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

  • Pharmacokinetics and Disposition
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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 P 450 (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*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.

Conclusion

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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Institute of Clinical Pharmacology, University Clinic Charité, Humboldt University of Berlin, Schumannstrasse 20/21, 10098 , Berlin, Germany

    Elena A. Gaikovitch, Przemyslaw M. Mrozikiewicz, Roland Frötschl, Karla Köpke, Thomas Gerloff & Ivar Roots

  2. Department of Clinical Pharmacology, Voronezh State Medical Academy, Voronezh, Russia

    Elena A. Gaikovitch & Jury N. Chernov

  3. Institute of Pharmacology, Ernst-Moritz-Arndt University, Greifswald, Germany

    Ingolf Cascorbi

  4. Department of Clinical Pharmacology, Georg-August University, Göttingen, Germany

    Jürgen Brockmöller

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  1. Elena A. Gaikovitch
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Correspondence to Elena A. Gaikovitch.

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Gaikovitch, E.A., Cascorbi, I., Mrozikiewicz, P.M. et al. Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol 59, 303–312 (2003). https://doi.org/10.1007/s00228-003-0606-2

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