GENETIC POLYMORPHISM OF CYTOCHROMES P450 2C9 AND 2C19 IN SLOVENIAN POPULATION
Keywords:
pharmacogenetic, genotyping, CYP2C9, CYP2C19Abstract
Background. Cytochrome P450 2C9 (CYP2C9) and 2C19 (CYP2C19) participate in metabolism of many clinically important drugs. Genetic polymorphisms of the CYP2C9 and CYP2C19 genes are described which may affect drug treatment. The aim of this study was to determine the frequencies of polymorphic CYP2C9 and CYP2C19 alleles in Slovenian population in order to estimate the proportion of the population that might experience adverse drug reaction.
Methods. The polymorphism of CYP2C9 and CYP2C19 was analysed by a genotyping technique, based on polymerase chain reaction (PCR) followed by restriction enzyme analysis. DNA samples from 129 unrelated healthy subjects were obtained from the Blood Transfusion Centre of Slovenia and University Children’s Hospital in Ljubljana.
Results. In the analysed group of samples one-third of individuals carried at least one of the defective CYP2C9 alleles while among them 3.2% of individuals had both alleles affected. The frequencies of CYP2C9*2 and CYP2C9*3 were 0.122 and 0.063, respectively. Almost one-third of Slovenian individuals analysed carried at least one of the CYP2C19 polymorphic allele. The frequencies of CYP2C19*2 and CYP2C19*3 were 0.159 and 0.004, respectively.
Conclusions. The results of our study indicate that approximately one-third of the patients from Slovenian population may require either adjustments of dose or increased monitoring when initiating treatment with CYP2C9 and CYP2C19 substrates having a narrow therapeutic index. High risk of adverse drug reaction may be expected in 1–3% of eventual patients.
Downloads
References
Nelson DR, Koymans L, Kamataki T et al. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996; 6: 1–42.
Gray IC, Nobile C, Muresu R, Ford S, Spurr NK. A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24. Genomics 1995; 28: 328–32.
Goldstein JA, de Morais SMF. Biochemistry and molecular biology of human CYP2C subfamily. Pharmacogenetics 1994; 4: 285–99.
Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717–19.
Van der Weide J, Steijns LS, van Weelden MJ, de Haan K. The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement. Pharmacogenetics 2001; 11: 287–91.
Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000; 96: 1816–9.
Margaglione M, Colaizzo D, D’Andrea G et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 2000; 84: 775–8.
Ingelman-Sundberg M, Oscarson M, McLellan RA. Polymorphic human cytochrome P450 enzymes: an opportunity for individualised drug treatment. TiPS 1999; 20: 342–9.
Goldstein JA. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 2001; 52: 349–55.
Miners JO, Birkett DJ. Cytochrome P450: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998; 45: 525–38.
Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant CYP2C9. Pharmacogenetics 1994; 4: 39–42.
Sullivan-Klose TH, Ghanayem BI, Bell DA et al. The role of the CYP2C9Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 1996; 6: 341–9.
Crespi CL, Miller VP. The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH: cytochrome P450 oxidoreductase. Pharmacogenetics 1997; 7: 203–10.
Haining RL, Hunter AP, Veronese ME, Trager WF, Rettie AE. Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterisation, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys 1996; 333: 447–58.
Kidd RS, Straughn AB, Meyer MC, Blaisdell J, Goldstein JA, Dalton JT. Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. Pharmacogenetics 1999; 9: 71–80.
Takanashi K, Tainaka H, Kobayashi K, Yasumori T, Hosakawa M, Chiba K. CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates. Pharmacogenetics 2000; 10: 95–104.
Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 2002; 12: 251–63.
Fromm MF, Kroemer HK, Eichelbaum M. Impact of P450 genetic polymorphism on the first-pass extraction of cardiovascular and neuroactive drugs. Adv Drug Deliv Rev 1997; 27: 171–99.
De Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA. The major genetic defect responsible for the polymorphism of Smephenytoin metabolism in humans. J Biol Chem 1994; 269: 15419–22.
De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 1994; 46: 594–8.
Xie HG, Stein CM, Kim RB, Wilkinson GR, Flockhart DA, Wood AJ. Allelic, genotypic and phenotypic distributions of S-mephenytoin 4'-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics 1999; 9: 539–49.
Yasar U, Eliasson E, Dahl ML, Johansson I, Ingelman-Sundberg M, Sjoqvist F. Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 1999; 254: 628–31.
Goldstein JA, Blaisdell J. Genetic tests which identify the principal defects in CYP2C19 responsible for the polymorphism in mephenytoin metabolism. Methods Enzymol 1996; 272: 210–8.
Ferguson RJ, de Morais SM, Benhamou S et al. A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin. J Pharmacol Exp Ther 1998; 284: 356–61.
Garcia-Martin E, Martinez C, Ladero JM, Gamito FJ, Agundez JA. High frequency of mutations related to impaired CYP2C9 metabolism in a Caucasian population. Eur J Clin Pharmacol 2001; 57: 47–9.
Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 2002; 12: 251–63.
Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg M. Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br J Clin Pharmacol 2001; 52: 447–50.
Xiao ZS, Goldstein JA, Xie HG et al. Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele. J Pharmacol Exp Ther 1997; 281: 604–9.
Ackermann E, Cascorbi I, Sachse C, Brockmöller J, Mrozikiewicz PM, Roots I. Frequencies and the allelic linkage of CYP2C9 mutations in a German population, and the detection of a C/T mutation in intron 2. Eur J Clin Pharmacol 1997; 52: A71–1.
Aynacioglu AS, Brockmoller J, Bauer S et al. Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 1999; 48: 409–15.
Bathum L, Andersen-Ranberg K, Boldsen J, Brosen K, Jeune B. Genotypes for the cytochrome P450 enzymes CYP2D6 and CYP2C19 in human longevity. Role of CYP2D6 and CYP2C19 in longevity. Eur J Clin Pharmacol 1998; 54: 427–30.
Brockmoller J, Rost KL, Gross D, Schenkel A, Roots I. Phenotyping of CYP2C19 with enantiospecific HPLC-quantification of R- and S-mephenytoin and comparison with the intron4/exon5 G→A-splice site mutation. Pharmacogenetics 1995; 5: 80–8.
Ruas JL, Lechner MC. Allele frequency of CYP2C19 in a Portuguese population. Pharmacogenetics 1997; 7: 333–5.
Chang M, Dahl ML, Tybring G, Gotharson E, Bertilsson L. Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics 1995; 5: 358–63.
Yamada H, Dahl ML, Lannfelt L, Viitanen M, Winblad B, Sjoqvist F. CYP2D6 and CYP2C19 genotypes in an elderly Swedish population. Eur J Clin Pharmacol 1998; 54: 479–81.
Downloads
Issue
Section
License
The Author transfers to the Publisher (Slovenian Medical Association) all economic copyrights following form Article 22 of the Slovene Copyright and Related Rights Act (ZASP), including the right of reproduction, the right of distribution, the rental right, the right of public performance, the right of public transmission, the right of public communication by means of phonograms and videograms, the right of public presentation, the right of broadcasting, the right of rebroadcasting, the right of secondary broadcasting, the right of communication to the public, the right of transformation, the right of audiovisual adaptation and all other rights of the author according to ZASP.
The aforementioned rights are transferred non-exclusively, for an unlimited number of editions, for the term of the statutory
The Author can make use of his work himself or transfer subjective rights to others only after 3 months from date of first publishing in the journal Zdravniški vestnik/Slovenian Medical Journal.
The Publisher (Slovenian Medical Association) has the right to transfer the rights of acquired parties without explicit consent of the Author.
The Author consents that the Article be published under the Creative Commons BY-NC 4.0 (attribution-non-commercial) or comparable licence.
