Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis. Mutat Res 65:506–507Google Scholar
  33. 33.
    Blömeke B, Sieben S, Spotter D, Landt O, Merk HF (1999) Identification of N-acetyltransferase 2 genotypes by continuous monitoring of fluorogenic hybridization probes. Anal Biochem 275:93–97CrossRefPubMedGoogle Scholar
  34. 34.
    Oselin K, Gerloff T, Mrozikiewicz PM, Pähkla R, Roots I (2003) MDR1 polymorphisms G2677T in exon 21 and C3435T in exon 26 fail to affect rhodamine 123 efflux in peripheral blood lymphocytes. Fundam Clin Pharmacol 17:1–7CrossRefPubMedGoogle Scholar
  35. 35.
    Rohde K, Fuerst R (2001) Haplotyping and estimation of haplotype frequencies for closely linked biallelic multilocus genetic phenotypes including nuclear family information. Hum Mutat 17:289–295CrossRefPubMedGoogle Scholar
  36. 36.
    Cascorbi I, Brockmöller J, Bauer S, Reum T, Roots I (1996) NAT2*12A (803A→G) codes for rapid arylamine N-acetylation in humans. Pharmacogenetics 6:257–259PubMedGoogle Scholar
  37. 37.
    Aithal GP, Day CP, Kesteven PJ, Daly AK (1999) Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353:717–719PubMedGoogle Scholar
  38. 38.
    Kirchheiner J, Bauer S, Meineke I, Rohde W, Prang V, Meisel C, Roots I, Brockmöller J (2002) Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kinetics and the insulin and glucose response in healthy volunteers. Pharmacogenetics 12:101–109CrossRefPubMedGoogle Scholar
  39. 39.
    Kirchheiner J, Meineke I, Freytag G, Meisel C, Roots I, Brockmöller J (2002) Enantiospecific effects of cytochrome P450 2C9 amino acid variants on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2. Clin Pharmacol Ther 72:62–75CrossRefPubMedGoogle Scholar
  40. 40.
    Miners JO, Birkett DJ (1998) Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 45:525–538CrossRefPubMedGoogle Scholar
  41. 41.
    Lee CR, Goldstein JA, Pieper JA (2002) Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 12:251–263CrossRefPubMedGoogle Scholar
  42. 42.
    Yasar U, Eliasson E, Dahl ML, Johansson I, Ingelman-Sundberg M, Sjoqvist F (1999) Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 254:628–631PubMedGoogle Scholar
  43. 43.
    Rost KL, Roots I (1996) Nonlinear kinetics after high-dose omeprazole caused by saturation of genetically variable CYP2C19. Hepatology 23:1491–1497PubMedGoogle Scholar
  44. 44.
    Bathum L, Skjelbo E, Mutabingwa TK, Madsen H, Horder M, Brøsen K (1999) Phenotypes and genotypes for CYP2D6 and CYP2C19 in a black Tanzanian population. Br J Clin Pharmacol 48:395–401PubMedGoogle Scholar
  45. 45.
    Xie HG (2000) Genetic variations of S-mephenytoin 4'-hydroxylase (CYP2C19) in the Chinese population. Life Sci 66:L175–L181CrossRefGoogle Scholar
  46. 46.
    Griese EU, Zanger UM, Brudermanns U, Gaedigk A, Mikus G, Mörike K, Stuven T, Eichelbaum M (1998) Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics 8:15–26PubMedGoogle Scholar
  47. 47.
    Schwarz D, Kisselev P, Cascorbi I, Schunck WH, Roots I (2001) Differential metabolism of benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol by human CYP1A1 variants. Carcinogenesis 22:453–459CrossRefPubMedGoogle Scholar
  48. 48.
    Houlston RS (2000) CYP1A1 polymorphisms and lung cancer risk: a meta-analysis. Pharmacogenetics 10:105–114CrossRefPubMedGoogle Scholar
  49. 49.
    Cascorbi I, Brockmöller J, Mrozikiewicz PM, Müller A, Roots I (1999) Arylamine N-acetyltransferase activity in man. Drug Metab Rev 31:489–502CrossRefPubMedGoogle Scholar
  50. 50.
    Okumura K, Kita T, Chikazawa S, Komada F, Iwakawa S, Tanigawara Y (1997) Genotyping of N-acetylation polymorphism and correlation with procainamide metabolism. Clin Pharmacol Ther 61:509–517PubMedGoogle Scholar
  51. 51.
    Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG, Wilkinson GR (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70:189–199Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Elena A. Gaikovitch
    • 1
    • 2
    Email author
  • Ingolf Cascorbi
    • 3
  • Przemyslaw M. Mrozikiewicz
    • 1
  • Jürgen Brockmöller
    • 4
  • Roland Frötschl
    • 1
  • Karla Köpke
    • 1
  • Thomas Gerloff
    • 1
  • Jury N. Chernov
    • 2
  • Ivar Roots
    • 1
  1. 1.Institute of Clinical Pharmacology, University Clinic CharitéHumboldt University of BerlinBerlinGermany
  2. 2.Department of Clinical PharmacologyVoronezh State Medical AcademyVoronezhRussia
  3. 3.Institute of PharmacologyErnst-Moritz-Arndt UniversityGreifswaldGermany
  4. 4.Department of Clinical PharmacologyGeorg-August UniversityGöttingenGermany

Personalised recommendations